The effectiveness and safety of advanced therapies for psoriatic arthritis (PsA) was a focus of many published studies last month. Janus kinase inhibitors (JAKi) are a recent class of drugs made available to treat PsA and related diseases, and several clinical trials have been published. Sarabia and colleagues reported the results of a meta-analysis of 15 randomized controlled trials including 6757 patients with psoriasis or PsA who received treatment with a JAKi or placebo. Their analyses revealed that treatment with JAKi vs placebo was associated with higher odds of achieving American College of Rheumatology 20 (ACR20) response (odds ratio [OR] 4.45; 95% CI 3.64-5.44), with similar outcomes observed with tofacitinib vs placebo (OR 2.96; 95% CI 2.01-4.35) and non-tofacitinib JAKi vs placebo (OR 5.41; 95% CI 3.95-7.40). Serious adverse event rates were low (1%-7% in the maximum-dose intervention group).

Interleukin-23i (guselkumab, tildrakizumab, or risankizumab) are another class of biologics recently approved for the treatment of PsA. Preliminary results from a real-world study demonstrate the efficacy of these drugs for PsA. In a retrospective observational study including 80 patients with psoriasis (22 with PsA) who received guselkumab, tildrakizumab, or risankizumab, Elgaard and colleagues demonstrated that 40.9% or 36.4% of the PsA patients achieved complete or partial remission, respectively, compared with only 18.2% of patients with no improvement.

Regarding drug safety, a recent study demonstrated low rates of opportunistic infections with biologic disease-modifying antirheumatic drugs (bDMARD) and targeted synthetic DMARD (tsDMARD). Vassilopoulos and colleagues conducted a meta-analysis of 47 randomized controlled trials and 26 follow-up extension studies that included patients with PsA who received at least one dose of a bDMARD or a tsDMARD (n = 11,790) or placebo (n = 6425) during the placebo-controlled period, and 17,197 patients who received at least one dose of a bDMARD or a tsDMARD in the long-term extension period.

The cumulative incidence of opportunistic infections was < 3% when stratified by the mechanism of action: JAKi (2.72%; 95% CI 1.05%-5.04%), anti-interleukin (IL)-17i (1.18%; 95% CI 0.60%-1.90%), anti-IL-23i (0.24%; 95% CI 0.04%-0.54%), and TNFi (0.01%; 95% CI 0.00%-0.21%). These results are consistent with my own observations in my clinic. Thus, currently available advanced therapies, including JAKi and IL-23i, are effective and safe for the management of patients with PsA when used as monotherapy with or without conventional synthetic DMARD (csDMARD). Ongoing studies on combination therapy will provide us with guidance on the efficacy and safety of combining these drugs for the treatment of resistant disease.

Many patients do not respond to treatment, however. Actionable risk factors for lack of response are of clinical interest. One such factor is obesity. In an observational study of 774 adult PsA patients who started their first b/tsDMARD, Vallejo-Yague and colleagues reported that the odds of achieving minimal disease activity (adjusted OR [aOR] 0.45; 95% CI 0.24-0.82) and Disease Activity Index for Psoriatic Arthritis (DAPSA)-remission (aOR 0.42; 95% CI 0.21-0.85) were lower in the obese vs normal-weight group within the first year. Thus, obese patients had ~50% lower likelihood of achieving a state of low disease activity. Comprehensive management of PsA must include management of obesity and other comorbid conditions to achieve optimal outcomes.

Finally, an interesting study by Freuer and colleagues used bidirectional two-sample Mendelian randomization in 12,882 patients with inflammatory bowel disease (IBD), 21,770 matched controls, 5621 patients with psoriasis, 2063 patients with PsA, and 252,323 controls. The study found that genetically predicted IBD was associated with a higher risk for PsA (pooled OR 1.11; P = .003) with the risk being majorly mediated by Crohn's disease (OR 1.12; P = .002) and not ulcerative colitis (P = .70). Thus, patients with Crohn's disease need to be carefully evaluated for the development of PsA.

The effectiveness and safety of advanced therapies for psoriatic arthritis (PsA) was a focus of many published studies last month. Janus kinase inhibitors (JAKi) are a recent class of drugs made available to treat PsA and related diseases, and several clinical trials have been published. Sarabia and colleagues reported the results of a meta-analysis of 15 randomized controlled trials including 6757 patients with psoriasis or PsA who received treatment with a JAKi or placebo. Their analyses revealed that treatment with JAKi vs placebo was associated with higher odds of achieving American College of Rheumatology 20 (ACR20) response (odds ratio [OR] 4.45; 95% CI 3.64-5.44), with similar outcomes observed with tofacitinib vs placebo (OR 2.96; 95% CI 2.01-4.35) and non-tofacitinib JAKi vs placebo (OR 5.41; 95% CI 3.95-7.40). Serious adverse event rates were low (1%-7% in the maximum-dose intervention group).

