Key clinical point: The probability of continued use of glucocorticoids after bridging was low among patients with rheumatoid arthritis (RA), with a shorter oral bridging schedule and lower initial dose being associated with fewer patients taking glucocorticoids at 18 months after bridging.

Major finding: The probability of using or restarting glucocorticoids decreased from 0.18 at 1 month to 0.07 at 6, 12, and 18 months of ending glucocorticoid bridging therapy. A longer duration of bridging schedule (odds ratio [OR] 1.14; 95% CI 1.05-1.24) and higher initial glucocorticoid dose (OR 1.04; 95% CI 1.01-1.06) were associated with more patients taking glucocorticoids at 18 months after bridging.

Study details: This individual patient data meta-analysis of seven clinical trials included 1653 patients with newly diagnosed RA, undifferentiated arthritis, or a high-risk profile for persistent arthritis who received glucocorticoids bridging therapy as initial treatment.

Disclosures: This study did not receive any specific funding. Several authors reported ties with various sources.

Source: van Ouwerkerk L et al. Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis. Ann Rheum Dis. 2022 (Dec 16). Doi: 10.1136/ard-2022-223443

Key clinical point: The probability of continued use of glucocorticoids after bridging was low among patients with rheumatoid arthritis (RA), with a shorter oral bridging schedule and lower initial dose being associated with fewer patients taking glucocorticoids at 18 months after bridging.

Major finding: The probability of using or restarting glucocorticoids decreased from 0.18 at 1 month to 0.07 at 6, 12, and 18 months of ending glucocorticoid bridging therapy. A longer duration of bridging schedule (odds ratio [OR] 1.14; 95% CI 1.05-1.24) and higher initial glucocorticoid dose (OR 1.04; 95% CI 1.01-1.06) were associated with more patients taking glucocorticoids at 18 months after bridging.

Study details: This individual patient data meta-analysis of seven clinical trials included 1653 patients with newly diagnosed RA, undifferentiated arthritis, or a high-risk profile for persistent arthritis who received glucocorticoids bridging therapy as initial treatment.

Disclosures: This study did not receive any specific funding. Several authors reported ties with various sources.

Source: van Ouwerkerk L et al. Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis. Ann Rheum Dis. 2022 (Dec 16). Doi: 10.1136/ard-2022-223443

Key clinical point: The probability of continued use of glucocorticoids after bridging was low among patients with rheumatoid arthritis (RA), with a shorter oral bridging schedule and lower initial dose being associated with fewer patients taking glucocorticoids at 18 months after bridging.

Major finding: The probability of using or restarting glucocorticoids decreased from 0.18 at 1 month to 0.07 at 6, 12, and 18 months of ending glucocorticoid bridging therapy. A longer duration of bridging schedule (odds ratio [OR] 1.14; 95% CI 1.05-1.24) and higher initial glucocorticoid dose (OR 1.04; 95% CI 1.01-1.06) were associated with more patients taking glucocorticoids at 18 months after bridging.

Study details: This individual patient data meta-analysis of seven clinical trials included 1653 patients with newly diagnosed RA, undifferentiated arthritis, or a high-risk profile for persistent arthritis who received glucocorticoids bridging therapy as initial treatment.

Disclosures: This study did not receive any specific funding. Several authors reported ties with various sources.

Source: van Ouwerkerk L et al. Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis. Ann Rheum Dis. 2022 (Dec 16). Doi: 10.1136/ard-2022-223443

Key clinical point: Methotrexate use before conception increased the risk for pregnancy losses and abortion in childbearing-age women with rheumatoid arthritis (RA), with the risk for elective termination of pregnancy (ETOP) being significantly higher with methotrexate use in the period close to conception.

Major finding: Methotrexate use any time before conception was significantly associated with a higher risk for pregnancy losses (adjusted odds ratio [aOR] 2.22; P < .001) and abortion (aOR 1.76; P < .01) in women with vs without RA, with the risk for ETOP being almost 4-fold higher with methotrexate use in the 3-month window before conception (aOR 4.77; P < .05).

Study details: Findings are from a retrospective cohort study including childbearing-age women with RA who did (n = 223) and did not (n = 323) receive methotrexate and those without RA who did not receive methotrexate (n = 1690).

Disclosures: This study was supported by the Italian Society for Rheumatology. This authors did not declare any conflicts of interest.

Source: Zanetti A et al. Impact of rheumatoid arthritis and methotrexate on pregnancy outcomes: Retrospective cohort study of the Italian Society for Rheumatology. RMD Open. 2022;8(2):e002412 (Dec 12). Doi: 10.1136/rmdopen-2022-002412

Key clinical point: Methotrexate use before conception increased the risk for pregnancy losses and abortion in childbearing-age women with rheumatoid arthritis (RA), with the risk for elective termination of pregnancy (ETOP) being significantly higher with methotrexate use in the period close to conception.

Major finding: Methotrexate use any time before conception was significantly associated with a higher risk for pregnancy losses (adjusted odds ratio [aOR] 2.22; P < .001) and abortion (aOR 1.76; P < .01) in women with vs without RA, with the risk for ETOP being almost 4-fold higher with methotrexate use in the 3-month window before conception (aOR 4.77; P < .05).

Study details: Findings are from a retrospective cohort study including childbearing-age women with RA who did (n = 223) and did not (n = 323) receive methotrexate and those without RA who did not receive methotrexate (n = 1690).

Disclosures: This study was supported by the Italian Society for Rheumatology. This authors did not declare any conflicts of interest.

Source: Zanetti A et al. Impact of rheumatoid arthritis and methotrexate on pregnancy outcomes: Retrospective cohort study of the Italian Society for Rheumatology. RMD Open. 2022;8(2):e002412 (Dec 12). Doi: 10.1136/rmdopen-2022-002412

Key clinical point: Methotrexate use before conception increased the risk for pregnancy losses and abortion in childbearing-age women with rheumatoid arthritis (RA), with the risk for elective termination of pregnancy (ETOP) being significantly higher with methotrexate use in the period close to conception.

Major finding: Methotrexate use any time before conception was significantly associated with a higher risk for pregnancy losses (adjusted odds ratio [aOR] 2.22; P < .001) and abortion (aOR 1.76; P < .01) in women with vs without RA, with the risk for ETOP being almost 4-fold higher with methotrexate use in the 3-month window before conception (aOR 4.77; P < .05).

Study details: Findings are from a retrospective cohort study including childbearing-age women with RA who did (n = 223) and did not (n = 323) receive methotrexate and those without RA who did not receive methotrexate (n = 1690).

Disclosures: This study was supported by the Italian Society for Rheumatology. This authors did not declare any conflicts of interest.

Source: Zanetti A et al. Impact of rheumatoid arthritis and methotrexate on pregnancy outcomes: Retrospective cohort study of the Italian Society for Rheumatology. RMD Open. 2022;8(2):e002412 (Dec 12). Doi: 10.1136/rmdopen-2022-002412

The selective estrogen receptor modulator ospemifene appears to improve the vaginal microbiome of postmenopausal women with vulvovaginal atrophy (VVA), according to results from a small Italian case-control study in the journal Menopause.

The study sheds microbiological light on the mechanisms of ospemifene and low-dose systemic hormone therapy, which are widely used to treat genitourinary symptoms. Both had a positive effect on vaginal well-being, likely by reducing potentially harmful bacteria and increasing health-promoting acid-friendly microorganisms, writes a group led by M. Cristina Meriggiola, MD, PhD, of the gynecology and physiopathology of human reproduction unit at the University of Bologna, Italy.

VVA occurs in about 50% of postmenopausal women and produces a less favorable, less acidic vaginal microbiome profile than that of unaffected women. “The loss of estrogen leads to lower concentrations of Lactobacilli, bacteria that lower the pH. As a result, other bacterial species fill in the void,” explained Stephanie S. Faubion, MD, MBA, director of the Mayo Clinic Center for Women’s Health in Jacksonville, Fla., and medical director of the North American Menopause Society.

Added Tina Murphy, APN, a NAMS-certified menopause practitioner at Northwestern Medicine Orland Park in Illinois, “When this protective flora declines, then pathogenic bacteria can predominate the microbiome, which can contribute to vaginal irritation, infection, UTI’s, dyspareunia, and discomfort. Balancing and restoring the microbiome can mitigate the effects of estrogen depletion on the vaginal tissue and prevent the untoward effects of the hypoestrogenic state.” While ospemifene and hormone therapy are common therapies for the genitourinary symptoms of menopause, the focus has been on their treatment efficacy, not their effect on the microbiome profile, added Dr. Faubion. Only about 9% of women with menopause-related genitourinary symptoms receive prescription treatment, she added.
 

The study

Of 67 eligible postmenopausal participants in their mid-50s enrolled at a gynecology clinic from April 2019 to February 2020, 39 were diagnosed with VVA and 28 were considered healthy controls. In the atrophic group, 20 were prescribed ospemifene and 19 received hormone treatment.

Only those women with VVA but no menopausal vasomotor symptoms received ospemifene (60 mg/day); symptomatic women received hormone therapy according to guidelines.

The researchers calculated the women’s vaginal health index (VHI) based on elasticity, secretions, pH level, epithelial mucosa, and hydration. They used swabs to assess vaginal maturation index (VMI) by percentages of superficial, intermediate, and parabasal cells. Evaluation of the vaginal microbiome was done with 16S rRNA gene sequencing, and clinical and microbiological analyses were repeated after 3 months.

The vaginal microbiome of atrophic women was characterized by a significant reduction of benign Lactobacillus bacteria (P = .002) and an increase of potentially pathogenic Streptococcus (P = .008) and Sneathia (P = .02) bacteria.

The vaginal microbiome of women with VVA was depleted, within the Lactobacillus genus, in the L. crispatus species, a hallmark of vaginal health that has significant antimicrobial activity against endogenous and exogenous pathogens.

Furthermore, there was a positive correlation between the VHI/VMI and Lactobacillus abundance (P = .002 and P = 0.035, respectively).

While the lactic acid–producing Lactobacillus and Bifidobacterium genera were strongly associated with healthy controls, the characteristics of VVA patients were strongly associated with Streptococcus, Prevotella, Alloscardovia, and Staphylococcus.

Both therapeutic approaches effectively improved vaginal indices but by different routes. Systemic hormone treatment induced changes in minority bacterial groups in the vaginal microbiome, whereas ospemifene eliminated specific harmful bacterial taxa, such as Staphylococcus (P = .04) and Clostridium (P = .01). Both treatments induced a trend in the increase of beneficial Bifidobacteria.

A 2022 study reported that vaginal estradiol tablets significantly changed the vaginal microbiota in postmenopausal women compared with vaginal moisturizer or placebo, but the reductions in bothersome symptoms were similar.
 

The future

“Areas for future study include the assessment of changes in the vaginal microbiome, proteomic profiles, and immunologic markers with various treatments and the associations between these changes and genitourinary symptoms,” Dr. Faubion said. She added that, while there may be a role at some point for oral or topical probiotics, “Thus far, probiotics have not demonstrated significant benefits.”

Meanwhile, said Ms. Murphy, “There are many options available that may benefit our patients. As a provider, meeting with your patient, discussing her concerns and individual risk factors is the most important part of choosing the correct treatment plan.”

The authors call for further studies to confirm the observed modifications of the vaginal ecosystem. In the meantime, Dr. Meriggiola said in an interview, “My best advice to physicians is to ask women if they have this problem. Do not ignore it; be proactive and treat. There are many options on the market for genitourinary symptoms – not just for postmenopausal women but breast cancer survivors as well.”

Dr. Meriggiola’s group is planning to study ospemifene in cancer patients, whose quality of life is severely affected by VVA.

This study received no financial support. Dr. Meriggiola reported past financial relationships with Shionogi Limited, Teramex, Organon, Italfarmaco, MDS Italia, and Bayer. Coauthor Dr. Baldassarre disclosed past financial relationships with Shionogi. Ms. Murphy disclosed no relevant conflicts of interest with respect to her comments. Dr. Faubion is medical director of the North American Menopause Society and editor of the journal Menopause.

The selective estrogen receptor modulator ospemifene appears to improve the vaginal microbiome of postmenopausal women with vulvovaginal atrophy (VVA), according to results from a small Italian case-control study in the journal Menopause.

The study sheds microbiological light on the mechanisms of ospemifene and low-dose systemic hormone therapy, which are widely used to treat genitourinary symptoms. Both had a positive effect on vaginal well-being, likely by reducing potentially harmful bacteria and increasing health-promoting acid-friendly microorganisms, writes a group led by M. Cristina Meriggiola, MD, PhD, of the gynecology and physiopathology of human reproduction unit at the University of Bologna, Italy.

VVA occurs in about 50% of postmenopausal women and produces a less favorable, less acidic vaginal microbiome profile than that of unaffected women. “The loss of estrogen leads to lower concentrations of Lactobacilli, bacteria that lower the pH. As a result, other bacterial species fill in the void,” explained Stephanie S. Faubion, MD, MBA, director of the Mayo Clinic Center for Women’s Health in Jacksonville, Fla., and medical director of the North American Menopause Society.

Added Tina Murphy, APN, a NAMS-certified menopause practitioner at Northwestern Medicine Orland Park in Illinois, “When this protective flora declines, then pathogenic bacteria can predominate the microbiome, which can contribute to vaginal irritation, infection, UTI’s, dyspareunia, and discomfort. Balancing and restoring the microbiome can mitigate the effects of estrogen depletion on the vaginal tissue and prevent the untoward effects of the hypoestrogenic state.” While ospemifene and hormone therapy are common therapies for the genitourinary symptoms of menopause, the focus has been on their treatment efficacy, not their effect on the microbiome profile, added Dr. Faubion. Only about 9% of women with menopause-related genitourinary symptoms receive prescription treatment, she added.
 

The study

Of 67 eligible postmenopausal participants in their mid-50s enrolled at a gynecology clinic from April 2019 to February 2020, 39 were diagnosed with VVA and 28 were considered healthy controls. In the atrophic group, 20 were prescribed ospemifene and 19 received hormone treatment.

Only those women with VVA but no menopausal vasomotor symptoms received ospemifene (60 mg/day); symptomatic women received hormone therapy according to guidelines.

The researchers calculated the women’s vaginal health index (VHI) based on elasticity, secretions, pH level, epithelial mucosa, and hydration. They used swabs to assess vaginal maturation index (VMI) by percentages of superficial, intermediate, and parabasal cells. Evaluation of the vaginal microbiome was done with 16S rRNA gene sequencing, and clinical and microbiological analyses were repeated after 3 months.

The vaginal microbiome of atrophic women was characterized by a significant reduction of benign Lactobacillus bacteria (P = .002) and an increase of potentially pathogenic Streptococcus (P = .008) and Sneathia (P = .02) bacteria.

The vaginal microbiome of women with VVA was depleted, within the Lactobacillus genus, in the L. crispatus species, a hallmark of vaginal health that has significant antimicrobial activity against endogenous and exogenous pathogens.

Furthermore, there was a positive correlation between the VHI/VMI and Lactobacillus abundance (P = .002 and P = 0.035, respectively).

While the lactic acid–producing Lactobacillus and Bifidobacterium genera were strongly associated with healthy controls, the characteristics of VVA patients were strongly associated with Streptococcus, Prevotella, Alloscardovia, and Staphylococcus.

Both therapeutic approaches effectively improved vaginal indices but by different routes. Systemic hormone treatment induced changes in minority bacterial groups in the vaginal microbiome, whereas ospemifene eliminated specific harmful bacterial taxa, such as Staphylococcus (P = .04) and Clostridium (P = .01). Both treatments induced a trend in the increase of beneficial Bifidobacteria.

A 2022 study reported that vaginal estradiol tablets significantly changed the vaginal microbiota in postmenopausal women compared with vaginal moisturizer or placebo, but the reductions in bothersome symptoms were similar.
 

The future

“Areas for future study include the assessment of changes in the vaginal microbiome, proteomic profiles, and immunologic markers with various treatments and the associations between these changes and genitourinary symptoms,” Dr. Faubion said. She added that, while there may be a role at some point for oral or topical probiotics, “Thus far, probiotics have not demonstrated significant benefits.”

Meanwhile, said Ms. Murphy, “There are many options available that may benefit our patients. As a provider, meeting with your patient, discussing her concerns and individual risk factors is the most important part of choosing the correct treatment plan.”

The authors call for further studies to confirm the observed modifications of the vaginal ecosystem. In the meantime, Dr. Meriggiola said in an interview, “My best advice to physicians is to ask women if they have this problem. Do not ignore it; be proactive and treat. There are many options on the market for genitourinary symptoms – not just for postmenopausal women but breast cancer survivors as well.”

Dr. Meriggiola’s group is planning to study ospemifene in cancer patients, whose quality of life is severely affected by VVA.

This study received no financial support. Dr. Meriggiola reported past financial relationships with Shionogi Limited, Teramex, Organon, Italfarmaco, MDS Italia, and Bayer. Coauthor Dr. Baldassarre disclosed past financial relationships with Shionogi. Ms. Murphy disclosed no relevant conflicts of interest with respect to her comments. Dr. Faubion is medical director of the North American Menopause Society and editor of the journal Menopause.

The selective estrogen receptor modulator ospemifene appears to improve the vaginal microbiome of postmenopausal women with vulvovaginal atrophy (VVA), according to results from a small Italian case-control study in the journal Menopause.

The study sheds microbiological light on the mechanisms of ospemifene and low-dose systemic hormone therapy, which are widely used to treat genitourinary symptoms. Both had a positive effect on vaginal well-being, likely by reducing potentially harmful bacteria and increasing health-promoting acid-friendly microorganisms, writes a group led by M. Cristina Meriggiola, MD, PhD, of the gynecology and physiopathology of human reproduction unit at the University of Bologna, Italy.