Interleukin-23i (guselkumab, tildrakizumab, or risankizumab) are another class of biologics recently approved for the treatment of PsA. Preliminary results from a real-world study demonstrate the efficacy of these drugs for PsA. In a retrospective observational study including 80 patients with psoriasis (22 with PsA) who received guselkumab, tildrakizumab, or risankizumab, Elgaard and colleagues demonstrated that 40.9% or 36.4% of the PsA patients achieved complete or partial remission, respectively, compared with only 18.2% of patients with no improvement.

Regarding drug safety, a recent study demonstrated low rates of opportunistic infections with biologic disease-modifying antirheumatic drugs (bDMARD) and targeted synthetic DMARD (tsDMARD). Vassilopoulos and colleagues conducted a meta-analysis of 47 randomized controlled trials and 26 follow-up extension studies that included patients with PsA who received at least one dose of a bDMARD or a tsDMARD (n = 11,790) or placebo (n = 6425) during the placebo-controlled period, and 17,197 patients who received at least one dose of a bDMARD or a tsDMARD in the long-term extension period.

The cumulative incidence of opportunistic infections was < 3% when stratified by the mechanism of action: JAKi (2.72%; 95% CI 1.05%-5.04%), anti-interleukin (IL)-17i (1.18%; 95% CI 0.60%-1.90%), anti-IL-23i (0.24%; 95% CI 0.04%-0.54%), and TNFi (0.01%; 95% CI 0.00%-0.21%). These results are consistent with my own observations in my clinic. Thus, currently available advanced therapies, including JAKi and IL-23i, are effective and safe for the management of patients with PsA when used as monotherapy with or without conventional synthetic DMARD (csDMARD). Ongoing studies on combination therapy will provide us with guidance on the efficacy and safety of combining these drugs for the treatment of resistant disease.

Many patients do not respond to treatment, however. Actionable risk factors for lack of response are of clinical interest. One such factor is obesity. In an observational study of 774 adult PsA patients who started their first b/tsDMARD, Vallejo-Yague and colleagues reported that the odds of achieving minimal disease activity (adjusted OR [aOR] 0.45; 95% CI 0.24-0.82) and Disease Activity Index for Psoriatic Arthritis (DAPSA)-remission (aOR 0.42; 95% CI 0.21-0.85) were lower in the obese vs normal-weight group within the first year. Thus, obese patients had ~50% lower likelihood of achieving a state of low disease activity. Comprehensive management of PsA must include management of obesity and other comorbid conditions to achieve optimal outcomes.

Finally, an interesting study by Freuer and colleagues used bidirectional two-sample Mendelian randomization in 12,882 patients with inflammatory bowel disease (IBD), 21,770 matched controls, 5621 patients with psoriasis, 2063 patients with PsA, and 252,323 controls. The study found that genetically predicted IBD was associated with a higher risk for PsA (pooled OR 1.11; P = .003) with the risk being majorly mediated by Crohn's disease (OR 1.12; P = .002) and not ulcerative colitis (P = .70). Thus, patients with Crohn's disease need to be carefully evaluated for the development of PsA.

The effectiveness and safety of advanced therapies for psoriatic arthritis (PsA) was a focus of many published studies last month. Janus kinase inhibitors (JAKi) are a recent class of drugs made available to treat PsA and related diseases, and several clinical trials have been published. Sarabia and colleagues reported the results of a meta-analysis of 15 randomized controlled trials including 6757 patients with psoriasis or PsA who received treatment with a JAKi or placebo. Their analyses revealed that treatment with JAKi vs placebo was associated with higher odds of achieving American College of Rheumatology 20 (ACR20) response (odds ratio [OR] 4.45; 95% CI 3.64-5.44), with similar outcomes observed with tofacitinib vs placebo (OR 2.96; 95% CI 2.01-4.35) and non-tofacitinib JAKi vs placebo (OR 5.41; 95% CI 3.95-7.40). Serious adverse event rates were low (1%-7% in the maximum-dose intervention group).

Interleukin-23i (guselkumab, tildrakizumab, or risankizumab) are another class of biologics recently approved for the treatment of PsA. Preliminary results from a real-world study demonstrate the efficacy of these drugs for PsA. In a retrospective observational study including 80 patients with psoriasis (22 with PsA) who received guselkumab, tildrakizumab, or risankizumab, Elgaard and colleagues demonstrated that 40.9% or 36.4% of the PsA patients achieved complete or partial remission, respectively, compared with only 18.2% of patients with no improvement.

Regarding drug safety, a recent study demonstrated low rates of opportunistic infections with biologic disease-modifying antirheumatic drugs (bDMARD) and targeted synthetic DMARD (tsDMARD). Vassilopoulos and colleagues conducted a meta-analysis of 47 randomized controlled trials and 26 follow-up extension studies that included patients with PsA who received at least one dose of a bDMARD or a tsDMARD (n = 11,790) or placebo (n = 6425) during the placebo-controlled period, and 17,197 patients who received at least one dose of a bDMARD or a tsDMARD in the long-term extension period.

The cumulative incidence of opportunistic infections was < 3% when stratified by the mechanism of action: JAKi (2.72%; 95% CI 1.05%-5.04%), anti-interleukin (IL)-17i (1.18%; 95% CI 0.60%-1.90%), anti-IL-23i (0.24%; 95% CI 0.04%-0.54%), and TNFi (0.01%; 95% CI 0.00%-0.21%). These results are consistent with my own observations in my clinic. Thus, currently available advanced therapies, including JAKi and IL-23i, are effective and safe for the management of patients with PsA when used as monotherapy with or without conventional synthetic DMARD (csDMARD). Ongoing studies on combination therapy will provide us with guidance on the efficacy and safety of combining these drugs for the treatment of resistant disease.

Many patients do not respond to treatment, however. Actionable risk factors for lack of response are of clinical interest. One such factor is obesity. In an observational study of 774 adult PsA patients who started their first b/tsDMARD, Vallejo-Yague and colleagues reported that the odds of achieving minimal disease activity (adjusted OR [aOR] 0.45; 95% CI 0.24-0.82) and Disease Activity Index for Psoriatic Arthritis (DAPSA)-remission (aOR 0.42; 95% CI 0.21-0.85) were lower in the obese vs normal-weight group within the first year. Thus, obese patients had ~50% lower likelihood of achieving a state of low disease activity. Comprehensive management of PsA must include management of obesity and other comorbid conditions to achieve optimal outcomes.

Finally, an interesting study by Freuer and colleagues used bidirectional two-sample Mendelian randomization in 12,882 patients with inflammatory bowel disease (IBD), 21,770 matched controls, 5621 patients with psoriasis, 2063 patients with PsA, and 252,323 controls. The study found that genetically predicted IBD was associated with a higher risk for PsA (pooled OR 1.11; P = .003) with the risk being majorly mediated by Crohn's disease (OR 1.12; P = .002) and not ulcerative colitis (P = .70). Thus, patients with Crohn's disease need to be carefully evaluated for the development of PsA.

Agents proven to reduce major kidney issues in type 2 diabetes include renin-angiotensin system blockers, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid inhibitors, but there are few data on the renal effects of the glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide. In a post-hoc analysis of the SURPASS-4 trial, Heerspink and colleagues reported that tirzepatide slowed the rate of estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (ACR) compared with insulin glargine U100. There was also a reduction (≥ 40% decline) in the composite kidney outcome of eGFR, end-stage kidney disease (ESKD), death due to kidney failure, and new-onset macroalbuminuria, and this was driven by the reduction in new-onset macroalbuminuria. Although this was a post-hoc, exploratory analysis, the benefit of tirzepatide on kidney effects suggests that this agent should be studied in type 2 diabetes patients at high risk for kidney disease progression to determine whether indeed there will be a kidney protective effect.

Diabetes is the leading cause of ESKD, and recognizing patients at high risk for progression to ESKD is paramount. Abnormal glycolipid metabolism contributes to the development and progression of diabetic kidney disease (DKD). Bile acids, by regulating glycolipid metabolism, may indirectly provide renoprotective effects. Xiao and colleagues have published a retrospective cohort study of 184 Chinese patients with type 2 diabetes and biopsy-proven DKD. They found that low levels of bile acids (≤2.8 mmol/L) were associated with an over fivefold risk for ESKD after adjusting for known factors associated with ESKD. This is the first study suggesting a link between low bile acid levels and adverse kidney outcomes in DKD, and it provides a rationale for studying bile acid analogs as therapeutic agents for the treatment of DKD.