VVA occurs in about 50% of postmenopausal women and produces a less favorable, less acidic vaginal microbiome profile than that of unaffected women. “The loss of estrogen leads to lower concentrations of Lactobacilli, bacteria that lower the pH. As a result, other bacterial species fill in the void,” explained Stephanie S. Faubion, MD, MBA, director of the Mayo Clinic Center for Women’s Health in Jacksonville, Fla., and medical director of the North American Menopause Society.

Added Tina Murphy, APN, a NAMS-certified menopause practitioner at Northwestern Medicine Orland Park in Illinois, “When this protective flora declines, then pathogenic bacteria can predominate the microbiome, which can contribute to vaginal irritation, infection, UTI’s, dyspareunia, and discomfort. Balancing and restoring the microbiome can mitigate the effects of estrogen depletion on the vaginal tissue and prevent the untoward effects of the hypoestrogenic state.” While ospemifene and hormone therapy are common therapies for the genitourinary symptoms of menopause, the focus has been on their treatment efficacy, not their effect on the microbiome profile, added Dr. Faubion. Only about 9% of women with menopause-related genitourinary symptoms receive prescription treatment, she added.
 

The study

Of 67 eligible postmenopausal participants in their mid-50s enrolled at a gynecology clinic from April 2019 to February 2020, 39 were diagnosed with VVA and 28 were considered healthy controls. In the atrophic group, 20 were prescribed ospemifene and 19 received hormone treatment.

Only those women with VVA but no menopausal vasomotor symptoms received ospemifene (60 mg/day); symptomatic women received hormone therapy according to guidelines.

The researchers calculated the women’s vaginal health index (VHI) based on elasticity, secretions, pH level, epithelial mucosa, and hydration. They used swabs to assess vaginal maturation index (VMI) by percentages of superficial, intermediate, and parabasal cells. Evaluation of the vaginal microbiome was done with 16S rRNA gene sequencing, and clinical and microbiological analyses were repeated after 3 months.

The vaginal microbiome of atrophic women was characterized by a significant reduction of benign Lactobacillus bacteria (P = .002) and an increase of potentially pathogenic Streptococcus (P = .008) and Sneathia (P = .02) bacteria.

The vaginal microbiome of women with VVA was depleted, within the Lactobacillus genus, in the L. crispatus species, a hallmark of vaginal health that has significant antimicrobial activity against endogenous and exogenous pathogens.

Furthermore, there was a positive correlation between the VHI/VMI and Lactobacillus abundance (P = .002 and P = 0.035, respectively).

While the lactic acid–producing Lactobacillus and Bifidobacterium genera were strongly associated with healthy controls, the characteristics of VVA patients were strongly associated with Streptococcus, Prevotella, Alloscardovia, and Staphylococcus.

Both therapeutic approaches effectively improved vaginal indices but by different routes. Systemic hormone treatment induced changes in minority bacterial groups in the vaginal microbiome, whereas ospemifene eliminated specific harmful bacterial taxa, such as Staphylococcus (P = .04) and Clostridium (P = .01). Both treatments induced a trend in the increase of beneficial Bifidobacteria.

A 2022 study reported that vaginal estradiol tablets significantly changed the vaginal microbiota in postmenopausal women compared with vaginal moisturizer or placebo, but the reductions in bothersome symptoms were similar.
 

The future

“Areas for future study include the assessment of changes in the vaginal microbiome, proteomic profiles, and immunologic markers with various treatments and the associations between these changes and genitourinary symptoms,” Dr. Faubion said. She added that, while there may be a role at some point for oral or topical probiotics, “Thus far, probiotics have not demonstrated significant benefits.”

Meanwhile, said Ms. Murphy, “There are many options available that may benefit our patients. As a provider, meeting with your patient, discussing her concerns and individual risk factors is the most important part of choosing the correct treatment plan.”

The authors call for further studies to confirm the observed modifications of the vaginal ecosystem. In the meantime, Dr. Meriggiola said in an interview, “My best advice to physicians is to ask women if they have this problem. Do not ignore it; be proactive and treat. There are many options on the market for genitourinary symptoms – not just for postmenopausal women but breast cancer survivors as well.”

Dr. Meriggiola’s group is planning to study ospemifene in cancer patients, whose quality of life is severely affected by VVA.

This study received no financial support. Dr. Meriggiola reported past financial relationships with Shionogi Limited, Teramex, Organon, Italfarmaco, MDS Italia, and Bayer. Coauthor Dr. Baldassarre disclosed past financial relationships with Shionogi. Ms. Murphy disclosed no relevant conflicts of interest with respect to her comments. Dr. Faubion is medical director of the North American Menopause Society and editor of the journal Menopause.

A recently discovered inflammatory disease known as VEXAS syndrome is more common, variable, and dangerous than previously understood, according to results of a retrospective observational study of a large health care system database. The findings, published in JAMA, found that it struck 1 in 4,269 men over the age of 50 in a largely White population and caused a wide variety of symptoms.

“The disease is quite severe,” study lead author David Beck, MD, PhD, of the department of medicine at NYU Langone Health, said in an interview. Patients with the condition “have a variety of clinical symptoms affecting different parts of the body and are being managed by different medical specialties.”

Dr. Beck and colleagues first described VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome in 2020. They linked it to mutations in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. The enzyme initiates a process that identifies misfolded proteins as targets for degradation.

“VEXAS syndrome is characterized by anemia and inflammation in the skin, lungs, cartilage, and joints,” Dr. Beck said. “These symptoms are frequently mistaken for other rheumatic or hematologic diseases. However, this syndrome has a different cause, is treated differently, requires additional monitoring, and can be far more severe.”

According to him, hundreds of people have been diagnosed with the disease in the short time since it was defined. The disease is believed to be fatal in some cases. A previous report found that the median survival was 9 years among patients with a certain variant; that was significantly less than patients with two other variants.

For the new study, researchers searched for UBA1 variants in genetic data from 163,096 subjects (mean age, 52.8 years; 94% White, 61% women) who took part in the Geisinger MyCode Community Health Initiative. The 1996-2022 data comes from patients at 10 Pennsylvania hospitals.

Eleven people (9 males, 2 females) had likely UBA1 variants, and all had anemia. The cases accounted for 1 in 13,591 unrelated people (95% confidence interval, 1:7,775-1:23,758), 1 in 4,269 men older than 50 years (95% CI, 1:2,319-1:7,859), and 1 in 26,238 women older than 50 years (95% CI, 1:7,196-1:147,669).

Other common findings included macrocytosis (91%), skin problems (73%), and pulmonary disease (91%). Ten patients (91%) required transfusions.

Five of the 11 subjects didn’t meet the previously defined criteria for VEXAS syndrome. None had been diagnosed with the condition, which is not surprising considering that it hadn’t been discovered and described until recently.

Just over half of the patients – 55% – had a clinical diagnosis that was previously linked to VEXAS syndrome. “This means that slightly less than half of the patients with VEXAS syndrome had no clear associated clinical diagnosis,” Dr. Beck said. “The lack of associated clinical diagnoses may be due to the variety of nonspecific clinical characteristics that span different subspecialities in VEXAS syndrome. VEXAS syndrome represents an example of a multisystem disease where patients and their symptoms may get lost in the shuffle.”

In the future, “professionals should look out for patients with unexplained inflammation – and some combination of hematologic, rheumatologic, pulmonary, and dermatologic clinical manifestations – that either don’t carry a clinical diagnosis or don’t respond to first-line therapies,” Dr. Beck said. “These patients will also frequently be anemic, have low platelet counts, elevated markers of inflammation in the blood, and be dependent on corticosteroids.”

Diagnosis can be made via genetic testing, but the study authors note that it “is not routinely offered on standard workup for myeloid neoplasms or immune dysregulation diagnostic panels.”

As for treatment, Dr. Beck said the disease “can be partially controlled by multiple different anticytokine therapies or biologics. However, in most cases, patients still need additional steroids and/or disease-modifying antirheumatic agents [DMARDs]. In addition, bone marrow transplantation has shown signs of being a highly effective therapy.”

The study authors say more research is needed to understand the disease’s prevalence in more diverse populations.

In an interview, Matthew J. Koster, MD, a rheumatologist at Mayo Clinic in Rochester, Minn., who’s studied the disease but didn’t take part in this research project, said the findings are valid and “highly important.

“The findings of this study highlight what many academic and quaternary referral centers were wondering: Is VEXAS really more common than we think, with patients hiding in plain sight? The answer is yes,” he said. “Currently, there are less than 400 cases reported in the literature of VEXAS, but large centers are diagnosing this condition with some frequency. For example, at Mayo Clinic in Rochester, we diagnose on average one new patient with VEXAS every 7-14 days and have diagnosed 60 in the past 18 months. A national collaborative group in France has diagnosed approximately 250 patients over that same time frame when pooling patients nationwide.”

The prevalence is high enough, he said, that “clinicians should consider that some of the patients with diseases that are not responding to treatment may in fact have VEXAS rather than ‘refractory’ relapsing polychondritis or ‘recalcitrant’ rheumatoid arthritis, etc.”

The National Institute of Health funded the study. Dr. Beck, the other authors, and Dr. Koster report no disclosures.

A recently discovered inflammatory disease known as VEXAS syndrome is more common, variable, and dangerous than previously understood, according to results of a retrospective observational study of a large health care system database. The findings, published in JAMA, found that it struck 1 in 4,269 men over the age of 50 in a largely White population and caused a wide variety of symptoms.

“The disease is quite severe,” study lead author David Beck, MD, PhD, of the department of medicine at NYU Langone Health, said in an interview. Patients with the condition “have a variety of clinical symptoms affecting different parts of the body and are being managed by different medical specialties.”

Dr. Beck and colleagues first described VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome in 2020. They linked it to mutations in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. The enzyme initiates a process that identifies misfolded proteins as targets for degradation.

“VEXAS syndrome is characterized by anemia and inflammation in the skin, lungs, cartilage, and joints,” Dr. Beck said. “These symptoms are frequently mistaken for other rheumatic or hematologic diseases. However, this syndrome has a different cause, is treated differently, requires additional monitoring, and can be far more severe.”

According to him, hundreds of people have been diagnosed with the disease in the short time since it was defined. The disease is believed to be fatal in some cases. A previous report found that the median survival was 9 years among patients with a certain variant; that was significantly less than patients with two other variants.

For the new study, researchers searched for UBA1 variants in genetic data from 163,096 subjects (mean age, 52.8 years; 94% White, 61% women) who took part in the Geisinger MyCode Community Health Initiative. The 1996-2022 data comes from patients at 10 Pennsylvania hospitals.

Eleven people (9 males, 2 females) had likely UBA1 variants, and all had anemia. The cases accounted for 1 in 13,591 unrelated people (95% confidence interval, 1:7,775-1:23,758), 1 in 4,269 men older than 50 years (95% CI, 1:2,319-1:7,859), and 1 in 26,238 women older than 50 years (95% CI, 1:7,196-1:147,669).

Other common findings included macrocytosis (91%), skin problems (73%), and pulmonary disease (91%). Ten patients (91%) required transfusions.

Five of the 11 subjects didn’t meet the previously defined criteria for VEXAS syndrome. None had been diagnosed with the condition, which is not surprising considering that it hadn’t been discovered and described until recently.

Just over half of the patients – 55% – had a clinical diagnosis that was previously linked to VEXAS syndrome. “This means that slightly less than half of the patients with VEXAS syndrome had no clear associated clinical diagnosis,” Dr. Beck said. “The lack of associated clinical diagnoses may be due to the variety of nonspecific clinical characteristics that span different subspecialities in VEXAS syndrome. VEXAS syndrome represents an example of a multisystem disease where patients and their symptoms may get lost in the shuffle.”

In the future, “professionals should look out for patients with unexplained inflammation – and some combination of hematologic, rheumatologic, pulmonary, and dermatologic clinical manifestations – that either don’t carry a clinical diagnosis or don’t respond to first-line therapies,” Dr. Beck said. “These patients will also frequently be anemic, have low platelet counts, elevated markers of inflammation in the blood, and be dependent on corticosteroids.”

Diagnosis can be made via genetic testing, but the study authors note that it “is not routinely offered on standard workup for myeloid neoplasms or immune dysregulation diagnostic panels.”

As for treatment, Dr. Beck said the disease “can be partially controlled by multiple different anticytokine therapies or biologics. However, in most cases, patients still need additional steroids and/or disease-modifying antirheumatic agents [DMARDs]. In addition, bone marrow transplantation has shown signs of being a highly effective therapy.”

The study authors say more research is needed to understand the disease’s prevalence in more diverse populations.

In an interview, Matthew J. Koster, MD, a rheumatologist at Mayo Clinic in Rochester, Minn., who’s studied the disease but didn’t take part in this research project, said the findings are valid and “highly important.

“The findings of this study highlight what many academic and quaternary referral centers were wondering: Is VEXAS really more common than we think, with patients hiding in plain sight? The answer is yes,” he said. “Currently, there are less than 400 cases reported in the literature of VEXAS, but large centers are diagnosing this condition with some frequency. For example, at Mayo Clinic in Rochester, we diagnose on average one new patient with VEXAS every 7-14 days and have diagnosed 60 in the past 18 months. A national collaborative group in France has diagnosed approximately 250 patients over that same time frame when pooling patients nationwide.”

The prevalence is high enough, he said, that “clinicians should consider that some of the patients with diseases that are not responding to treatment may in fact have VEXAS rather than ‘refractory’ relapsing polychondritis or ‘recalcitrant’ rheumatoid arthritis, etc.”

The National Institute of Health funded the study. Dr. Beck, the other authors, and Dr. Koster report no disclosures.

A recently discovered inflammatory disease known as VEXAS syndrome is more common, variable, and dangerous than previously understood, according to results of a retrospective observational study of a large health care system database. The findings, published in JAMA, found that it struck 1 in 4,269 men over the age of 50 in a largely White population and caused a wide variety of symptoms.

“The disease is quite severe,” study lead author David Beck, MD, PhD, of the department of medicine at NYU Langone Health, said in an interview. Patients with the condition “have a variety of clinical symptoms affecting different parts of the body and are being managed by different medical specialties.”

Dr. Beck and colleagues first described VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome in 2020. They linked it to mutations in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. The enzyme initiates a process that identifies misfolded proteins as targets for degradation.

“VEXAS syndrome is characterized by anemia and inflammation in the skin, lungs, cartilage, and joints,” Dr. Beck said. “These symptoms are frequently mistaken for other rheumatic or hematologic diseases. However, this syndrome has a different cause, is treated differently, requires additional monitoring, and can be far more severe.”

According to him, hundreds of people have been diagnosed with the disease in the short time since it was defined. The disease is believed to be fatal in some cases. A previous report found that the median survival was 9 years among patients with a certain variant; that was significantly less than patients with two other variants.

For the new study, researchers searched for UBA1 variants in genetic data from 163,096 subjects (mean age, 52.8 years; 94% White, 61% women) who took part in the Geisinger MyCode Community Health Initiative. The 1996-2022 data comes from patients at 10 Pennsylvania hospitals.

Eleven people (9 males, 2 females) had likely UBA1 variants, and all had anemia. The cases accounted for 1 in 13,591 unrelated people (95% confidence interval, 1:7,775-1:23,758), 1 in 4,269 men older than 50 years (95% CI, 1:2,319-1:7,859), and 1 in 26,238 women older than 50 years (95% CI, 1:7,196-1:147,669).

Other common findings included macrocytosis (91%), skin problems (73%), and pulmonary disease (91%). Ten patients (91%) required transfusions.

Five of the 11 subjects didn’t meet the previously defined criteria for VEXAS syndrome. None had been diagnosed with the condition, which is not surprising considering that it hadn’t been discovered and described until recently.

Just over half of the patients – 55% – had a clinical diagnosis that was previously linked to VEXAS syndrome. “This means that slightly less than half of the patients with VEXAS syndrome had no clear associated clinical diagnosis,” Dr. Beck said. “The lack of associated clinical diagnoses may be due to the variety of nonspecific clinical characteristics that span different subspecialities in VEXAS syndrome. VEXAS syndrome represents an example of a multisystem disease where patients and their symptoms may get lost in the shuffle.”

In the future, “professionals should look out for patients with unexplained inflammation – and some combination of hematologic, rheumatologic, pulmonary, and dermatologic clinical manifestations – that either don’t carry a clinical diagnosis or don’t respond to first-line therapies,” Dr. Beck said. “These patients will also frequently be anemic, have low platelet counts, elevated markers of inflammation in the blood, and be dependent on corticosteroids.”

Diagnosis can be made via genetic testing, but the study authors note that it “is not routinely offered on standard workup for myeloid neoplasms or immune dysregulation diagnostic panels.”

As for treatment, Dr. Beck said the disease “can be partially controlled by multiple different anticytokine therapies or biologics. However, in most cases, patients still need additional steroids and/or disease-modifying antirheumatic agents [DMARDs]. In addition, bone marrow transplantation has shown signs of being a highly effective therapy.”

The study authors say more research is needed to understand the disease’s prevalence in more diverse populations.

In an interview, Matthew J. Koster, MD, a rheumatologist at Mayo Clinic in Rochester, Minn., who’s studied the disease but didn’t take part in this research project, said the findings are valid and “highly important.

“The findings of this study highlight what many academic and quaternary referral centers were wondering: Is VEXAS really more common than we think, with patients hiding in plain sight? The answer is yes,” he said. “Currently, there are less than 400 cases reported in the literature of VEXAS, but large centers are diagnosing this condition with some frequency. For example, at Mayo Clinic in Rochester, we diagnose on average one new patient with VEXAS every 7-14 days and have diagnosed 60 in the past 18 months. A national collaborative group in France has diagnosed approximately 250 patients over that same time frame when pooling patients nationwide.”

The prevalence is high enough, he said, that “clinicians should consider that some of the patients with diseases that are not responding to treatment may in fact have VEXAS rather than ‘refractory’ relapsing polychondritis or ‘recalcitrant’ rheumatoid arthritis, etc.”

The National Institute of Health funded the study. Dr. Beck, the other authors, and Dr. Koster report no disclosures.

Considerable advances in artificial intelligence (AI) and machine-learning (ML) methodologies have led to the emergence of promising tools in the field of gastrointestinal endoscopy. Computer vision is an application of AI/ML that has been successfully applied for the computer-aided detection (CADe) and computer-aided diagnosis (CADx) of colon polyps and numerous other conditions encountered during GI endoscopy. Outside of computer vision, a wide variety of other AI applications have been applied to gastroenterology, ranging from natural language processing (NLP) to optimize clinical documentation and endoscopy quality reporting to ML techniques that predict disease severity/treatment response and augment clinical decision-making. This article focuses on opportunities for AI applications in colonoscopy, reviews the existing data, describes the challenges limiting widespread adoption, and explores future directions.

In the United States, colonoscopy is the standard for colon cancer screening and prevention; however, precancerous polyps can be missed for various reasons, ranging from subtle surface appearance of the polyp or location behind a colonic fold to operator-dependent reasons such as inadequate mucosal inspection. Though clinical practice guidelines have set adenoma detection rate (ADR) thresholds at 20% for women and 30% for men, studies have shown a 4- to 10-fold variation in ADR among physicians in clinical practice settings^,1 with an estimated adenoma miss rate (AMR) of 25% and a false-negative colonoscopy rate of 12%.² Variability in adenoma detection affects the risk of interval colorectal cancer post colonoscopy.^3,4

AI provides an opportunity for mitigating this risk. Advances in deep learning and computer vision have led to the development of CADe systems that automatically detect polyps in real time during colonoscopy, resulting in reduced adenoma miss rates (Table 1). In addition to polyp detection, deep-learning technologies are also being used in CADx systems for polyp diagnosis and characterization of malignancy risk. This could aid therapeutic decision-making: Unnecessary resection or histopathologic analysis could be obviated for benign hyperplastic polyps. On the other end of the polyp spectrum, an AI tool that could predict the presence or absence of submucosal invasion could be a powerful tool when evaluating early colon cancers for consideration of endoscopic submucosal dissection vs. surgery. Examples of CADe polyp detection and CADx polyp characterization are shown in Figure 1.

Other potential computer vision applications that may improve colonoscopy quality include tools that help measure adequacy of mucosal exposure, segmental inspection time, and a variety of other parameters associated with polyp detection performance. These are promising areas for future research. Beyond improving colonoscopy technique, natural language processing tools already are being used to optimize clinical documentation as well as extract information from colonoscopy and pathology reports that can facilitate reporting of colonoscopy quality metrics such as ADR, cecal intubation rate, withdrawal time, and bowel preparation adequacy. AI-powered analytics may help unlock large-scale reporting of colonoscopy quality metrics on a health-systems level⁵ or population-level,⁶ helping to ensure optimal performance and identifying avenues for colonoscopy quality improvement.

In comparison, the data landscape for CADx is nascent and currently limited to several retrospective studies dating back to 2009 and a few prospective studies that have shown promising results.^10,11 There is an expectation that integrated CADx also may support the adoption of “resect and discard” or “diagnose and leave” strategies for low-risk polyps. About two-thirds of polyps identified on average-risk screening colonoscopies are diminutive polyps (less than 5 mm in size), which rarely have advanced histologic features (about 0.5%) and are sometimes non-neoplastic (30%). Malignancy risk is even lower in the distal colon.¹² As routine histopathologic assessment of such polyps is mostly of limited clinical utility and comes with added pathology costs, CADx technologies may offer a more cost-effective approach where polyps that are characterized in real-time as low-risk adenomas or non-neoplastic are “resected and discarded” or “left in” respectively. In 2011, prior to the development of current AI tools, the American Society for Gastrointestinal Endoscopy set performance thresholds for technologies supporting real-time endoscopic assessment of the histology of diminutive colorectal polyps. The ASGE recommended 90% histopathologic concordance for “resect and discard” tools and 90% negative predictive value for adenomatous histology for “diagnose and leave,” tools.¹³ Narrow-band imaging (NBI), for example, has been shown to meet these benchmarks^14,15 with a modeling study suggesting that implementing “resect and discard” strategies with such tools could result in annual savings of $33 million without adversely affecting efficacy, although practical adoption has been limited.¹⁶ More recent work has directly explored the feasibility of leveraging CADx to support “leave-in-situ” and “resect-and-discard” strategies.¹⁷

Similarly, while CADe use in colonoscopy is associated with additional up-front costs, a modeling study suggests that its associated gains in ADR (as detailed in Table 1) make it a cost-saving strategy for colorectal cancer prevention in the long term.¹⁸ There is still uncertainty on whether the incremental CADe-associated gains in adenoma detection will necessarily translate to significant reductions in interval colorectal cancer risk, particularly for endoscopists who are already high-performing polyp detectors. A recent study suggests that, although higher ADRs were associated with lower rates of interval colorectal cancer, the gains in interval colorectal cancer risk reduction appeared to level off with ADRs above 35%-40% (this finding may be limited by statistical power).¹⁹ Further, most of the data from CADe trials suggest that gains in adenoma detection are not driven by increased detection of advanced lesions with high malignancy risk but by small polyps with long latency periods of about 5-10 years, which may not significantly alter interval cancer risk. It remains to be determined whether adoption of CADe will have an impact on hard outcomes, most importantly interval colorectal cancer risk, or merely result in increased resource utilization without moving the needle on colorectal cancer prevention. To answer this question, the OperA study – a large-scale randomized clinical trial of 200,000 patients across 18 centers from 13 countries – was launched in 2022. It will investigate the effect of colonoscopy with CADe on a number of critical measures, including long-term interval colon cancer risk.²⁰

Despite commercial availability of regulatory-approved CADe systems and data supporting use for adenoma detection in colonoscopy, mainstream adoption in clinical practice has been sluggish. Physician survey studies have shown that, although there is considerable interest in integrating CADe into clinical practice, there are concerns about access, cost and reimbursement, integration into clinical work-flow, increased procedural times, over-reliance on AI, and algorithmic bias leading to errors.^21,22 In addition, without mandatory requirements for ADR reporting or clinical practice guideline recommendations for CADe use, these systems may not be perceived as valuable or ready for prime time even though the evidence suggests otherwise.^23,24 For CADe systems to see widespread adoption in clinical practice, it is important that future research studies rigorously investigate and characterize these potential barriers to better inform strategies to address AI hesitancy and implementation challenges. Such efforts can provide an integration framework for future AI applications in gastroenterology beyond colonoscopy, such as CADe of esophageal and gastric premalignant lesions in upper endoscopy, CADx for pancreatic cysts and liver lesions on imaging, NLP tools to optimizing efficient clinical documentation and reporting, and many others.

Dr. Uche-Anya is in the division of gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston. Dr. Berzin is with the Center for Advanced Endoscopy, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston. Dr. Berzin is a consultant for Wision AI, Medtronic, Magentiq Eye, RSIP Vision, and Docbot.

Corresponding Author: Eugenia Uche-Anya [email protected] Twitter: @UcheAnyaMD @tberzin

References

1. Corley DA et al. Can we improve adenoma detection rates? A systematic review of intervention studies. Gastrointest Endosc. Sep 2011;74(3):656-65. doi: 10.1016/j.gie.2011.04.017.

2. Zhao S et al. Magnitude, risk factors, and factors associated with adenoma miss rate of tandem colonoscopy: A systematic review and meta-analysis. Gastroenterology. 05 2019;156(6):1661-74.e11. doi: 10.1053/j.gastro.2019.01.260.

3. Kaminski MF et al. Quality indicators for colonoscopy and the risk of interval cancer. N Engl J Med. May 13 2010;362(19):1795-803. doi: 10.1056/NEJMoa0907667.

4. Corley DA et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. Apr 03 2014;370(14):1298-306. doi: 10.1056/NEJMoa1309086.

5. Laique SN et al. Application of optical character recognition with natural language processing for large-scale quality metric data extraction in colonoscopy reports. Gastrointest Endosc. 03 2021;93(3):750-7. doi: 10.1016/j.gie.2020.08.038.

6. Tinmouth J et al. Validation of a natural language processing algorithm to identify adenomas and measure adenoma detection rates across a health system: a population-level study. Gastrointest Endosc. Jul 14 2022. doi: 10.1016/j.gie.2022.07.009.

7. Glissen Brown JR et al. Deep learning computer-aided polyp detection reduces adenoma miss rate: A United States multi-center randomized tandem colonoscopy study (CADeT-CS Trial). Clin Gastroenterol Hepatol. 07 2022;20(7):1499-1507.e4. doi: 10.1016/j.cgh.2021.09.009.

8. Wallace MB et al. Impact of artificial intelligence on miss rate of colorectal neoplasia. Gastroenterology. 07 2022;163(1):295-304.e5. doi: 10.1053/j.gastro.2022.03.007.

9. Hassan C et al. Performance of artificial intelligence in colonoscopy for adenoma and polyp detection: a systematic review and meta-analysis. Gastrointest Endosc. 01 2021;93(1):77-85.e6. doi: 10.1016/j.gie.2020.06.059.

10. Glissen Brown JR and Berzin TM. Adoption of new technologies: Artificial intelligence. Gastrointest Endosc Clin N Am. Oct 2021;31(4):743-58. doi: 10.1016/j.giec.2021.05.010.

11. Larsen SLV and Mori Y. Artificial intelligence in colonoscopy: A review on the current status. DEN open. Apr 2022;2(1):e109. doi: 10.1002/deo2.109.

12. Gupta N et al. Prevalence of advanced histological features in diminutive and small colon polyps. Gastrointest Endosc. May 2012;75(5):1022-30. doi: 10.1016/j.gie.2012.01.020.

13. Rex DK et al. The American Society for Gastrointestinal Endoscopy PIVI (Preservation and Incorporation of Valuable Endoscopic Innovations) on real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest Endosc. Mar 2011;73(3):419-22. doi: 10.1016/j.gie.2011.01.023.

14. Abu Dayyeh BK et al. ASGE Technology Committee systematic review and meta-analysis assessing the ASGE PIVI thresholds for adopting real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest Endosc. Mar 2015;81(3):502.e1-16. doi: 10.1016/j.gie.2014.12.022.

15. Mori Y et al. Real-time use of artificial intelligence in identification of diminutive polyps during colonoscopy: A prospective study. Ann Intern Med. Sep 18 2018;169(6):357-66. doi: 10.7326/M18-0249.

16. Hassan C et al.. A resect and discard strategy would improve cost-effectiveness of colorectal cancer screening. Clin Gastroenterol Hepatol. Oct 2010;8(10):865-9, 869.e1-3. doi: 10.1016/j.cgh.2010.05.018.

17. Hassan C et al. Artificial intelligence allows leaving-in-situ colorectal polyps. Clin Gastroenterol Hepatol. Nov 2022;20(11):2505-13.e4. doi: 10.1016/j.cgh.2022.04.045.

18. Areia M et al. Cost-effectiveness of artificial intelligence for screening colonoscopy: a modelling study. Lancet Digit Health. 06 2022;4(6):e436-44. doi: 10.1016/S2589-7500(22)00042-5.

19. Schottinger JE et al. Association of physician adenoma detection rates with postcolonoscopy colorectal cancer. JAMA. 2022 Jun 7;327(21):2114-22. doi: 10.1001/jama.2022.6644.

20. Oslo Uo. Optimising colorectal cancer prevention through personalised treatment with artificial intelligence. 2022.

21. Wadhwa V et al. Physician sentiment toward artificial intelligence (AI) in colonoscopic practice: a survey of US gastroenterologists. Endosc Int Open. Oct 2020;8(10):E1379-84. doi: 10.1055/a-1223-1926.

22. Kader R et al. Survey on the perceptions of UK gastroenterologists and endoscopists to artificial intelligence. Frontline Gastroenterol. 2022;13(5):423-9. doi: 10.1136/flgastro-2021-101994.

23. Rex DKet al. Artificial intelligence improves detection at colonoscopy: Why aren’t we all already using it? Gastroenterology. 07 2022;163(1):35-7. doi: 10.1053/j.gastro.2022.04.042.

24. Ahmad OF et al. Establishing key research questions for the implementation of artificial intelligence in colonoscopy: A modified Delphi method. Endoscopy. 09 2021;53(9):893-901. doi: 10.1055/a-1306-7590

Considerable advances in artificial intelligence (AI) and machine-learning (ML) methodologies have led to the emergence of promising tools in the field of gastrointestinal endoscopy. Computer vision is an application of AI/ML that has been successfully applied for the computer-aided detection (CADe) and computer-aided diagnosis (CADx) of colon polyps and numerous other conditions encountered during GI endoscopy. Outside of computer vision, a wide variety of other AI applications have been applied to gastroenterology, ranging from natural language processing (NLP) to optimize clinical documentation and endoscopy quality reporting to ML techniques that predict disease severity/treatment response and augment clinical decision-making. This article focuses on opportunities for AI applications in colonoscopy, reviews the existing data, describes the challenges limiting widespread adoption, and explores future directions.

In the United States, colonoscopy is the standard for colon cancer screening and prevention; however, precancerous polyps can be missed for various reasons, ranging from subtle surface appearance of the polyp or location behind a colonic fold to operator-dependent reasons such as inadequate mucosal inspection. Though clinical practice guidelines have set adenoma detection rate (ADR) thresholds at 20% for women and 30% for men, studies have shown a 4- to 10-fold variation in ADR among physicians in clinical practice settings^,1 with an estimated adenoma miss rate (AMR) of 25% and a false-negative colonoscopy rate of 12%.² Variability in adenoma detection affects the risk of interval colorectal cancer post colonoscopy.^3,4

AI provides an opportunity for mitigating this risk. Advances in deep learning and computer vision have led to the development of CADe systems that automatically detect polyps in real time during colonoscopy, resulting in reduced adenoma miss rates (Table 1). In addition to polyp detection, deep-learning technologies are also being used in CADx systems for polyp diagnosis and characterization of malignancy risk. This could aid therapeutic decision-making: Unnecessary resection or histopathologic analysis could be obviated for benign hyperplastic polyps. On the other end of the polyp spectrum, an AI tool that could predict the presence or absence of submucosal invasion could be a powerful tool when evaluating early colon cancers for consideration of endoscopic submucosal dissection vs. surgery. Examples of CADe polyp detection and CADx polyp characterization are shown in Figure 1.

Other potential computer vision applications that may improve colonoscopy quality include tools that help measure adequacy of mucosal exposure, segmental inspection time, and a variety of other parameters associated with polyp detection performance. These are promising areas for future research. Beyond improving colonoscopy technique, natural language processing tools already are being used to optimize clinical documentation as well as extract information from colonoscopy and pathology reports that can facilitate reporting of colonoscopy quality metrics such as ADR, cecal intubation rate, withdrawal time, and bowel preparation adequacy. AI-powered analytics may help unlock large-scale reporting of colonoscopy quality metrics on a health-systems level⁵ or population-level,⁶ helping to ensure optimal performance and identifying avenues for colonoscopy quality improvement.