SGLT2 inhibitors and GLP-1 receptor agonists have proven cardiorenal benefits in type 2 diabetes, and each is recommended in guidelines for patients at higher risk for cardiorenal complications. There are no head-to-head randomized trials of SGLT2 inhibitors vs GLP-1 receptor agonists, and studies suggesting an increased risk for lower-extremity amputation with SGLT2 inhibitors have shown inconsistent results. Lee and colleagues conducted a retrospective cohort study in Taiwan, and, after propensity score-matching patients with type 2 diabetes treated with SGLT inhibitors or GLP-1 receptor agonists, they found no significant difference in major adverse limb events between the two groups. Although limited by retrospective design, short follow-up, and a low number of events, this study suggests that SGLT2 inhibitors and GLP-1 receptor agonists should continue to be used as indicated and according to diabetes guidelines, with no difference in amputation rates between these two classes of antihyperglycemic agents.

Gastrointestinal adverse events are the most common side effects related to metformin use. Many clinicians choose an extended-release metformin preparation over immediate-release, believing that there may be better tolerability, but studies have shown inconsistent results. In a systematic review, meta-analysis, and meta-regression of randomized controlled trials, Nabrdalik and colleagues demonstrated an increased risk for abdominal pain, nausea, and diarrhea with metformin compared with other antidiabetic drugs or placebo, as well as a reduced risk for bloating and diarrhea with extended-release metformin compared with immediate-release formulations. These findings reinforce the practice for considering metformin extended-release over immediate-release formulations to reduce the chance of gastrointestinal side effects.

Agents proven to reduce major kidney issues in type 2 diabetes include renin-angiotensin system blockers, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid inhibitors, but there are few data on the renal effects of the glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide. In a post-hoc analysis of the SURPASS-4 trial, Heerspink and colleagues reported that tirzepatide slowed the rate of estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (ACR) compared with insulin glargine U100. There was also a reduction (≥ 40% decline) in the composite kidney outcome of eGFR, end-stage kidney disease (ESKD), death due to kidney failure, and new-onset macroalbuminuria, and this was driven by the reduction in new-onset macroalbuminuria. Although this was a post-hoc, exploratory analysis, the benefit of tirzepatide on kidney effects suggests that this agent should be studied in type 2 diabetes patients at high risk for kidney disease progression to determine whether indeed there will be a kidney protective effect.

Diabetes is the leading cause of ESKD, and recognizing patients at high risk for progression to ESKD is paramount. Abnormal glycolipid metabolism contributes to the development and progression of diabetic kidney disease (DKD). Bile acids, by regulating glycolipid metabolism, may indirectly provide renoprotective effects. Xiao and colleagues have published a retrospective cohort study of 184 Chinese patients with type 2 diabetes and biopsy-proven DKD. They found that low levels of bile acids (≤2.8 mmol/L) were associated with an over fivefold risk for ESKD after adjusting for known factors associated with ESKD. This is the first study suggesting a link between low bile acid levels and adverse kidney outcomes in DKD, and it provides a rationale for studying bile acid analogs as therapeutic agents for the treatment of DKD.

SGLT2 inhibitors and GLP-1 receptor agonists have proven cardiorenal benefits in type 2 diabetes, and each is recommended in guidelines for patients at higher risk for cardiorenal complications. There are no head-to-head randomized trials of SGLT2 inhibitors vs GLP-1 receptor agonists, and studies suggesting an increased risk for lower-extremity amputation with SGLT2 inhibitors have shown inconsistent results. Lee and colleagues conducted a retrospective cohort study in Taiwan, and, after propensity score-matching patients with type 2 diabetes treated with SGLT inhibitors or GLP-1 receptor agonists, they found no significant difference in major adverse limb events between the two groups. Although limited by retrospective design, short follow-up, and a low number of events, this study suggests that SGLT2 inhibitors and GLP-1 receptor agonists should continue to be used as indicated and according to diabetes guidelines, with no difference in amputation rates between these two classes of antihyperglycemic agents.

Gastrointestinal adverse events are the most common side effects related to metformin use. Many clinicians choose an extended-release metformin preparation over immediate-release, believing that there may be better tolerability, but studies have shown inconsistent results. In a systematic review, meta-analysis, and meta-regression of randomized controlled trials, Nabrdalik and colleagues demonstrated an increased risk for abdominal pain, nausea, and diarrhea with metformin compared with other antidiabetic drugs or placebo, as well as a reduced risk for bloating and diarrhea with extended-release metformin compared with immediate-release formulations. These findings reinforce the practice for considering metformin extended-release over immediate-release formulations to reduce the chance of gastrointestinal side effects.