In comparison, the data landscape for CADx is nascent and currently limited to several retrospective studies dating back to 2009 and a few prospective studies that have shown promising results.^10,11 There is an expectation that integrated CADx also may support the adoption of “resect and discard” or “diagnose and leave” strategies for low-risk polyps. About two-thirds of polyps identified on average-risk screening colonoscopies are diminutive polyps (less than 5 mm in size), which rarely have advanced histologic features (about 0.5%) and are sometimes non-neoplastic (30%). Malignancy risk is even lower in the distal colon.¹² As routine histopathologic assessment of such polyps is mostly of limited clinical utility and comes with added pathology costs, CADx technologies may offer a more cost-effective approach where polyps that are characterized in real-time as low-risk adenomas or non-neoplastic are “resected and discarded” or “left in” respectively. In 2011, prior to the development of current AI tools, the American Society for Gastrointestinal Endoscopy set performance thresholds for technologies supporting real-time endoscopic assessment of the histology of diminutive colorectal polyps. The ASGE recommended 90% histopathologic concordance for “resect and discard” tools and 90% negative predictive value for adenomatous histology for “diagnose and leave,” tools.¹³ Narrow-band imaging (NBI), for example, has been shown to meet these benchmarks^14,15 with a modeling study suggesting that implementing “resect and discard” strategies with such tools could result in annual savings of $33 million without adversely affecting efficacy, although practical adoption has been limited.¹⁶ More recent work has directly explored the feasibility of leveraging CADx to support “leave-in-situ” and “resect-and-discard” strategies.¹⁷

Similarly, while CADe use in colonoscopy is associated with additional up-front costs, a modeling study suggests that its associated gains in ADR (as detailed in Table 1) make it a cost-saving strategy for colorectal cancer prevention in the long term.¹⁸ There is still uncertainty on whether the incremental CADe-associated gains in adenoma detection will necessarily translate to significant reductions in interval colorectal cancer risk, particularly for endoscopists who are already high-performing polyp detectors. A recent study suggests that, although higher ADRs were associated with lower rates of interval colorectal cancer, the gains in interval colorectal cancer risk reduction appeared to level off with ADRs above 35%-40% (this finding may be limited by statistical power).¹⁹ Further, most of the data from CADe trials suggest that gains in adenoma detection are not driven by increased detection of advanced lesions with high malignancy risk but by small polyps with long latency periods of about 5-10 years, which may not significantly alter interval cancer risk. It remains to be determined whether adoption of CADe will have an impact on hard outcomes, most importantly interval colorectal cancer risk, or merely result in increased resource utilization without moving the needle on colorectal cancer prevention. To answer this question, the OperA study – a large-scale randomized clinical trial of 200,000 patients across 18 centers from 13 countries – was launched in 2022. It will investigate the effect of colonoscopy with CADe on a number of critical measures, including long-term interval colon cancer risk.²⁰

Despite commercial availability of regulatory-approved CADe systems and data supporting use for adenoma detection in colonoscopy, mainstream adoption in clinical practice has been sluggish. Physician survey studies have shown that, although there is considerable interest in integrating CADe into clinical practice, there are concerns about access, cost and reimbursement, integration into clinical work-flow, increased procedural times, over-reliance on AI, and algorithmic bias leading to errors.^21,22 In addition, without mandatory requirements for ADR reporting or clinical practice guideline recommendations for CADe use, these systems may not be perceived as valuable or ready for prime time even though the evidence suggests otherwise.^23,24 For CADe systems to see widespread adoption in clinical practice, it is important that future research studies rigorously investigate and characterize these potential barriers to better inform strategies to address AI hesitancy and implementation challenges. Such efforts can provide an integration framework for future AI applications in gastroenterology beyond colonoscopy, such as CADe of esophageal and gastric premalignant lesions in upper endoscopy, CADx for pancreatic cysts and liver lesions on imaging, NLP tools to optimizing efficient clinical documentation and reporting, and many others.

Dr. Uche-Anya is in the division of gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston. Dr. Berzin is with the Center for Advanced Endoscopy, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston. Dr. Berzin is a consultant for Wision AI, Medtronic, Magentiq Eye, RSIP Vision, and Docbot.

Corresponding Author: Eugenia Uche-Anya [email protected] Twitter: @UcheAnyaMD @tberzin

References

1. Corley DA et al. Can we improve adenoma detection rates? A systematic review of intervention studies. Gastrointest Endosc. Sep 2011;74(3):656-65. doi: 10.1016/j.gie.2011.04.017.

2. Zhao S et al. Magnitude, risk factors, and factors associated with adenoma miss rate of tandem colonoscopy: A systematic review and meta-analysis. Gastroenterology. 05 2019;156(6):1661-74.e11. doi: 10.1053/j.gastro.2019.01.260.

3. Kaminski MF et al. Quality indicators for colonoscopy and the risk of interval cancer. N Engl J Med. May 13 2010;362(19):1795-803. doi: 10.1056/NEJMoa0907667.

4. Corley DA et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. Apr 03 2014;370(14):1298-306. doi: 10.1056/NEJMoa1309086.

5. Laique SN et al. Application of optical character recognition with natural language processing for large-scale quality metric data extraction in colonoscopy reports. Gastrointest Endosc. 03 2021;93(3):750-7. doi: 10.1016/j.gie.2020.08.038.

6. Tinmouth J et al. Validation of a natural language processing algorithm to identify adenomas and measure adenoma detection rates across a health system: a population-level study. Gastrointest Endosc. Jul 14 2022. doi: 10.1016/j.gie.2022.07.009.

7. Glissen Brown JR et al. Deep learning computer-aided polyp detection reduces adenoma miss rate: A United States multi-center randomized tandem colonoscopy study (CADeT-CS Trial). Clin Gastroenterol Hepatol. 07 2022;20(7):1499-1507.e4. doi: 10.1016/j.cgh.2021.09.009.

8. Wallace MB et al. Impact of artificial intelligence on miss rate of colorectal neoplasia. Gastroenterology. 07 2022;163(1):295-304.e5. doi: 10.1053/j.gastro.2022.03.007.

9. Hassan C et al. Performance of artificial intelligence in colonoscopy for adenoma and polyp detection: a systematic review and meta-analysis. Gastrointest Endosc. 01 2021;93(1):77-85.e6. doi: 10.1016/j.gie.2020.06.059.

10. Glissen Brown JR and Berzin TM. Adoption of new technologies: Artificial intelligence. Gastrointest Endosc Clin N Am. Oct 2021;31(4):743-58. doi: 10.1016/j.giec.2021.05.010.

11. Larsen SLV and Mori Y. Artificial intelligence in colonoscopy: A review on the current status. DEN open. Apr 2022;2(1):e109. doi: 10.1002/deo2.109.

12. Gupta N et al. Prevalence of advanced histological features in diminutive and small colon polyps. Gastrointest Endosc. May 2012;75(5):1022-30. doi: 10.1016/j.gie.2012.01.020.

13. Rex DK et al. The American Society for Gastrointestinal Endoscopy PIVI (Preservation and Incorporation of Valuable Endoscopic Innovations) on real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest Endosc. Mar 2011;73(3):419-22. doi: 10.1016/j.gie.2011.01.023.

14. Abu Dayyeh BK et al. ASGE Technology Committee systematic review and meta-analysis assessing the ASGE PIVI thresholds for adopting real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest Endosc. Mar 2015;81(3):502.e1-16. doi: 10.1016/j.gie.2014.12.022.

15. Mori Y et al. Real-time use of artificial intelligence in identification of diminutive polyps during colonoscopy: A prospective study. Ann Intern Med. Sep 18 2018;169(6):357-66. doi: 10.7326/M18-0249.

16. Hassan C et al.. A resect and discard strategy would improve cost-effectiveness of colorectal cancer screening. Clin Gastroenterol Hepatol. Oct 2010;8(10):865-9, 869.e1-3. doi: 10.1016/j.cgh.2010.05.018.

17. Hassan C et al. Artificial intelligence allows leaving-in-situ colorectal polyps. Clin Gastroenterol Hepatol. Nov 2022;20(11):2505-13.e4. doi: 10.1016/j.cgh.2022.04.045.

18. Areia M et al. Cost-effectiveness of artificial intelligence for screening colonoscopy: a modelling study. Lancet Digit Health. 06 2022;4(6):e436-44. doi: 10.1016/S2589-7500(22)00042-5.

19. Schottinger JE et al. Association of physician adenoma detection rates with postcolonoscopy colorectal cancer. JAMA. 2022 Jun 7;327(21):2114-22. doi: 10.1001/jama.2022.6644.

20. Oslo Uo. Optimising colorectal cancer prevention through personalised treatment with artificial intelligence. 2022.

21. Wadhwa V et al. Physician sentiment toward artificial intelligence (AI) in colonoscopic practice: a survey of US gastroenterologists. Endosc Int Open. Oct 2020;8(10):E1379-84. doi: 10.1055/a-1223-1926.

22. Kader R et al. Survey on the perceptions of UK gastroenterologists and endoscopists to artificial intelligence. Frontline Gastroenterol. 2022;13(5):423-9. doi: 10.1136/flgastro-2021-101994.

23. Rex DKet al. Artificial intelligence improves detection at colonoscopy: Why aren’t we all already using it? Gastroenterology. 07 2022;163(1):35-7. doi: 10.1053/j.gastro.2022.04.042.

24. Ahmad OF et al. Establishing key research questions for the implementation of artificial intelligence in colonoscopy: A modified Delphi method. Endoscopy. 09 2021;53(9):893-901. doi: 10.1055/a-1306-7590

Considerable advances in artificial intelligence (AI) and machine-learning (ML) methodologies have led to the emergence of promising tools in the field of gastrointestinal endoscopy. Computer vision is an application of AI/ML that has been successfully applied for the computer-aided detection (CADe) and computer-aided diagnosis (CADx) of colon polyps and numerous other conditions encountered during GI endoscopy. Outside of computer vision, a wide variety of other AI applications have been applied to gastroenterology, ranging from natural language processing (NLP) to optimize clinical documentation and endoscopy quality reporting to ML techniques that predict disease severity/treatment response and augment clinical decision-making. This article focuses on opportunities for AI applications in colonoscopy, reviews the existing data, describes the challenges limiting widespread adoption, and explores future directions.

In the United States, colonoscopy is the standard for colon cancer screening and prevention; however, precancerous polyps can be missed for various reasons, ranging from subtle surface appearance of the polyp or location behind a colonic fold to operator-dependent reasons such as inadequate mucosal inspection. Though clinical practice guidelines have set adenoma detection rate (ADR) thresholds at 20% for women and 30% for men, studies have shown a 4- to 10-fold variation in ADR among physicians in clinical practice settings^,1 with an estimated adenoma miss rate (AMR) of 25% and a false-negative colonoscopy rate of 12%.² Variability in adenoma detection affects the risk of interval colorectal cancer post colonoscopy.^3,4

AI provides an opportunity for mitigating this risk. Advances in deep learning and computer vision have led to the development of CADe systems that automatically detect polyps in real time during colonoscopy, resulting in reduced adenoma miss rates (Table 1). In addition to polyp detection, deep-learning technologies are also being used in CADx systems for polyp diagnosis and characterization of malignancy risk. This could aid therapeutic decision-making: Unnecessary resection or histopathologic analysis could be obviated for benign hyperplastic polyps. On the other end of the polyp spectrum, an AI tool that could predict the presence or absence of submucosal invasion could be a powerful tool when evaluating early colon cancers for consideration of endoscopic submucosal dissection vs. surgery. Examples of CADe polyp detection and CADx polyp characterization are shown in Figure 1.

Other potential computer vision applications that may improve colonoscopy quality include tools that help measure adequacy of mucosal exposure, segmental inspection time, and a variety of other parameters associated with polyp detection performance. These are promising areas for future research. Beyond improving colonoscopy technique, natural language processing tools already are being used to optimize clinical documentation as well as extract information from colonoscopy and pathology reports that can facilitate reporting of colonoscopy quality metrics such as ADR, cecal intubation rate, withdrawal time, and bowel preparation adequacy. AI-powered analytics may help unlock large-scale reporting of colonoscopy quality metrics on a health-systems level⁵ or population-level,⁶ helping to ensure optimal performance and identifying avenues for colonoscopy quality improvement.

In comparison, the data landscape for CADx is nascent and currently limited to several retrospective studies dating back to 2009 and a few prospective studies that have shown promising results.^10,11 There is an expectation that integrated CADx also may support the adoption of “resect and discard” or “diagnose and leave” strategies for low-risk polyps. About two-thirds of polyps identified on average-risk screening colonoscopies are diminutive polyps (less than 5 mm in size), which rarely have advanced histologic features (about 0.5%) and are sometimes non-neoplastic (30%). Malignancy risk is even lower in the distal colon.¹² As routine histopathologic assessment of such polyps is mostly of limited clinical utility and comes with added pathology costs, CADx technologies may offer a more cost-effective approach where polyps that are characterized in real-time as low-risk adenomas or non-neoplastic are “resected and discarded” or “left in” respectively. In 2011, prior to the development of current AI tools, the American Society for Gastrointestinal Endoscopy set performance thresholds for technologies supporting real-time endoscopic assessment of the histology of diminutive colorectal polyps. The ASGE recommended 90% histopathologic concordance for “resect and discard” tools and 90% negative predictive value for adenomatous histology for “diagnose and leave,” tools.¹³ Narrow-band imaging (NBI), for example, has been shown to meet these benchmarks^14,15 with a modeling study suggesting that implementing “resect and discard” strategies with such tools could result in annual savings of $33 million without adversely affecting efficacy, although practical adoption has been limited.¹⁶ More recent work has directly explored the feasibility of leveraging CADx to support “leave-in-situ” and “resect-and-discard” strategies.¹⁷

Similarly, while CADe use in colonoscopy is associated with additional up-front costs, a modeling study suggests that its associated gains in ADR (as detailed in Table 1) make it a cost-saving strategy for colorectal cancer prevention in the long term.¹⁸ There is still uncertainty on whether the incremental CADe-associated gains in adenoma detection will necessarily translate to significant reductions in interval colorectal cancer risk, particularly for endoscopists who are already high-performing polyp detectors. A recent study suggests that, although higher ADRs were associated with lower rates of interval colorectal cancer, the gains in interval colorectal cancer risk reduction appeared to level off with ADRs above 35%-40% (this finding may be limited by statistical power).¹⁹ Further, most of the data from CADe trials suggest that gains in adenoma detection are not driven by increased detection of advanced lesions with high malignancy risk but by small polyps with long latency periods of about 5-10 years, which may not significantly alter interval cancer risk. It remains to be determined whether adoption of CADe will have an impact on hard outcomes, most importantly interval colorectal cancer risk, or merely result in increased resource utilization without moving the needle on colorectal cancer prevention. To answer this question, the OperA study – a large-scale randomized clinical trial of 200,000 patients across 18 centers from 13 countries – was launched in 2022. It will investigate the effect of colonoscopy with CADe on a number of critical measures, including long-term interval colon cancer risk.²⁰

Despite commercial availability of regulatory-approved CADe systems and data supporting use for adenoma detection in colonoscopy, mainstream adoption in clinical practice has been sluggish. Physician survey studies have shown that, although there is considerable interest in integrating CADe into clinical practice, there are concerns about access, cost and reimbursement, integration into clinical work-flow, increased procedural times, over-reliance on AI, and algorithmic bias leading to errors.^21,22 In addition, without mandatory requirements for ADR reporting or clinical practice guideline recommendations for CADe use, these systems may not be perceived as valuable or ready for prime time even though the evidence suggests otherwise.^23,24 For CADe systems to see widespread adoption in clinical practice, it is important that future research studies rigorously investigate and characterize these potential barriers to better inform strategies to address AI hesitancy and implementation challenges. Such efforts can provide an integration framework for future AI applications in gastroenterology beyond colonoscopy, such as CADe of esophageal and gastric premalignant lesions in upper endoscopy, CADx for pancreatic cysts and liver lesions on imaging, NLP tools to optimizing efficient clinical documentation and reporting, and many others.

Dr. Uche-Anya is in the division of gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston. Dr. Berzin is with the Center for Advanced Endoscopy, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston. Dr. Berzin is a consultant for Wision AI, Medtronic, Magentiq Eye, RSIP Vision, and Docbot.

Corresponding Author: Eugenia Uche-Anya [email protected] Twitter: @UcheAnyaMD @tberzin

References

1. Corley DA et al. Can we improve adenoma detection rates? A systematic review of intervention studies. Gastrointest Endosc. Sep 2011;74(3):656-65. doi: 10.1016/j.gie.2011.04.017.

2. Zhao S et al. Magnitude, risk factors, and factors associated with adenoma miss rate of tandem colonoscopy: A systematic review and meta-analysis. Gastroenterology. 05 2019;156(6):1661-74.e11. doi: 10.1053/j.gastro.2019.01.260.

3. Kaminski MF et al. Quality indicators for colonoscopy and the risk of interval cancer. N Engl J Med. May 13 2010;362(19):1795-803. doi: 10.1056/NEJMoa0907667.

4. Corley DA et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. Apr 03 2014;370(14):1298-306. doi: 10.1056/NEJMoa1309086.

5. Laique SN et al. Application of optical character recognition with natural language processing for large-scale quality metric data extraction in colonoscopy reports. Gastrointest Endosc. 03 2021;93(3):750-7. doi: 10.1016/j.gie.2020.08.038.

6. Tinmouth J et al. Validation of a natural language processing algorithm to identify adenomas and measure adenoma detection rates across a health system: a population-level study. Gastrointest Endosc. Jul 14 2022. doi: 10.1016/j.gie.2022.07.009.

7. Glissen Brown JR et al. Deep learning computer-aided polyp detection reduces adenoma miss rate: A United States multi-center randomized tandem colonoscopy study (CADeT-CS Trial). Clin Gastroenterol Hepatol. 07 2022;20(7):1499-1507.e4. doi: 10.1016/j.cgh.2021.09.009.

8. Wallace MB et al. Impact of artificial intelligence on miss rate of colorectal neoplasia. Gastroenterology. 07 2022;163(1):295-304.e5. doi: 10.1053/j.gastro.2022.03.007.

9. Hassan C et al. Performance of artificial intelligence in colonoscopy for adenoma and polyp detection: a systematic review and meta-analysis. Gastrointest Endosc. 01 2021;93(1):77-85.e6. doi: 10.1016/j.gie.2020.06.059.

10. Glissen Brown JR and Berzin TM. Adoption of new technologies: Artificial intelligence. Gastrointest Endosc Clin N Am. Oct 2021;31(4):743-58. doi: 10.1016/j.giec.2021.05.010.

11. Larsen SLV and Mori Y. Artificial intelligence in colonoscopy: A review on the current status. DEN open. Apr 2022;2(1):e109. doi: 10.1002/deo2.109.

12. Gupta N et al. Prevalence of advanced histological features in diminutive and small colon polyps. Gastrointest Endosc. May 2012;75(5):1022-30. doi: 10.1016/j.gie.2012.01.020.

13. Rex DK et al. The American Society for Gastrointestinal Endoscopy PIVI (Preservation and Incorporation of Valuable Endoscopic Innovations) on real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest Endosc. Mar 2011;73(3):419-22. doi: 10.1016/j.gie.2011.01.023.

14. Abu Dayyeh BK et al. ASGE Technology Committee systematic review and meta-analysis assessing the ASGE PIVI thresholds for adopting real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest Endosc. Mar 2015;81(3):502.e1-16. doi: 10.1016/j.gie.2014.12.022.

15. Mori Y et al. Real-time use of artificial intelligence in identification of diminutive polyps during colonoscopy: A prospective study. Ann Intern Med. Sep 18 2018;169(6):357-66. doi: 10.7326/M18-0249.

16. Hassan C et al.. A resect and discard strategy would improve cost-effectiveness of colorectal cancer screening. Clin Gastroenterol Hepatol. Oct 2010;8(10):865-9, 869.e1-3. doi: 10.1016/j.cgh.2010.05.018.

17. Hassan C et al. Artificial intelligence allows leaving-in-situ colorectal polyps. Clin Gastroenterol Hepatol. Nov 2022;20(11):2505-13.e4. doi: 10.1016/j.cgh.2022.04.045.

18. Areia M et al. Cost-effectiveness of artificial intelligence for screening colonoscopy: a modelling study. Lancet Digit Health. 06 2022;4(6):e436-44. doi: 10.1016/S2589-7500(22)00042-5.

19. Schottinger JE et al. Association of physician adenoma detection rates with postcolonoscopy colorectal cancer. JAMA. 2022 Jun 7;327(21):2114-22. doi: 10.1001/jama.2022.6644.

20. Oslo Uo. Optimising colorectal cancer prevention through personalised treatment with artificial intelligence. 2022.

21. Wadhwa V et al. Physician sentiment toward artificial intelligence (AI) in colonoscopic practice: a survey of US gastroenterologists. Endosc Int Open. Oct 2020;8(10):E1379-84. doi: 10.1055/a-1223-1926.

22. Kader R et al. Survey on the perceptions of UK gastroenterologists and endoscopists to artificial intelligence. Frontline Gastroenterol. 2022;13(5):423-9. doi: 10.1136/flgastro-2021-101994.

23. Rex DKet al. Artificial intelligence improves detection at colonoscopy: Why aren’t we all already using it? Gastroenterology. 07 2022;163(1):35-7. doi: 10.1053/j.gastro.2022.04.042.

24. Ahmad OF et al. Establishing key research questions for the implementation of artificial intelligence in colonoscopy: A modified Delphi method. Endoscopy. 09 2021;53(9):893-901. doi: 10.1055/a-1306-7590

In 2020, the rapid spread of the newly identified SARS-CoV-2 coronavirus led various global public health institutions to establish strategies to stop transmission and reduce mortality. Nonpharmacological measures – including social distancing, regular hand washing, and the use of face masks – contributed to reducing the impact of the COVID-19 pandemic on health systems in different regions of the world. However, because of the implementation of these measures, the transmission of other infectious agents also experienced a marked reduction.

Approximately 3 years after the start of the pandemic, it is evident that SARS-COV-2 has also affected the dynamic of other infectious agents, generating phenomena ranging from an immunity gap, which favors the increase in some diseases, to the apparent disappearance of an influenza virus lineage.
 

Understanding the phenomenon

In mid-2021, doctors and researchers around the world began to share their opinions about the side effect of the strict measures implemented to contain COVID-19.

In May 2021, along with some coresearchers, Emmanuel Grimprel, MD, of the Pediatric Infectious Pathology Group in Créteil, France, wrote for Infectious Disease Now, “The transmission of some pathogens is often similar to that of SARS-CoV-2, essentially large droplets, aerosols, and direct hand contact, often with lower transmissibility. The lack of immune system stimulation due to nonpharmaceutical measures induces an ‘immune debt’ that may have negative consequences when the pandemic is under control.” According to the authors, mathematical models evaluated up to that point were already suggesting that the respiratory syncytial virus (RSV) and influenza A epidemics would be more serious in subsequent years.

In July 2022, a commentary in The Lancet led by Kevin Messacar, MD, of the University of Colorado at Denver, Aurora, grew in relevance and gave prominence to the phenomenon. In the commentary, Dr. Messacar and a group of experts explained how the decrease in exposure to endemic viruses had given rise to an immunity gap.

“The immunity gap phenomenon that has been reported in articles such as The Lancet publication is mainly due to the isolation that took place to prevent SARS-CoV-2 infections. Although this distancing was a good response to combat infections, or at least delay them while coronavirus research advanced, what we are now experiencing is the increase in cases of respiratory diseases caused by other agents such as respiratory syncytial virus and influenza due to lack of exposure,” as explained to this news organization by Erandeni Martínez Jiménez, biomedicine graduate and member of the Medical Virology Laboratory of the Mexican Institute of Social Security, at the Zone No. 5 General Hospital in Metepec-Atlixco, Mexico.

“This phenomenon occurs in all age groups. However, it is more evident in children and babies, since at their age, they have been exposed to fewer pathogens and, when added to isolation, makes this immunity gap more evident. Many immunologists compare this to hygiene theory in which it is explained that a ‘sterile’ environment will cause children to avoid the everyday and common pathogens required to be able to develop an adequate immune system,” added Martínez Jimenez.

“In addition, due to the isolation, the vaccination rate in children decreased, since many parents did not risk their children going out. This causes the immunity gap to grow even further as these children are not protected against common pathogens. While a mother passes antibodies to the child through the uterus via her placenta, the mother will only pass on those antibodies to which she has been exposed and as expected due to the lockdown, exposure to other pathogens has been greatly reduced.”

On the other hand, Andreu Comas, MD, PhD, MHS, of the Center for Research in Health Sciences and Biomedicine of the Autonomous University of San Luis Potosí (Mexico), considered that there are other immunity gaps that are not limited to respiratory infections and that are related to the fall in vaccination coverage. “Children are going to experience several immunity gaps. In the middle of the previous 6-year term, we had a vaccination schedule coverage of around 70% for children. Now that vaccination coverage has fallen to 30%, today we have an immunity gap for measles, rubella, mumps, tetanus, diphtheria, whooping cough, and meningeal tuberculosis. We have a significant growth or risk for other diseases.”
 

Lineage extinction

Three types of influenza viruses – A, B, and C – cause infections in humans. Although influenza A virus is the main type associated with infections during seasonal periods, as of 2020, influenza B virus was considered the causative agent of about a quarter of annual influenza cases.

During the onset of the COVID-19 pandemic, cocirculation of the two distinct lineages of influenza B viruses, B/Victoria/2/1987 (B/Victoria) and B/Yamagata/16/1988 (B/Yamagata), decreased significantly. According to data from the FluNet tool, which is coordinated by the World Health Organization, since March 2020 the isolation or sequencing of viruses belonging to the Yamagata lineage was not conclusively carried out.

Specialists like John Paget, PhD, from the Netherlands Institute for Health Services Research (Nivel) in Utrecht, have indicated that determining the extinction of the B/Yamagata lineage is critical. There is the possibility of a reintroduction of the lineage, as has occurred in the past with the reemergence of influenza A (H1N1) in 1997, which could represent a risk in subsequent years.

“In the next few years, research related to viruses such as influenza B and the impact on population immunity will be important. Let’s remember that influenza changes every year due to its characteristics, so a lack of exposure will also have an impact on the development of the disease,” said Martínez Jiménez.
 

Vaccination is essential

According to Dr. Comas, the only way to overcome the immunity gap phenomenon is through vaccination campaigns. “There is no other way to overcome the phenomenon, and how fast it is done will depend on the effort,” he said.

“In the case of COVID-19, it is not planned to vaccinate children under 5 years of age, and if we do not vaccinate children under 5 years of age, that gap will exist. In addition, this winter season will be important to know whether we are already endemic or not. It will be the key point, and it will determine if we will have a peak or not in the summer.

“In the case of the rest of the diseases, we need to correct what has been deficient in different governments, and we are going to have the resurgence of other infectious diseases that had already been forgotten. We have the example of poliomyelitis, the increase in meningeal tuberculosis, and we will have an increase in whooping cough and pertussislike syndrome. In this sense, we are going back to the point where Mexico and the world were around the ‘60s and ‘70s, and we have to be very alert to detect, isolate, and revaccinate.”

Finally, Dr. Comas called for continuing precautionary measures before the arrival of the sixth wave. “At a national level, the sixth wave of COVID-19 has already begun, and an increase in cases is expected in January. Regarding vaccines, if you are over 18 years of age and have not had any vaccine dose, you can get Abdala, however, there are no studies on this vaccine as a booster, and it is not authorized by the Mexican government for this purpose. Therefore, it is necessary to continue with measures such as the use of face masks in crowded places or with poor ventilation, and in the event of having symptoms, avoid going out and encourage ventilation at work and schools. If we do this, at least in the case of diseases that are transmitted by the respiratory route, the impact will be minimal.”

Martínez Jiménez and Dr. Comas have disclosed no relevant financial relationships.

This article was translated from the Medscape Spanish Edition.

A version of this article first appeared on Medscape.com.

In 2020, the rapid spread of the newly identified SARS-CoV-2 coronavirus led various global public health institutions to establish strategies to stop transmission and reduce mortality. Nonpharmacological measures – including social distancing, regular hand washing, and the use of face masks – contributed to reducing the impact of the COVID-19 pandemic on health systems in different regions of the world. However, because of the implementation of these measures, the transmission of other infectious agents also experienced a marked reduction.

Approximately 3 years after the start of the pandemic, it is evident that SARS-COV-2 has also affected the dynamic of other infectious agents, generating phenomena ranging from an immunity gap, which favors the increase in some diseases, to the apparent disappearance of an influenza virus lineage.
 

Understanding the phenomenon

In mid-2021, doctors and researchers around the world began to share their opinions about the side effect of the strict measures implemented to contain COVID-19.

In May 2021, along with some coresearchers, Emmanuel Grimprel, MD, of the Pediatric Infectious Pathology Group in Créteil, France, wrote for Infectious Disease Now, “The transmission of some pathogens is often similar to that of SARS-CoV-2, essentially large droplets, aerosols, and direct hand contact, often with lower transmissibility. The lack of immune system stimulation due to nonpharmaceutical measures induces an ‘immune debt’ that may have negative consequences when the pandemic is under control.” According to the authors, mathematical models evaluated up to that point were already suggesting that the respiratory syncytial virus (RSV) and influenza A epidemics would be more serious in subsequent years.

In July 2022, a commentary in The Lancet led by Kevin Messacar, MD, of the University of Colorado at Denver, Aurora, grew in relevance and gave prominence to the phenomenon. In the commentary, Dr. Messacar and a group of experts explained how the decrease in exposure to endemic viruses had given rise to an immunity gap.

“The immunity gap phenomenon that has been reported in articles such as The Lancet publication is mainly due to the isolation that took place to prevent SARS-CoV-2 infections. Although this distancing was a good response to combat infections, or at least delay them while coronavirus research advanced, what we are now experiencing is the increase in cases of respiratory diseases caused by other agents such as respiratory syncytial virus and influenza due to lack of exposure,” as explained to this news organization by Erandeni Martínez Jiménez, biomedicine graduate and member of the Medical Virology Laboratory of the Mexican Institute of Social Security, at the Zone No. 5 General Hospital in Metepec-Atlixco, Mexico.

“This phenomenon occurs in all age groups. However, it is more evident in children and babies, since at their age, they have been exposed to fewer pathogens and, when added to isolation, makes this immunity gap more evident. Many immunologists compare this to hygiene theory in which it is explained that a ‘sterile’ environment will cause children to avoid the everyday and common pathogens required to be able to develop an adequate immune system,” added Martínez Jimenez.

“In addition, due to the isolation, the vaccination rate in children decreased, since many parents did not risk their children going out. This causes the immunity gap to grow even further as these children are not protected against common pathogens. While a mother passes antibodies to the child through the uterus via her placenta, the mother will only pass on those antibodies to which she has been exposed and as expected due to the lockdown, exposure to other pathogens has been greatly reduced.”

On the other hand, Andreu Comas, MD, PhD, MHS, of the Center for Research in Health Sciences and Biomedicine of the Autonomous University of San Luis Potosí (Mexico), considered that there are other immunity gaps that are not limited to respiratory infections and that are related to the fall in vaccination coverage. “Children are going to experience several immunity gaps. In the middle of the previous 6-year term, we had a vaccination schedule coverage of around 70% for children. Now that vaccination coverage has fallen to 30%, today we have an immunity gap for measles, rubella, mumps, tetanus, diphtheria, whooping cough, and meningeal tuberculosis. We have a significant growth or risk for other diseases.”
 

Lineage extinction

Three types of influenza viruses – A, B, and C – cause infections in humans. Although influenza A virus is the main type associated with infections during seasonal periods, as of 2020, influenza B virus was considered the causative agent of about a quarter of annual influenza cases.

During the onset of the COVID-19 pandemic, cocirculation of the two distinct lineages of influenza B viruses, B/Victoria/2/1987 (B/Victoria) and B/Yamagata/16/1988 (B/Yamagata), decreased significantly. According to data from the FluNet tool, which is coordinated by the World Health Organization, since March 2020 the isolation or sequencing of viruses belonging to the Yamagata lineage was not conclusively carried out.

Specialists like John Paget, PhD, from the Netherlands Institute for Health Services Research (Nivel) in Utrecht, have indicated that determining the extinction of the B/Yamagata lineage is critical. There is the possibility of a reintroduction of the lineage, as has occurred in the past with the reemergence of influenza A (H1N1) in 1997, which could represent a risk in subsequent years.

“In the next few years, research related to viruses such as influenza B and the impact on population immunity will be important. Let’s remember that influenza changes every year due to its characteristics, so a lack of exposure will also have an impact on the development of the disease,” said Martínez Jiménez.
 

Vaccination is essential

According to Dr. Comas, the only way to overcome the immunity gap phenomenon is through vaccination campaigns. “There is no other way to overcome the phenomenon, and how fast it is done will depend on the effort,” he said.

“In the case of COVID-19, it is not planned to vaccinate children under 5 years of age, and if we do not vaccinate children under 5 years of age, that gap will exist. In addition, this winter season will be important to know whether we are already endemic or not. It will be the key point, and it will determine if we will have a peak or not in the summer.

“In the case of the rest of the diseases, we need to correct what has been deficient in different governments, and we are going to have the resurgence of other infectious diseases that had already been forgotten. We have the example of poliomyelitis, the increase in meningeal tuberculosis, and we will have an increase in whooping cough and pertussislike syndrome. In this sense, we are going back to the point where Mexico and the world were around the ‘60s and ‘70s, and we have to be very alert to detect, isolate, and revaccinate.”

Finally, Dr. Comas called for continuing precautionary measures before the arrival of the sixth wave. “At a national level, the sixth wave of COVID-19 has already begun, and an increase in cases is expected in January. Regarding vaccines, if you are over 18 years of age and have not had any vaccine dose, you can get Abdala, however, there are no studies on this vaccine as a booster, and it is not authorized by the Mexican government for this purpose. Therefore, it is necessary to continue with measures such as the use of face masks in crowded places or with poor ventilation, and in the event of having symptoms, avoid going out and encourage ventilation at work and schools. If we do this, at least in the case of diseases that are transmitted by the respiratory route, the impact will be minimal.”

Martínez Jiménez and Dr. Comas have disclosed no relevant financial relationships.

This article was translated from the Medscape Spanish Edition.

A version of this article first appeared on Medscape.com.

In 2020, the rapid spread of the newly identified SARS-CoV-2 coronavirus led various global public health institutions to establish strategies to stop transmission and reduce mortality. Nonpharmacological measures – including social distancing, regular hand washing, and the use of face masks – contributed to reducing the impact of the COVID-19 pandemic on health systems in different regions of the world. However, because of the implementation of these measures, the transmission of other infectious agents also experienced a marked reduction.

Approximately 3 years after the start of the pandemic, it is evident that SARS-COV-2 has also affected the dynamic of other infectious agents, generating phenomena ranging from an immunity gap, which favors the increase in some diseases, to the apparent disappearance of an influenza virus lineage.
 

Understanding the phenomenon

In mid-2021, doctors and researchers around the world began to share their opinions about the side effect of the strict measures implemented to contain COVID-19.

In May 2021, along with some coresearchers, Emmanuel Grimprel, MD, of the Pediatric Infectious Pathology Group in Créteil, France, wrote for Infectious Disease Now, “The transmission of some pathogens is often similar to that of SARS-CoV-2, essentially large droplets, aerosols, and direct hand contact, often with lower transmissibility. The lack of immune system stimulation due to nonpharmaceutical measures induces an ‘immune debt’ that may have negative consequences when the pandemic is under control.” According to the authors, mathematical models evaluated up to that point were already suggesting that the respiratory syncytial virus (RSV) and influenza A epidemics would be more serious in subsequent years.

In July 2022, a commentary in The Lancet led by Kevin Messacar, MD, of the University of Colorado at Denver, Aurora, grew in relevance and gave prominence to the phenomenon. In the commentary, Dr. Messacar and a group of experts explained how the decrease in exposure to endemic viruses had given rise to an immunity gap.

“The immunity gap phenomenon that has been reported in articles such as The Lancet publication is mainly due to the isolation that took place to prevent SARS-CoV-2 infections. Although this distancing was a good response to combat infections, or at least delay them while coronavirus research advanced, what we are now experiencing is the increase in cases of respiratory diseases caused by other agents such as respiratory syncytial virus and influenza due to lack of exposure,” as explained to this news organization by Erandeni Martínez Jiménez, biomedicine graduate and member of the Medical Virology Laboratory of the Mexican Institute of Social Security, at the Zone No. 5 General Hospital in Metepec-Atlixco, Mexico.