Agents proven to reduce major kidney issues in type 2 diabetes include renin-angiotensin system blockers, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid inhibitors, but there are few data on the renal effects of the glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide. In a post-hoc analysis of the SURPASS-4 trial, Heerspink and colleagues reported that tirzepatide slowed the rate of estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (ACR) compared with insulin glargine U100. There was also a reduction (≥ 40% decline) in the composite kidney outcome of eGFR, end-stage kidney disease (ESKD), death due to kidney failure, and new-onset macroalbuminuria, and this was driven by the reduction in new-onset macroalbuminuria. Although this was a post-hoc, exploratory analysis, the benefit of tirzepatide on kidney effects suggests that this agent should be studied in type 2 diabetes patients at high risk for kidney disease progression to determine whether indeed there will be a kidney protective effect.

Diabetes is the leading cause of ESKD, and recognizing patients at high risk for progression to ESKD is paramount. Abnormal glycolipid metabolism contributes to the development and progression of diabetic kidney disease (DKD). Bile acids, by regulating glycolipid metabolism, may indirectly provide renoprotective effects. Xiao and colleagues have published a retrospective cohort study of 184 Chinese patients with type 2 diabetes and biopsy-proven DKD. They found that low levels of bile acids (≤2.8 mmol/L) were associated with an over fivefold risk for ESKD after adjusting for known factors associated with ESKD. This is the first study suggesting a link between low bile acid levels and adverse kidney outcomes in DKD, and it provides a rationale for studying bile acid analogs as therapeutic agents for the treatment of DKD.

SGLT2 inhibitors and GLP-1 receptor agonists have proven cardiorenal benefits in type 2 diabetes, and each is recommended in guidelines for patients at higher risk for cardiorenal complications. There are no head-to-head randomized trials of SGLT2 inhibitors vs GLP-1 receptor agonists, and studies suggesting an increased risk for lower-extremity amputation with SGLT2 inhibitors have shown inconsistent results. Lee and colleagues conducted a retrospective cohort study in Taiwan, and, after propensity score-matching patients with type 2 diabetes treated with SGLT inhibitors or GLP-1 receptor agonists, they found no significant difference in major adverse limb events between the two groups. Although limited by retrospective design, short follow-up, and a low number of events, this study suggests that SGLT2 inhibitors and GLP-1 receptor agonists should continue to be used as indicated and according to diabetes guidelines, with no difference in amputation rates between these two classes of antihyperglycemic agents.

Gastrointestinal adverse events are the most common side effects related to metformin use. Many clinicians choose an extended-release metformin preparation over immediate-release, believing that there may be better tolerability, but studies have shown inconsistent results. In a systematic review, meta-analysis, and meta-regression of randomized controlled trials, Nabrdalik and colleagues demonstrated an increased risk for abdominal pain, nausea, and diarrhea with metformin compared with other antidiabetic drugs or placebo, as well as a reduced risk for bloating and diarrhea with extended-release metformin compared with immediate-release formulations. These findings reinforce the practice for considering metformin extended-release over immediate-release formulations to reduce the chance of gastrointestinal side effects.

Richards and colleagues explored the effects of aspirin prophylaxis in women with chronic hypertension. They did not detect a lowered risk for preeclampsia but did note a significantly decreased risk for preterm birth in the aspirin group. This was a systematic review and meta-analysis of nine studies (including retrospective cohort and randomized controlled trials). The mixed quality of the source data did limit the meta-analysis. However, this finding suggests that further research is warranted, and we may have a new role for aspirin in helping to decrease preterm birth in women with chronic hypertension.

Cleary and colleagues investigated the use of 30 mg oral nifedipine ER given every 24 hours until delivery in patients with preE with SF. In this randomized, triple-blinded, placebo-controlled trial, 110 patients were randomly assigned to nifedipine treatment or placebo. The results suggest a role for this medication early in the treatment of preE with SF, as the treated patients were much less likely to require acute therapy for severe-range blood pressure. The researchers also noted a trend toward fewer cesarean deliveries (20.8% vs 34.7%) and lower neonatal intensive care unit admissions (29.1% vs 47.1%) in the nifedipine ER group. This favors the use of nifedipine ER in patients with preE with SF.