“This phenomenon occurs in all age groups. However, it is more evident in children and babies, since at their age, they have been exposed to fewer pathogens and, when added to isolation, makes this immunity gap more evident. Many immunologists compare this to hygiene theory in which it is explained that a ‘sterile’ environment will cause children to avoid the everyday and common pathogens required to be able to develop an adequate immune system,” added Martínez Jimenez.

“In addition, due to the isolation, the vaccination rate in children decreased, since many parents did not risk their children going out. This causes the immunity gap to grow even further as these children are not protected against common pathogens. While a mother passes antibodies to the child through the uterus via her placenta, the mother will only pass on those antibodies to which she has been exposed and as expected due to the lockdown, exposure to other pathogens has been greatly reduced.”

On the other hand, Andreu Comas, MD, PhD, MHS, of the Center for Research in Health Sciences and Biomedicine of the Autonomous University of San Luis Potosí (Mexico), considered that there are other immunity gaps that are not limited to respiratory infections and that are related to the fall in vaccination coverage. “Children are going to experience several immunity gaps. In the middle of the previous 6-year term, we had a vaccination schedule coverage of around 70% for children. Now that vaccination coverage has fallen to 30%, today we have an immunity gap for measles, rubella, mumps, tetanus, diphtheria, whooping cough, and meningeal tuberculosis. We have a significant growth or risk for other diseases.”
 

Lineage extinction

Three types of influenza viruses – A, B, and C – cause infections in humans. Although influenza A virus is the main type associated with infections during seasonal periods, as of 2020, influenza B virus was considered the causative agent of about a quarter of annual influenza cases.

During the onset of the COVID-19 pandemic, cocirculation of the two distinct lineages of influenza B viruses, B/Victoria/2/1987 (B/Victoria) and B/Yamagata/16/1988 (B/Yamagata), decreased significantly. According to data from the FluNet tool, which is coordinated by the World Health Organization, since March 2020 the isolation or sequencing of viruses belonging to the Yamagata lineage was not conclusively carried out.

Specialists like John Paget, PhD, from the Netherlands Institute for Health Services Research (Nivel) in Utrecht, have indicated that determining the extinction of the B/Yamagata lineage is critical. There is the possibility of a reintroduction of the lineage, as has occurred in the past with the reemergence of influenza A (H1N1) in 1997, which could represent a risk in subsequent years.

“In the next few years, research related to viruses such as influenza B and the impact on population immunity will be important. Let’s remember that influenza changes every year due to its characteristics, so a lack of exposure will also have an impact on the development of the disease,” said Martínez Jiménez.
 

Vaccination is essential

According to Dr. Comas, the only way to overcome the immunity gap phenomenon is through vaccination campaigns. “There is no other way to overcome the phenomenon, and how fast it is done will depend on the effort,” he said.

“In the case of COVID-19, it is not planned to vaccinate children under 5 years of age, and if we do not vaccinate children under 5 years of age, that gap will exist. In addition, this winter season will be important to know whether we are already endemic or not. It will be the key point, and it will determine if we will have a peak or not in the summer.

“In the case of the rest of the diseases, we need to correct what has been deficient in different governments, and we are going to have the resurgence of other infectious diseases that had already been forgotten. We have the example of poliomyelitis, the increase in meningeal tuberculosis, and we will have an increase in whooping cough and pertussislike syndrome. In this sense, we are going back to the point where Mexico and the world were around the ‘60s and ‘70s, and we have to be very alert to detect, isolate, and revaccinate.”

Finally, Dr. Comas called for continuing precautionary measures before the arrival of the sixth wave. “At a national level, the sixth wave of COVID-19 has already begun, and an increase in cases is expected in January. Regarding vaccines, if you are over 18 years of age and have not had any vaccine dose, you can get Abdala, however, there are no studies on this vaccine as a booster, and it is not authorized by the Mexican government for this purpose. Therefore, it is necessary to continue with measures such as the use of face masks in crowded places or with poor ventilation, and in the event of having symptoms, avoid going out and encourage ventilation at work and schools. If we do this, at least in the case of diseases that are transmitted by the respiratory route, the impact will be minimal.”

Martínez Jiménez and Dr. Comas have disclosed no relevant financial relationships.

This article was translated from the Medscape Spanish Edition.

A version of this article first appeared on Medscape.com.

Appendectomy may lead to harmful changes in the gut microbiome that contribute to colorectal cancer (CRC), a new report from China suggests.

In one part of a three-part analysis, researchers observed a 73% increase in CRC risk among appendectomy cases compared, with controls over a 20-year follow-up.

The study, published in Oncogene, suggests that appendectomy may promote colorectal tumorigenesis by influencing the gut microbiome and that surgeons should “more cautiously consider the necessity of appendectomy,” the authors concluded.

Charles Dinerstein, MD, who was not involved in the research, said that the findings are “intriguing,” but it’s “too soon to tell” what the potential clinical implications may be. For now, “I would not think those patients having undergone an appendectomy should have more intense screening,” said Dr. Dinerstein, medical director of the American Council on Science and Health.

A growing body of evidence suggests that microbes in the gut may play a role in CRC risk, and other research indicates that the appendix might play a role in maintaining the diversity of the gut microbiome. However, whether removing the appendix influences a person’s risk for CRC remains controversial.

In the current study, Feiyu Shi, MD, of The First Affiliated Hospital of Xi’an Jiaotong University, and colleagues sought to better understand a possible association between appendectomy and CRC risk.

The team performed a three-part study: (1) analyzed a population of 129,155 adults who had an appendectomy and those who did not to assess a possible clinical connection between appendectomy and CRC risk; (2) performed fecal metagenomics sequencing to evaluate characteristics of the gut microbiome in appendectomy cases versus matched normal controls without appendectomy; and (3) investigated a CRC mouse model with appendectomy to uncover a mechanism of appendectomy-induced colorectal tumorigenesis.

In the large epidemiological study, Dr. Shi and colleagues compared CRC risk in almost 44,000 appendectomy cases versus more than 85,000 age- and gender-matched nonappendectomy controls. The researchers found that, over the 20-year follow-up, the risk for CRC increased by 73% in appendectomy cases (adjusted hazard ratio, 1.73; P < .001). CRC risk and gut dysbiosis were more pronounced in adults older than 50 years with a history of appendectomy.

In the gut microbiome analysis, Dr. Shi’s team performed metagenomic sequencing on fecal samples from 314 participants – 157 appendectomy cases and 157 controls – and found significant alterations in the gut microbiome in appendectomy cases. The changes were characterized by enrichment of seven CRC-promoting bacteria, including Bacteroides vulgatus and Bacteroides fragilis, and depletion of five beneficial bacteria, including Collinsella aerofaciens and Enterococcus hirae.

Finally, to examine the influence of appendectomy on microbial dysbiosis and CRC tumorigenesis, Dr. Shi’s team performed an appendectomy or a sham procedure in a carcinogen-induced CRC mouse model and found that appendectomy appeared to promote CRC tumorigenesis by prompting gut dysbiosis.

Aasma Shaukat, MD, MPH, a gastroenterologist at NYU Langone Health, who was not involved in the research, urged caution in interpreting the findings, which “need confirmation in larger diverse cohorts.”

First, Dr. Shaukat explained, “the two groups are not comparable, even though [they were] matched for age and gender, and many known and unknown factors can explain the results.” For instance, information on which subjects underwent colon cancer screening is not known, which may explain differences.

Dr. Shaukat also cautioned that the researchers only profiled the microbiome in “a small group of individuals and a cross-sectional analysis is not sufficient to explain causation.”

The study had no commercial funding. Dr. Shi, Dr. Dinerstein, and Dr. Shaukat have no relevant conflicts of interest to report.

A version of this article first appeared on Medscape.com.

Appendectomy may lead to harmful changes in the gut microbiome that contribute to colorectal cancer (CRC), a new report from China suggests.

In one part of a three-part analysis, researchers observed a 73% increase in CRC risk among appendectomy cases compared, with controls over a 20-year follow-up.

The study, published in Oncogene, suggests that appendectomy may promote colorectal tumorigenesis by influencing the gut microbiome and that surgeons should “more cautiously consider the necessity of appendectomy,” the authors concluded.

Charles Dinerstein, MD, who was not involved in the research, said that the findings are “intriguing,” but it’s “too soon to tell” what the potential clinical implications may be. For now, “I would not think those patients having undergone an appendectomy should have more intense screening,” said Dr. Dinerstein, medical director of the American Council on Science and Health.

A growing body of evidence suggests that microbes in the gut may play a role in CRC risk, and other research indicates that the appendix might play a role in maintaining the diversity of the gut microbiome. However, whether removing the appendix influences a person’s risk for CRC remains controversial.

In the current study, Feiyu Shi, MD, of The First Affiliated Hospital of Xi’an Jiaotong University, and colleagues sought to better understand a possible association between appendectomy and CRC risk.

The team performed a three-part study: (1) analyzed a population of 129,155 adults who had an appendectomy and those who did not to assess a possible clinical connection between appendectomy and CRC risk; (2) performed fecal metagenomics sequencing to evaluate characteristics of the gut microbiome in appendectomy cases versus matched normal controls without appendectomy; and (3) investigated a CRC mouse model with appendectomy to uncover a mechanism of appendectomy-induced colorectal tumorigenesis.

In the large epidemiological study, Dr. Shi and colleagues compared CRC risk in almost 44,000 appendectomy cases versus more than 85,000 age- and gender-matched nonappendectomy controls. The researchers found that, over the 20-year follow-up, the risk for CRC increased by 73% in appendectomy cases (adjusted hazard ratio, 1.73; P < .001). CRC risk and gut dysbiosis were more pronounced in adults older than 50 years with a history of appendectomy.

In the gut microbiome analysis, Dr. Shi’s team performed metagenomic sequencing on fecal samples from 314 participants – 157 appendectomy cases and 157 controls – and found significant alterations in the gut microbiome in appendectomy cases. The changes were characterized by enrichment of seven CRC-promoting bacteria, including Bacteroides vulgatus and Bacteroides fragilis, and depletion of five beneficial bacteria, including Collinsella aerofaciens and Enterococcus hirae.

Finally, to examine the influence of appendectomy on microbial dysbiosis and CRC tumorigenesis, Dr. Shi’s team performed an appendectomy or a sham procedure in a carcinogen-induced CRC mouse model and found that appendectomy appeared to promote CRC tumorigenesis by prompting gut dysbiosis.

Aasma Shaukat, MD, MPH, a gastroenterologist at NYU Langone Health, who was not involved in the research, urged caution in interpreting the findings, which “need confirmation in larger diverse cohorts.”

First, Dr. Shaukat explained, “the two groups are not comparable, even though [they were] matched for age and gender, and many known and unknown factors can explain the results.” For instance, information on which subjects underwent colon cancer screening is not known, which may explain differences.

Dr. Shaukat also cautioned that the researchers only profiled the microbiome in “a small group of individuals and a cross-sectional analysis is not sufficient to explain causation.”

The study had no commercial funding. Dr. Shi, Dr. Dinerstein, and Dr. Shaukat have no relevant conflicts of interest to report.

A version of this article first appeared on Medscape.com.

Appendectomy may lead to harmful changes in the gut microbiome that contribute to colorectal cancer (CRC), a new report from China suggests.

In one part of a three-part analysis, researchers observed a 73% increase in CRC risk among appendectomy cases compared, with controls over a 20-year follow-up.

The study, published in Oncogene, suggests that appendectomy may promote colorectal tumorigenesis by influencing the gut microbiome and that surgeons should “more cautiously consider the necessity of appendectomy,” the authors concluded.

Charles Dinerstein, MD, who was not involved in the research, said that the findings are “intriguing,” but it’s “too soon to tell” what the potential clinical implications may be. For now, “I would not think those patients having undergone an appendectomy should have more intense screening,” said Dr. Dinerstein, medical director of the American Council on Science and Health.

A growing body of evidence suggests that microbes in the gut may play a role in CRC risk, and other research indicates that the appendix might play a role in maintaining the diversity of the gut microbiome. However, whether removing the appendix influences a person’s risk for CRC remains controversial.

In the current study, Feiyu Shi, MD, of The First Affiliated Hospital of Xi’an Jiaotong University, and colleagues sought to better understand a possible association between appendectomy and CRC risk.

The team performed a three-part study: (1) analyzed a population of 129,155 adults who had an appendectomy and those who did not to assess a possible clinical connection between appendectomy and CRC risk; (2) performed fecal metagenomics sequencing to evaluate characteristics of the gut microbiome in appendectomy cases versus matched normal controls without appendectomy; and (3) investigated a CRC mouse model with appendectomy to uncover a mechanism of appendectomy-induced colorectal tumorigenesis.

In the large epidemiological study, Dr. Shi and colleagues compared CRC risk in almost 44,000 appendectomy cases versus more than 85,000 age- and gender-matched nonappendectomy controls. The researchers found that, over the 20-year follow-up, the risk for CRC increased by 73% in appendectomy cases (adjusted hazard ratio, 1.73; P < .001). CRC risk and gut dysbiosis were more pronounced in adults older than 50 years with a history of appendectomy.

In the gut microbiome analysis, Dr. Shi’s team performed metagenomic sequencing on fecal samples from 314 participants – 157 appendectomy cases and 157 controls – and found significant alterations in the gut microbiome in appendectomy cases. The changes were characterized by enrichment of seven CRC-promoting bacteria, including Bacteroides vulgatus and Bacteroides fragilis, and depletion of five beneficial bacteria, including Collinsella aerofaciens and Enterococcus hirae.

Finally, to examine the influence of appendectomy on microbial dysbiosis and CRC tumorigenesis, Dr. Shi’s team performed an appendectomy or a sham procedure in a carcinogen-induced CRC mouse model and found that appendectomy appeared to promote CRC tumorigenesis by prompting gut dysbiosis.

Aasma Shaukat, MD, MPH, a gastroenterologist at NYU Langone Health, who was not involved in the research, urged caution in interpreting the findings, which “need confirmation in larger diverse cohorts.”

First, Dr. Shaukat explained, “the two groups are not comparable, even though [they were] matched for age and gender, and many known and unknown factors can explain the results.” For instance, information on which subjects underwent colon cancer screening is not known, which may explain differences.

Dr. Shaukat also cautioned that the researchers only profiled the microbiome in “a small group of individuals and a cross-sectional analysis is not sufficient to explain causation.”

The study had no commercial funding. Dr. Shi, Dr. Dinerstein, and Dr. Shaukat have no relevant conflicts of interest to report.

A version of this article first appeared on Medscape.com.

FROM WORLD JOURNAL OF GASTROENTEROLOGY

One year after a diagnosis of celiac disease, more than one in five children present with functional gastrointestinal disorders (FGIDs) despite following a gluten-free diet (GFD). Developing FGIDs may be linked to caloric intake and percentage of food fat, but it does not change between a GFD with processed foods or a GFD with natural products.

These are the main findings of a study run jointly by the “Federico II” University of Naples and the “Luigi Vanvitelli” University of Campania, the results of which were published in the World Journal of Gastroenterology.

Unlike in previous studies, the criteria used in this study (the Rome IV criteria) allowed investigators to diagnose FGIDs even when other organic diseases, such as celiac disease or chronic inflammatory bowel disease, were present. The evidence obtained shows that adult individuals with celiac disease are at an increased risk for functional abdominal pain, even if they adhere well to a GFD. The researchers at the University of Campania wanted to determine the prevalence of FGIDs in the pediatric age group, which has been a poorly explored area.

The study authors enrolled 104 pediatric patients (aged 1-18 years) who had been diagnosed with celiac disease. The patients were randomly divided into two groups. Group A (n = 55) received a controlled GFD with processed foods (diet 1), and group B (n = 49) received a controlled GFD with > 60% natural products (diet 2). The presence of FGIDs was assessed at diagnosis (T0) and after 12 months (T1), and any potential link to the type of diet was analyzed.

The number of symptomatic children at enrollment was 30 of 55 (54.5%) in group A and 25 of 49 (51%) in group B. After 12 months, despite negative serology for celiac disease, the prevalence of FGIDs was 10/55 (18%) in group A and 8/49 (16.3%) in group B. There was no statistically significant difference between the two groups at T1. The most common disorder was functional constipation, followed by postprandial distress syndrome. At T1, the macro- and micronutrient intake was similar between the two groups, with no significant differences in nutrient analysis. However, in both groups, the prevalence of FGIDs was lower in patients who were consuming fewer calories (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.99-1.00) and fat (OR, 0.33; 95% CI, 0.65-0.95). The figure was very close to being statistically significant (P = .055).

“This is the first study to show that the presence of functional GI symptoms in children with celiac disease on a GFD are possibly related to higher caloric and fat intake,” wrote the study authors. “It remains to be determined whether the risk is due to the persistence of a chronic inflammatory process or to nutritional factors. Long-term monitoring studies will assist in determining the natural history of these functional symptoms.”

The study authors reported having no relevant financial conflicts.

This article was translated from Univadis Italy and a version appeared on Medscape.com.

FROM WORLD JOURNAL OF GASTROENTEROLOGY

One year after a diagnosis of celiac disease, more than one in five children present with functional gastrointestinal disorders (FGIDs) despite following a gluten-free diet (GFD). Developing FGIDs may be linked to caloric intake and percentage of food fat, but it does not change between a GFD with processed foods or a GFD with natural products.

These are the main findings of a study run jointly by the “Federico II” University of Naples and the “Luigi Vanvitelli” University of Campania, the results of which were published in the World Journal of Gastroenterology.