Stewart and colleagues examined the more common morbidities associated with MTOP after 20 weeks estimated gestational age using a 10-year retrospective cohort study involving 407 patients. They found that 99% of the women had a successful vaginal delivery; however, 25% had some morbidity. Additionally, 16% of the women needed manual removal of placental tissue, 11% had postpartum hemorrhage, and 1.3% experienced severe maternal morbidity (including amniotic fluid embolism), but no maternal deaths occurred. Increased surveillance for postpartum hemorrhage in this patient population should be considered.

Righini and colleagues provide reassurance regarding a commonly used test to rule out pulmonary embolism in pregnant women. They present ancillary data from a prospective management outcome study of 149 women who underwent CT pulmonary angiography testing in pregnancy. There have been concerns raised regarding potential harmful effects related to intravenous iodinated contrast agents on thyroid function. None of the infants born to these patients had evidence of neonatal hypothyroidism (assessed via thyroid-stimulating hormone measurements). This gives reassurance that the use of CT pulmonary angiography testing for pulmonary embolism in pregnancy is safe.

Richards and colleagues explored the effects of aspirin prophylaxis in women with chronic hypertension. They did not detect a lowered risk for preeclampsia but did note a significantly decreased risk for preterm birth in the aspirin group. This was a systematic review and meta-analysis of nine studies (including retrospective cohort and randomized controlled trials). The mixed quality of the source data did limit the meta-analysis. However, this finding suggests that further research is warranted, and we may have a new role for aspirin in helping to decrease preterm birth in women with chronic hypertension.

Cleary and colleagues investigated the use of 30 mg oral nifedipine ER given every 24 hours until delivery in patients with preE with SF. In this randomized, triple-blinded, placebo-controlled trial, 110 patients were randomly assigned to nifedipine treatment or placebo. The results suggest a role for this medication early in the treatment of preE with SF, as the treated patients were much less likely to require acute therapy for severe-range blood pressure. The researchers also noted a trend toward fewer cesarean deliveries (20.8% vs 34.7%) and lower neonatal intensive care unit admissions (29.1% vs 47.1%) in the nifedipine ER group. This favors the use of nifedipine ER in patients with preE with SF.

Stewart and colleagues examined the more common morbidities associated with MTOP after 20 weeks estimated gestational age using a 10-year retrospective cohort study involving 407 patients. They found that 99% of the women had a successful vaginal delivery; however, 25% had some morbidity. Additionally, 16% of the women needed manual removal of placental tissue, 11% had postpartum hemorrhage, and 1.3% experienced severe maternal morbidity (including amniotic fluid embolism), but no maternal deaths occurred. Increased surveillance for postpartum hemorrhage in this patient population should be considered.

Righini and colleagues provide reassurance regarding a commonly used test to rule out pulmonary embolism in pregnant women. They present ancillary data from a prospective management outcome study of 149 women who underwent CT pulmonary angiography testing in pregnancy. There have been concerns raised regarding potential harmful effects related to intravenous iodinated contrast agents on thyroid function. None of the infants born to these patients had evidence of neonatal hypothyroidism (assessed via thyroid-stimulating hormone measurements). This gives reassurance that the use of CT pulmonary angiography testing for pulmonary embolism in pregnancy is safe.

Richards and colleagues explored the effects of aspirin prophylaxis in women with chronic hypertension. They did not detect a lowered risk for preeclampsia but did note a significantly decreased risk for preterm birth in the aspirin group. This was a systematic review and meta-analysis of nine studies (including retrospective cohort and randomized controlled trials). The mixed quality of the source data did limit the meta-analysis. However, this finding suggests that further research is warranted, and we may have a new role for aspirin in helping to decrease preterm birth in women with chronic hypertension.

Cleary and colleagues investigated the use of 30 mg oral nifedipine ER given every 24 hours until delivery in patients with preE with SF. In this randomized, triple-blinded, placebo-controlled trial, 110 patients were randomly assigned to nifedipine treatment or placebo. The results suggest a role for this medication early in the treatment of preE with SF, as the treated patients were much less likely to require acute therapy for severe-range blood pressure. The researchers also noted a trend toward fewer cesarean deliveries (20.8% vs 34.7%) and lower neonatal intensive care unit admissions (29.1% vs 47.1%) in the nifedipine ER group. This favors the use of nifedipine ER in patients with preE with SF.

Stewart and colleagues examined the more common morbidities associated with MTOP after 20 weeks estimated gestational age using a 10-year retrospective cohort study involving 407 patients. They found that 99% of the women had a successful vaginal delivery; however, 25% had some morbidity. Additionally, 16% of the women needed manual removal of placental tissue, 11% had postpartum hemorrhage, and 1.3% experienced severe maternal morbidity (including amniotic fluid embolism), but no maternal deaths occurred. Increased surveillance for postpartum hemorrhage in this patient population should be considered.

Righini and colleagues provide reassurance regarding a commonly used test to rule out pulmonary embolism in pregnant women. They present ancillary data from a prospective management outcome study of 149 women who underwent CT pulmonary angiography testing in pregnancy. There have been concerns raised regarding potential harmful effects related to intravenous iodinated contrast agents on thyroid function. None of the infants born to these patients had evidence of neonatal hypothyroidism (assessed via thyroid-stimulating hormone measurements). This gives reassurance that the use of CT pulmonary angiography testing for pulmonary embolism in pregnancy is safe.

A total of 126 patients were included in the full analysis set; median progression-free survival (PFS) was 18.8 months, overall response rate was 64.3%, and the safety profile was similar to prior studies. The median PFS in this observational study was comparable to a median PFS of 16.9 months in the CLEOPTRA study among 88 patients with prior (neo)adjuvant trastuzumab. HELENA also demonstrated similar PFS results for the hormone receptor (HR)-negative and HR-positive (HR+) subgroups (19.4 months vs 18.2 months), as well as for patients with nonvisceral and visceral metastases (20.5 months vs 18.0 months). These findings provide further support for use of the THP regimen as first-line treatment in the real-world setting for patients with HER2+ MBC and prior receipt of trastuzumab.

Adjuvant endocrine therapy (ET) is associated with a survival benefit for early-stage HR+ breast cancer; however, the absolute degree of benefit depends on various clinicopathologic features.² Although it generally has a manageable toxicity profile, some side effects carry more significant consequences (thromboembolism, endometrial carcinoma, osteoporosis), and some of the more common ones can affect routine quality of life (hot flashes, vaginal dryness, arthralgia).

A retrospective observational study including 5545 patients with pT1a-b estrogen receptor-positive (ER+) breast cancer demonstrated improvements in disease-free survival (DFS) and recurrence-free survival (RFS) among those who received ET vs those who did not receive ET after 5 and 7 years of follow-up (DFS: increases of 2.5% and 3.3%; RFS: increases of 1.9% and 4.3%) (Houvenaeghel et al). Among all patients, absence of ET was associated with decreased DFS (hazard ratio [HR] 1.275; P = .047) but no difference in RFS or OS. Patients with pT1a-b ER+ grade 2-3 tumors (n = 2363) experienced decreased DFS (HR 1.502, P = .049) without ET; however, those with pT1a-b ER+ grade 1 tumors did not experience a negative effect on DFS without ET.

These results provide further support for the survival improvements seen with adjuvant ET — although the relative benefit may be fairly modest — and that ET omission is a relevant consideration in patients with comorbidities or tolerance issues, particularly those with pT1a-b grade 1 tumors.

Advancements in breast cancer therapies have led to improvements in survival outcomes, and it is therefore increasingly essential to recognize risks for other cancer types in breast cancer survivors. Male breast cancer is rare, and although clinical management for the most part mirrors that of female breast cancer, it is important to be aware of potential differences in this population, including risks for subsequent non-breast primary cancers.³

A meta-analysis including eight retrospective cohort studies with male breast cancer survivors reported the standardized incidence ratio (SIR), which compares the incidence of non-breast second primary cancers (SPC) among men with first primary breast cancer vs the expected incidence of non-breast primary cancers in the general male population. The summary SIR estimate was 1.27 (95% CI 1.03-1.56), with increased risk for certain SPCs: colorectal (SIR 1.29; 95% CI 1.03-1.61), pancreatic (SIR 1.64; 95% CI 1.05-2.55), and thyroid (SIR 5.58; 95% CI 1.04-30.05) (Allen et al). Additionally, men diagnosed with breast cancer before 50 years of age were observed to have increased SPC risk compared with men who were older than 50 years at breast cancer onset (SIR 1.50 vs 1.14; P = .040).

This study highlights the importance of genetic assessment for men diagnosed with breast cancer, so they can be appropriately counseled on subsequent cancer risk. It also stimulates thinking regarding other potential contributing factors to the observed increased SPC risk among male breast cancer survivors, including the effect of various treatments, hormonal influences, and significant family history.

Studies have shown that older women derive a survival benefit with adjuvant chemotherapy; however, they may be at increased risk of experiencing toxicities owing to physical functioning and comorbidities.⁴ A comprehensive geriatric assessment is key, and it is also beneficial for identifying which patients have a higher likelihood of clinical decline after chemotherapy.