Unlike in previous studies, the criteria used in this study (the Rome IV criteria) allowed investigators to diagnose FGIDs even when other organic diseases, such as celiac disease or chronic inflammatory bowel disease, were present. The evidence obtained shows that adult individuals with celiac disease are at an increased risk for functional abdominal pain, even if they adhere well to a GFD. The researchers at the University of Campania wanted to determine the prevalence of FGIDs in the pediatric age group, which has been a poorly explored area.

The study authors enrolled 104 pediatric patients (aged 1-18 years) who had been diagnosed with celiac disease. The patients were randomly divided into two groups. Group A (n = 55) received a controlled GFD with processed foods (diet 1), and group B (n = 49) received a controlled GFD with > 60% natural products (diet 2). The presence of FGIDs was assessed at diagnosis (T0) and after 12 months (T1), and any potential link to the type of diet was analyzed.

The number of symptomatic children at enrollment was 30 of 55 (54.5%) in group A and 25 of 49 (51%) in group B. After 12 months, despite negative serology for celiac disease, the prevalence of FGIDs was 10/55 (18%) in group A and 8/49 (16.3%) in group B. There was no statistically significant difference between the two groups at T1. The most common disorder was functional constipation, followed by postprandial distress syndrome. At T1, the macro- and micronutrient intake was similar between the two groups, with no significant differences in nutrient analysis. However, in both groups, the prevalence of FGIDs was lower in patients who were consuming fewer calories (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.99-1.00) and fat (OR, 0.33; 95% CI, 0.65-0.95). The figure was very close to being statistically significant (P = .055).

“This is the first study to show that the presence of functional GI symptoms in children with celiac disease on a GFD are possibly related to higher caloric and fat intake,” wrote the study authors. “It remains to be determined whether the risk is due to the persistence of a chronic inflammatory process or to nutritional factors. Long-term monitoring studies will assist in determining the natural history of these functional symptoms.”

The study authors reported having no relevant financial conflicts.

This article was translated from Univadis Italy and a version appeared on Medscape.com.

FROM WORLD JOURNAL OF GASTROENTEROLOGY

One year after a diagnosis of celiac disease, more than one in five children present with functional gastrointestinal disorders (FGIDs) despite following a gluten-free diet (GFD). Developing FGIDs may be linked to caloric intake and percentage of food fat, but it does not change between a GFD with processed foods or a GFD with natural products.

These are the main findings of a study run jointly by the “Federico II” University of Naples and the “Luigi Vanvitelli” University of Campania, the results of which were published in the World Journal of Gastroenterology.

Unlike in previous studies, the criteria used in this study (the Rome IV criteria) allowed investigators to diagnose FGIDs even when other organic diseases, such as celiac disease or chronic inflammatory bowel disease, were present. The evidence obtained shows that adult individuals with celiac disease are at an increased risk for functional abdominal pain, even if they adhere well to a GFD. The researchers at the University of Campania wanted to determine the prevalence of FGIDs in the pediatric age group, which has been a poorly explored area.

The study authors enrolled 104 pediatric patients (aged 1-18 years) who had been diagnosed with celiac disease. The patients were randomly divided into two groups. Group A (n = 55) received a controlled GFD with processed foods (diet 1), and group B (n = 49) received a controlled GFD with > 60% natural products (diet 2). The presence of FGIDs was assessed at diagnosis (T0) and after 12 months (T1), and any potential link to the type of diet was analyzed.

The number of symptomatic children at enrollment was 30 of 55 (54.5%) in group A and 25 of 49 (51%) in group B. After 12 months, despite negative serology for celiac disease, the prevalence of FGIDs was 10/55 (18%) in group A and 8/49 (16.3%) in group B. There was no statistically significant difference between the two groups at T1. The most common disorder was functional constipation, followed by postprandial distress syndrome. At T1, the macro- and micronutrient intake was similar between the two groups, with no significant differences in nutrient analysis. However, in both groups, the prevalence of FGIDs was lower in patients who were consuming fewer calories (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.99-1.00) and fat (OR, 0.33; 95% CI, 0.65-0.95). The figure was very close to being statistically significant (P = .055).

“This is the first study to show that the presence of functional GI symptoms in children with celiac disease on a GFD are possibly related to higher caloric and fat intake,” wrote the study authors. “It remains to be determined whether the risk is due to the persistence of a chronic inflammatory process or to nutritional factors. Long-term monitoring studies will assist in determining the natural history of these functional symptoms.”

The study authors reported having no relevant financial conflicts.

This article was translated from Univadis Italy and a version appeared on Medscape.com.

Exercise helps patients with knee osteoarthritis, but more isn’t necessarily better, new research shows.

A low-dose exercise regimen helped patients with knee OA about as much as a more intense workout plan, according to trial results published online in Annals of Internal Medicine.

kali9/Getty Images

Both high and low doses of exercise reduced pain and improved function and quality of life.

The improvements with the lower-dose plan and its 98% adherence rate are encouraging, said Nick Trasolini, MD, assistant professor of orthopedic surgery at Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, N.C.

“This is a very doable amount of medical exercise therapy for patients with knee osteoarthritis, and one that makes a big difference in patient-reported symptoms,” Dr. Trasolini, who was not involved in the study, said in an interview.
 

What’s the right dose?

Exercise is a go-to treatment for knee OA, but the precise dose to recommend has been unclear. To study this question, Tom Arild Torstensen, MSc, RPT, with Karolinska Institutet, Huddinge, Sweden, and Holten Institute, Stockholm, and colleagues conducted a trial at four centers in Sweden and Norway.

The study included 189 men and women with knee OA. Participants were randomly assigned to low- or high-dose exercise plans, which they performed three times per week for 12 weeks under the supervision of a physiotherapist.

Participants in the high-dose group performed 11 exercises during each session, which lasted 70-90 minutes.

The low-dose regimen consisted of five exercises – cycling, squats, step-ups, step-downs, and knee extensions – performed for 20–30 minutes.

The researchers measured outcomes using the Knee Injury and Osteoarthritis Outcome Score, which assesses pain, other symptoms, function in daily living, function in sports and recreation, and knee-related quality of life.

“Patients in both groups improved significantly over time, but high-dose exercise was not superior to low-dose exercise in most comparisons,” the study investigators reported

High-dose exercise was associated with better function in sports and recreational activity and knee-related quality of life at 6 months. Those differences did not persist at 1 year, however. The researchers reported no safety concerns with either intervention.

Adherence was “nearly perfect” in the low-dose group. It was slightly lower in the high-dose group, the researchers said.

“Interestingly, it seems that high-dose treatment could be preferable to low-dose treatment in the long run for people who lead active lives,” they wrote. “This should be the subject of future studies.”

All clinical practice guidelines for knee OA recommend exercise, but “we do not know the optimal dose,” Kim Bennell, PhD, a research physiotherapist at the University of Melbourne, said in an interview.

Dose has components, including number of times per week, number of exercises, sets and repetitions, intensity, and duration of exercise sessions, Dr. Bennell said.

“These results suggest that an exercise program that involves less time and fewer exercises can still offer benefits and may be easier for patients to undertake and stick at than one that involves greater time and effort,” she said.

The study was supported by the Swedish Rheumatic Fund. Dr. Trasolini and Dr. Bennell have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Exercise helps patients with knee osteoarthritis, but more isn’t necessarily better, new research shows.

A low-dose exercise regimen helped patients with knee OA about as much as a more intense workout plan, according to trial results published online in Annals of Internal Medicine.

kali9/Getty Images

Both high and low doses of exercise reduced pain and improved function and quality of life.

The improvements with the lower-dose plan and its 98% adherence rate are encouraging, said Nick Trasolini, MD, assistant professor of orthopedic surgery at Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, N.C.

“This is a very doable amount of medical exercise therapy for patients with knee osteoarthritis, and one that makes a big difference in patient-reported symptoms,” Dr. Trasolini, who was not involved in the study, said in an interview.
 

What’s the right dose?

Exercise is a go-to treatment for knee OA, but the precise dose to recommend has been unclear. To study this question, Tom Arild Torstensen, MSc, RPT, with Karolinska Institutet, Huddinge, Sweden, and Holten Institute, Stockholm, and colleagues conducted a trial at four centers in Sweden and Norway.

The study included 189 men and women with knee OA. Participants were randomly assigned to low- or high-dose exercise plans, which they performed three times per week for 12 weeks under the supervision of a physiotherapist.

Participants in the high-dose group performed 11 exercises during each session, which lasted 70-90 minutes.

The low-dose regimen consisted of five exercises – cycling, squats, step-ups, step-downs, and knee extensions – performed for 20–30 minutes.

The researchers measured outcomes using the Knee Injury and Osteoarthritis Outcome Score, which assesses pain, other symptoms, function in daily living, function in sports and recreation, and knee-related quality of life.

“Patients in both groups improved significantly over time, but high-dose exercise was not superior to low-dose exercise in most comparisons,” the study investigators reported

High-dose exercise was associated with better function in sports and recreational activity and knee-related quality of life at 6 months. Those differences did not persist at 1 year, however. The researchers reported no safety concerns with either intervention.

Adherence was “nearly perfect” in the low-dose group. It was slightly lower in the high-dose group, the researchers said.

“Interestingly, it seems that high-dose treatment could be preferable to low-dose treatment in the long run for people who lead active lives,” they wrote. “This should be the subject of future studies.”

All clinical practice guidelines for knee OA recommend exercise, but “we do not know the optimal dose,” Kim Bennell, PhD, a research physiotherapist at the University of Melbourne, said in an interview.

Dose has components, including number of times per week, number of exercises, sets and repetitions, intensity, and duration of exercise sessions, Dr. Bennell said.

“These results suggest that an exercise program that involves less time and fewer exercises can still offer benefits and may be easier for patients to undertake and stick at than one that involves greater time and effort,” she said.

The study was supported by the Swedish Rheumatic Fund. Dr. Trasolini and Dr. Bennell have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Exercise helps patients with knee osteoarthritis, but more isn’t necessarily better, new research shows.

A low-dose exercise regimen helped patients with knee OA about as much as a more intense workout plan, according to trial results published online in Annals of Internal Medicine.

kali9/Getty Images

Both high and low doses of exercise reduced pain and improved function and quality of life.

The improvements with the lower-dose plan and its 98% adherence rate are encouraging, said Nick Trasolini, MD, assistant professor of orthopedic surgery at Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, N.C.

“This is a very doable amount of medical exercise therapy for patients with knee osteoarthritis, and one that makes a big difference in patient-reported symptoms,” Dr. Trasolini, who was not involved in the study, said in an interview.
 

What’s the right dose?

Exercise is a go-to treatment for knee OA, but the precise dose to recommend has been unclear. To study this question, Tom Arild Torstensen, MSc, RPT, with Karolinska Institutet, Huddinge, Sweden, and Holten Institute, Stockholm, and colleagues conducted a trial at four centers in Sweden and Norway.

The study included 189 men and women with knee OA. Participants were randomly assigned to low- or high-dose exercise plans, which they performed three times per week for 12 weeks under the supervision of a physiotherapist.

Participants in the high-dose group performed 11 exercises during each session, which lasted 70-90 minutes.

The low-dose regimen consisted of five exercises – cycling, squats, step-ups, step-downs, and knee extensions – performed for 20–30 minutes.

The researchers measured outcomes using the Knee Injury and Osteoarthritis Outcome Score, which assesses pain, other symptoms, function in daily living, function in sports and recreation, and knee-related quality of life.

“Patients in both groups improved significantly over time, but high-dose exercise was not superior to low-dose exercise in most comparisons,” the study investigators reported

High-dose exercise was associated with better function in sports and recreational activity and knee-related quality of life at 6 months. Those differences did not persist at 1 year, however. The researchers reported no safety concerns with either intervention.

Adherence was “nearly perfect” in the low-dose group. It was slightly lower in the high-dose group, the researchers said.

“Interestingly, it seems that high-dose treatment could be preferable to low-dose treatment in the long run for people who lead active lives,” they wrote. “This should be the subject of future studies.”

All clinical practice guidelines for knee OA recommend exercise, but “we do not know the optimal dose,” Kim Bennell, PhD, a research physiotherapist at the University of Melbourne, said in an interview.

Dose has components, including number of times per week, number of exercises, sets and repetitions, intensity, and duration of exercise sessions, Dr. Bennell said.

“These results suggest that an exercise program that involves less time and fewer exercises can still offer benefits and may be easier for patients to undertake and stick at than one that involves greater time and effort,” she said.

The study was supported by the Swedish Rheumatic Fund. Dr. Trasolini and Dr. Bennell have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Recurrent ovarian cancer is difficult to treat; it has high recurrence rates and poor targeted treatment options. Between 60% and 75% of patients initially diagnosed with advanced-stage ovarian cancer will relapse within 2-3 years.¹ Survival for these patients is poor, with an average overall survival (OS) of 30-40 months from the time of recurrence.² Historically, immunotherapy has shown poor efficacy for recurrent ovarian malignancy, leaving few options for patients and their providers. Given the lack of effective treatment options, secondary cytoreductive surgery (surgery at the time of recurrence) has been heavily studied as a potential therapeutic option.

The initial rationale for cytoreductive surgery (CRS) in patients with advanced ovarian cancer focused on palliation of symptoms from large, bulky disease that frequently caused obstructive symptoms and pain. Now, cytoreduction is a critical part of therapy. It decreases chemotherapy-resistant tumor cells, improves the immune response, and is thought to optimize perfusion of the residual cancer for systemic therapy. The survival benefit of surgery in the frontline setting, either with primary or interval debulking, is well established, and much of the data now demonstrate that complete resection of all macroscopic disease (also known as an R0 resection) has the greatest survival benefit.³ Given the benefits of an initial debulking surgery, secondary cytoreduction has been studied since the 1980s with mixed results. These data have demonstrated that the largest barrier to care has been appropriate patient selection for this often complex surgical procedure.

The 2020 National Comprehensive Cancer Network guidelines list secondary CRS as a treatment option; however, the procedure should only be considered in patients who have platinum sensitive disease, a performance status of 0-1, no ascites, and an isolated focus or limited focus of disease that is amenable to complete resection. Numerous retrospective studies have suggested that secondary CRS is beneficial to patients with recurrent ovarian cancer, especially if complete cytoreduction can be accomplished. Many of these studies have similarly concluded that there are benefits, such as less ascites at the time of recurrence, smaller disease burden, and a longer disease-free interval. From that foundation, multiple groups used retrospective data to investigate prognostic models to determine who would benefit most from secondary cytoreduction.

The DESKTOP Group initially published their retrospective study in 2006 and created a scoring system assessing who would benefit from secondary CRS.⁴ Data demonstrated that a performance status of 0, FIGO stage of I/II at the time of initial diagnosis, no residual tumor after primary surgery, and ascites less than 500 mL were associated with improved survival after secondary cytoreduction. They created the AGO score out of these data, which is positive only if three criteria are met: a performance status of 0, R0 after primary debulk, and ascites less than 500 mL at the time of recurrence.

They prospectively tested this score in DESKTOP II, which validated their findings and showed that complete secondary CRS could be achieved in 76% of those with a positive AGO score.⁵ Many believed that the AGO score was too restrictive, and a second retrospective study performed by a group at Memorial Sloan Kettering showed that optimal secondary cytoreduction could be achieved to prolong survival by a median of 30 months in patients with a longer disease-free interval, a single site of recurrence, and residual disease measuring less than 5 mm at time of initial/first-line surgery.⁶ Many individuals now use this scoring system to determine candidacy for secondary debulking: disease-free interval, number of sites of recurrence (ideally oligometastatic disease), and residual disease less than 5 mm at the time of primary debulking.

Finally, the iMODEL was developed by a group from China and found that complete R0 secondary CRS was associated with a low initial FIGO stage, no residual disease after primary surgery, longer platinum-free interval, better Eastern Cooperative Oncology Group performance status, lower CA-125 levels, as well as no ascites at the time of recurrence. Based on these criteria, individuals received either high or low iMODEL scores, and those with a low score were said to be candidates for secondary CRS. Overall, these models demonstrate that the strongest predictive factor that suggests a survival benefit from secondary CRS is the ability to achieve a complete R0 resection at the time of surgery.
 

Secondary debulking surgery has been tested in three large randomized controlled trials. The DESKTOP investigators and the SOC-1 trial have been the most successful groups to publish on this topic with positive results. Both groups use prognostic models for their inclusion criteria to select candidates in whom an R0 resection is believed to be most feasible. The first randomized controlled trial to publish on this topic was GOG-213,⁷ which did not use prognostic modeling for their inclusion criteria. Patients were randomized to secondary cytoreduction followed by platinum-based chemotherapy with or without bevacizumab versus chemotherapy alone. The median OS was 50.6 months in the surgery group and 64.7 months in the no-surgery group (P = .08), suggesting no survival benefit to secondary cytoreduction; however, an ad hoc exploratory analysis of the surgery arm showed that both overall and progression-free survival were significantly improved in the complete cytoreduction group, compared with those with residual disease at time of surgery.

The results from the GOG-213 group suggested that improved survival from secondary debulking might be achieved when prognostic modeling is used to select optimal surgical candidates. The SOC-1 trial, published in 2021, was a phase 3, randomized, controlled trial that used the iMODEL scoring system combined with PET/CT imaging for patient selection.⁸ Patients were again randomized to surgery followed by platinum-based chemotherapy versus chemotherapy alone. Complete cytoreduction was achieved in 73% of patients with a low iMODEL score, and these data showed improved OS in the surgery group of 58.1 months versus 53.9 months (P < .05) in the no-surgery group. Lastly, the DESKTOP group most recently published results on this topic in a large randomized, controlled trial.⁹ Patients were again randomized to surgery followed by platinum-based chemotherapy versus chemotherapy alone. Inclusion criteria were only met in patients with a positive AGO score. An improved OS of 7.7 months (53.7 vs. 46 months; P < .05) was demonstrated in patients that underwent surgery versus those exposed to only chemotherapy. Again, this group showed that overall survival was further improved when complete cytoreduction was achieved.

Given the results of these three trials, the Society for Gynecologic Oncology has released a statement on secondary cytoreduction in recurrent ovarian cancer (see Table).¹⁰ While it is important to use caution when comparing the three studies as study populations differed substantially, the most important takeaway the difference in survival outcomes in patients in whom complete gross resection was achieved versus no complete gross resection versus no surgery. This comparison highlights the benefit of complete cytoreduction as well as the potential harms of secondary debulking when an R0 resection cannot be achieved. Although not yet evaluated in this clinical setting, laparoscopic exploration may be useful to augment assessment of disease extent and possibility of disease resection, just as it is in frontline ovarian cancer surgery.

The importance of bevacizumab use in recurrent ovarian cancer is also highlighted in the SGO statement. In GOG-213, 84% of the total study population (in both the surgery and no surgery cohort) were treated with concurrent followed by maintenance bevacizumab with an improved survival outcome, which may suggest that this trial generalizes better than the others to contemporary management of platinum-sensitive recurrent ovarian cancer.

Overall, given the mixed data, the recommendation is for surgeons to consider all available data to guide them in treatment planning with a strong emphasis on using all available technology to assess whether complete cytoreduction can be achieved in the setting of recurrence so as to not delay the patient’s ability to receive chemotherapy.

Dr. John is a gynecologic oncology fellow at the University of North Carolina at Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the university.

References

1. du Bois A et al. J Natl Cancer Inst. 2003;95:1320-9.

2. Wagner U et al. Br J Cancer. 2012;107:588-91.

3. Vergote I et al. N Engl J Med. 2010;363:943-53.

4. Harter P et al. Ann Surg Oncol. 2006;13:1702-10.

5. Harter P et al. Int J Gynecol Cancer. 2011;21:289-95.

6. Chi DS et al. Cancer. 2006 106:1933-9.

7. Coleman RL et al. Lancet Oncol. 2017;18:779-1.

8. Shi T et al. Lancet Oncol. 2021;22:439-49.

9. Harter P et al. N Engl J Med 2021;385:2123-31.

10. Harrison R, et al. Gynecol Oncol. 2021;163:448-52.

Recurrent ovarian cancer is difficult to treat; it has high recurrence rates and poor targeted treatment options. Between 60% and 75% of patients initially diagnosed with advanced-stage ovarian cancer will relapse within 2-3 years.¹ Survival for these patients is poor, with an average overall survival (OS) of 30-40 months from the time of recurrence.² Historically, immunotherapy has shown poor efficacy for recurrent ovarian malignancy, leaving few options for patients and their providers. Given the lack of effective treatment options, secondary cytoreductive surgery (surgery at the time of recurrence) has been heavily studied as a potential therapeutic option.

The initial rationale for cytoreductive surgery (CRS) in patients with advanced ovarian cancer focused on palliation of symptoms from large, bulky disease that frequently caused obstructive symptoms and pain. Now, cytoreduction is a critical part of therapy. It decreases chemotherapy-resistant tumor cells, improves the immune response, and is thought to optimize perfusion of the residual cancer for systemic therapy. The survival benefit of surgery in the frontline setting, either with primary or interval debulking, is well established, and much of the data now demonstrate that complete resection of all macroscopic disease (also known as an R0 resection) has the greatest survival benefit.³ Given the benefits of an initial debulking surgery, secondary cytoreduction has been studied since the 1980s with mixed results. These data have demonstrated that the largest barrier to care has been appropriate patient selection for this often complex surgical procedure.

The 2020 National Comprehensive Cancer Network guidelines list secondary CRS as a treatment option; however, the procedure should only be considered in patients who have platinum sensitive disease, a performance status of 0-1, no ascites, and an isolated focus or limited focus of disease that is amenable to complete resection. Numerous retrospective studies have suggested that secondary CRS is beneficial to patients with recurrent ovarian cancer, especially if complete cytoreduction can be accomplished. Many of these studies have similarly concluded that there are benefits, such as less ascites at the time of recurrence, smaller disease burden, and a longer disease-free interval. From that foundation, multiple groups used retrospective data to investigate prognostic models to determine who would benefit most from secondary cytoreduction.

The DESKTOP Group initially published their retrospective study in 2006 and created a scoring system assessing who would benefit from secondary CRS.⁴ Data demonstrated that a performance status of 0, FIGO stage of I/II at the time of initial diagnosis, no residual tumor after primary surgery, and ascites less than 500 mL were associated with improved survival after secondary cytoreduction. They created the AGO score out of these data, which is positive only if three criteria are met: a performance status of 0, R0 after primary debulk, and ascites less than 500 mL at the time of recurrence.

They prospectively tested this score in DESKTOP II, which validated their findings and showed that complete secondary CRS could be achieved in 76% of those with a positive AGO score.⁵ Many believed that the AGO score was too restrictive, and a second retrospective study performed by a group at Memorial Sloan Kettering showed that optimal secondary cytoreduction could be achieved to prolong survival by a median of 30 months in patients with a longer disease-free interval, a single site of recurrence, and residual disease measuring less than 5 mm at time of initial/first-line surgery.⁶ Many individuals now use this scoring system to determine candidacy for secondary debulking: disease-free interval, number of sites of recurrence (ideally oligometastatic disease), and residual disease less than 5 mm at the time of primary debulking.

Finally, the iMODEL was developed by a group from China and found that complete R0 secondary CRS was associated with a low initial FIGO stage, no residual disease after primary surgery, longer platinum-free interval, better Eastern Cooperative Oncology Group performance status, lower CA-125 levels, as well as no ascites at the time of recurrence. Based on these criteria, individuals received either high or low iMODEL scores, and those with a low score were said to be candidates for secondary CRS. Overall, these models demonstrate that the strongest predictive factor that suggests a survival benefit from secondary CRS is the ability to achieve a complete R0 resection at the time of surgery.
 

Secondary debulking surgery has been tested in three large randomized controlled trials. The DESKTOP investigators and the SOC-1 trial have been the most successful groups to publish on this topic with positive results. Both groups use prognostic models for their inclusion criteria to select candidates in whom an R0 resection is believed to be most feasible. The first randomized controlled trial to publish on this topic was GOG-213,⁷ which did not use prognostic modeling for their inclusion criteria. Patients were randomized to secondary cytoreduction followed by platinum-based chemotherapy with or without bevacizumab versus chemotherapy alone. The median OS was 50.6 months in the surgery group and 64.7 months in the no-surgery group (P = .08), suggesting no survival benefit to secondary cytoreduction; however, an ad hoc exploratory analysis of the surgery arm showed that both overall and progression-free survival were significantly improved in the complete cytoreduction group, compared with those with residual disease at time of surgery.

The results from the GOG-213 group suggested that improved survival from secondary debulking might be achieved when prognostic modeling is used to select optimal surgical candidates. The SOC-1 trial, published in 2021, was a phase 3, randomized, controlled trial that used the iMODEL scoring system combined with PET/CT imaging for patient selection.⁸ Patients were again randomized to surgery followed by platinum-based chemotherapy versus chemotherapy alone. Complete cytoreduction was achieved in 73% of patients with a low iMODEL score, and these data showed improved OS in the surgery group of 58.1 months versus 53.9 months (P < .05) in the no-surgery group. Lastly, the DESKTOP group most recently published results on this topic in a large randomized, controlled trial.⁹ Patients were again randomized to surgery followed by platinum-based chemotherapy versus chemotherapy alone. Inclusion criteria were only met in patients with a positive AGO score. An improved OS of 7.7 months (53.7 vs. 46 months; P < .05) was demonstrated in patients that underwent surgery versus those exposed to only chemotherapy. Again, this group showed that overall survival was further improved when complete cytoreduction was achieved.

Given the results of these three trials, the Society for Gynecologic Oncology has released a statement on secondary cytoreduction in recurrent ovarian cancer (see Table).¹⁰ While it is important to use caution when comparing the three studies as study populations differed substantially, the most important takeaway the difference in survival outcomes in patients in whom complete gross resection was achieved versus no complete gross resection versus no surgery. This comparison highlights the benefit of complete cytoreduction as well as the potential harms of secondary debulking when an R0 resection cannot be achieved. Although not yet evaluated in this clinical setting, laparoscopic exploration may be useful to augment assessment of disease extent and possibility of disease resection, just as it is in frontline ovarian cancer surgery.

The importance of bevacizumab use in recurrent ovarian cancer is also highlighted in the SGO statement. In GOG-213, 84% of the total study population (in both the surgery and no surgery cohort) were treated with concurrent followed by maintenance bevacizumab with an improved survival outcome, which may suggest that this trial generalizes better than the others to contemporary management of platinum-sensitive recurrent ovarian cancer.

Overall, given the mixed data, the recommendation is for surgeons to consider all available data to guide them in treatment planning with a strong emphasis on using all available technology to assess whether complete cytoreduction can be achieved in the setting of recurrence so as to not delay the patient’s ability to receive chemotherapy.

Dr. John is a gynecologic oncology fellow at the University of North Carolina at Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the university.

References

1. du Bois A et al. J Natl Cancer Inst. 2003;95:1320-9.

2. Wagner U et al. Br J Cancer. 2012;107:588-91.

3. Vergote I et al. N Engl J Med. 2010;363:943-53.

4. Harter P et al. Ann Surg Oncol. 2006;13:1702-10.

5. Harter P et al. Int J Gynecol Cancer. 2011;21:289-95.

6. Chi DS et al. Cancer. 2006 106:1933-9.

7. Coleman RL et al. Lancet Oncol. 2017;18:779-1.

8. Shi T et al. Lancet Oncol. 2021;22:439-49.

9. Harter P et al. N Engl J Med 2021;385:2123-31.

10. Harrison R, et al. Gynecol Oncol. 2021;163:448-52.

Recurrent ovarian cancer is difficult to treat; it has high recurrence rates and poor targeted treatment options. Between 60% and 75% of patients initially diagnosed with advanced-stage ovarian cancer will relapse within 2-3 years.¹ Survival for these patients is poor, with an average overall survival (OS) of 30-40 months from the time of recurrence.² Historically, immunotherapy has shown poor efficacy for recurrent ovarian malignancy, leaving few options for patients and their providers. Given the lack of effective treatment options, secondary cytoreductive surgery (surgery at the time of recurrence) has been heavily studied as a potential therapeutic option.

The initial rationale for cytoreductive surgery (CRS) in patients with advanced ovarian cancer focused on palliation of symptoms from large, bulky disease that frequently caused obstructive symptoms and pain. Now, cytoreduction is a critical part of therapy. It decreases chemotherapy-resistant tumor cells, improves the immune response, and is thought to optimize perfusion of the residual cancer for systemic therapy. The survival benefit of surgery in the frontline setting, either with primary or interval debulking, is well established, and much of the data now demonstrate that complete resection of all macroscopic disease (also known as an R0 resection) has the greatest survival benefit.³ Given the benefits of an initial debulking surgery, secondary cytoreduction has been studied since the 1980s with mixed results. These data have demonstrated that the largest barrier to care has been appropriate patient selection for this often complex surgical procedure.

The 2020 National Comprehensive Cancer Network guidelines list secondary CRS as a treatment option; however, the procedure should only be considered in patients who have platinum sensitive disease, a performance status of 0-1, no ascites, and an isolated focus or limited focus of disease that is amenable to complete resection. Numerous retrospective studies have suggested that secondary CRS is beneficial to patients with recurrent ovarian cancer, especially if complete cytoreduction can be accomplished. Many of these studies have similarly concluded that there are benefits, such as less ascites at the time of recurrence, smaller disease burden, and a longer disease-free interval. From that foundation, multiple groups used retrospective data to investigate prognostic models to determine who would benefit most from secondary cytoreduction.

The DESKTOP Group initially published their retrospective study in 2006 and created a scoring system assessing who would benefit from secondary CRS.⁴ Data demonstrated that a performance status of 0, FIGO stage of I/II at the time of initial diagnosis, no residual tumor after primary surgery, and ascites less than 500 mL were associated with improved survival after secondary cytoreduction. They created the AGO score out of these data, which is positive only if three criteria are met: a performance status of 0, R0 after primary debulk, and ascites less than 500 mL at the time of recurrence.

They prospectively tested this score in DESKTOP II, which validated their findings and showed that complete secondary CRS could be achieved in 76% of those with a positive AGO score.⁵ Many believed that the AGO score was too restrictive, and a second retrospective study performed by a group at Memorial Sloan Kettering showed that optimal secondary cytoreduction could be achieved to prolong survival by a median of 30 months in patients with a longer disease-free interval, a single site of recurrence, and residual disease measuring less than 5 mm at time of initial/first-line surgery.⁶ Many individuals now use this scoring system to determine candidacy for secondary debulking: disease-free interval, number of sites of recurrence (ideally oligometastatic disease), and residual disease less than 5 mm at the time of primary debulking.

Finally, the iMODEL was developed by a group from China and found that complete R0 secondary CRS was associated with a low initial FIGO stage, no residual disease after primary surgery, longer platinum-free interval, better Eastern Cooperative Oncology Group performance status, lower CA-125 levels, as well as no ascites at the time of recurrence. Based on these criteria, individuals received either high or low iMODEL scores, and those with a low score were said to be candidates for secondary CRS. Overall, these models demonstrate that the strongest predictive factor that suggests a survival benefit from secondary CRS is the ability to achieve a complete R0 resection at the time of surgery.
 

Secondary debulking surgery has been tested in three large randomized controlled trials. The DESKTOP investigators and the SOC-1 trial have been the most successful groups to publish on this topic with positive results. Both groups use prognostic models for their inclusion criteria to select candidates in whom an R0 resection is believed to be most feasible. The first randomized controlled trial to publish on this topic was GOG-213,⁷ which did not use prognostic modeling for their inclusion criteria. Patients were randomized to secondary cytoreduction followed by platinum-based chemotherapy with or without bevacizumab versus chemotherapy alone. The median OS was 50.6 months in the surgery group and 64.7 months in the no-surgery group (P = .08), suggesting no survival benefit to secondary cytoreduction; however, an ad hoc exploratory analysis of the surgery arm showed that both overall and progression-free survival were significantly improved in the complete cytoreduction group, compared with those with residual disease at time of surgery.

The results from the GOG-213 group suggested that improved survival from secondary debulking might be achieved when prognostic modeling is used to select optimal surgical candidates. The SOC-1 trial, published in 2021, was a phase 3, randomized, controlled trial that used the iMODEL scoring system combined with PET/CT imaging for patient selection.⁸ Patients were again randomized to surgery followed by platinum-based chemotherapy versus chemotherapy alone. Complete cytoreduction was achieved in 73% of patients with a low iMODEL score, and these data showed improved OS in the surgery group of 58.1 months versus 53.9 months (P < .05) in the no-surgery group. Lastly, the DESKTOP group most recently published results on this topic in a large randomized, controlled trial.⁹ Patients were again randomized to surgery followed by platinum-based chemotherapy versus chemotherapy alone. Inclusion criteria were only met in patients with a positive AGO score. An improved OS of 7.7 months (53.7 vs. 46 months; P < .05) was demonstrated in patients that underwent surgery versus those exposed to only chemotherapy. Again, this group showed that overall survival was further improved when complete cytoreduction was achieved.

Given the results of these three trials, the Society for Gynecologic Oncology has released a statement on secondary cytoreduction in recurrent ovarian cancer (see Table).¹⁰ While it is important to use caution when comparing the three studies as study populations differed substantially, the most important takeaway the difference in survival outcomes in patients in whom complete gross resection was achieved versus no complete gross resection versus no surgery. This comparison highlights the benefit of complete cytoreduction as well as the potential harms of secondary debulking when an R0 resection cannot be achieved. Although not yet evaluated in this clinical setting, laparoscopic exploration may be useful to augment assessment of disease extent and possibility of disease resection, just as it is in frontline ovarian cancer surgery.

The importance of bevacizumab use in recurrent ovarian cancer is also highlighted in the SGO statement. In GOG-213, 84% of the total study population (in both the surgery and no surgery cohort) were treated with concurrent followed by maintenance bevacizumab with an improved survival outcome, which may suggest that this trial generalizes better than the others to contemporary management of platinum-sensitive recurrent ovarian cancer.

Overall, given the mixed data, the recommendation is for surgeons to consider all available data to guide them in treatment planning with a strong emphasis on using all available technology to assess whether complete cytoreduction can be achieved in the setting of recurrence so as to not delay the patient’s ability to receive chemotherapy.

Dr. John is a gynecologic oncology fellow at the University of North Carolina at Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the university.

References

1. du Bois A et al. J Natl Cancer Inst. 2003;95:1320-9.

2. Wagner U et al. Br J Cancer. 2012;107:588-91.

3. Vergote I et al. N Engl J Med. 2010;363:943-53.

4. Harter P et al. Ann Surg Oncol. 2006;13:1702-10.

5. Harter P et al. Int J Gynecol Cancer. 2011;21:289-95.

6. Chi DS et al. Cancer. 2006 106:1933-9.

7. Coleman RL et al. Lancet Oncol. 2017;18:779-1.

8. Shi T et al. Lancet Oncol. 2021;22:439-49.

9. Harter P et al. N Engl J Med 2021;385:2123-31.

10. Harrison R, et al. Gynecol Oncol. 2021;163:448-52.