A prospective study including 295 robust women age ≥ 65 years with stage I-III breast cancer treated with chemotherapy showed that 26% had a chemotherapy-induced decline in frailty status; patients with high interleukin-6 (IL-6) and C-reactive protein (CRP) inflammatory markers before chemotherapy had a more than threefold odds of experiencing a chemotherapy-induced decline in frailty compared with those with low IL-6 and CRP (odds ratio 3.52; 95% CI 1.55-8.01; P = .003) (Ji et al).

These findings support the relationship between inflammation, aging, and chemotherapy-induced functional decline. Further research is warranted to identify whether there are specific drugs that are implicated, methods to enhance anti-inflammatory effects, and any downstream effect on breast cancer outcomes of these patients.

Additional References

1. Swain SM, Miles D, Kim SB, et al; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): End-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519-530. Doi: 10.1016/S1470-2045(19)30863-0
2. Ma SJ, Oladeru OT, Singh AK. Association of endocrine therapy with overall survival in women with small, hormone receptor-positive, ERBB2-negative breast cancer. JAMA Netw Open. 2020;3:e2013973. Doi: 10.1001/jamanetworkopen.2020.13973
3. Pritzlaff M, Summerour P, McFarland R, et al. Male breast cancer in a multi-gene panel testing cohort: Insights and unexpected results. Breast Cancer Res Treat. 2017;161:575-586. Doi: 10.1007/s10549-016-4085-4
4. Tamirisa N, Lin H, Shen Y, et al. Association of chemotherapy with survival in elderly patients with multiple comorbidities and estrogen receptor-positive, node-positive breast cancer. JAMA Oncol. 2020;6:1548-155 Doi: 10.1001/jamaoncol.2020.2388

A total of 126 patients were included in the full analysis set; median progression-free survival (PFS) was 18.8 months, overall response rate was 64.3%, and the safety profile was similar to prior studies. The median PFS in this observational study was comparable to a median PFS of 16.9 months in the CLEOPTRA study among 88 patients with prior (neo)adjuvant trastuzumab. HELENA also demonstrated similar PFS results for the hormone receptor (HR)-negative and HR-positive (HR+) subgroups (19.4 months vs 18.2 months), as well as for patients with nonvisceral and visceral metastases (20.5 months vs 18.0 months). These findings provide further support for use of the THP regimen as first-line treatment in the real-world setting for patients with HER2+ MBC and prior receipt of trastuzumab.

Adjuvant endocrine therapy (ET) is associated with a survival benefit for early-stage HR+ breast cancer; however, the absolute degree of benefit depends on various clinicopathologic features.² Although it generally has a manageable toxicity profile, some side effects carry more significant consequences (thromboembolism, endometrial carcinoma, osteoporosis), and some of the more common ones can affect routine quality of life (hot flashes, vaginal dryness, arthralgia).

A retrospective observational study including 5545 patients with pT1a-b estrogen receptor-positive (ER+) breast cancer demonstrated improvements in disease-free survival (DFS) and recurrence-free survival (RFS) among those who received ET vs those who did not receive ET after 5 and 7 years of follow-up (DFS: increases of 2.5% and 3.3%; RFS: increases of 1.9% and 4.3%) (Houvenaeghel et al). Among all patients, absence of ET was associated with decreased DFS (hazard ratio [HR] 1.275; P = .047) but no difference in RFS or OS. Patients with pT1a-b ER+ grade 2-3 tumors (n = 2363) experienced decreased DFS (HR 1.502, P = .049) without ET; however, those with pT1a-b ER+ grade 1 tumors did not experience a negative effect on DFS without ET.

These results provide further support for the survival improvements seen with adjuvant ET — although the relative benefit may be fairly modest — and that ET omission is a relevant consideration in patients with comorbidities or tolerance issues, particularly those with pT1a-b grade 1 tumors.

Advancements in breast cancer therapies have led to improvements in survival outcomes, and it is therefore increasingly essential to recognize risks for other cancer types in breast cancer survivors. Male breast cancer is rare, and although clinical management for the most part mirrors that of female breast cancer, it is important to be aware of potential differences in this population, including risks for subsequent non-breast primary cancers.³

A meta-analysis including eight retrospective cohort studies with male breast cancer survivors reported the standardized incidence ratio (SIR), which compares the incidence of non-breast second primary cancers (SPC) among men with first primary breast cancer vs the expected incidence of non-breast primary cancers in the general male population. The summary SIR estimate was 1.27 (95% CI 1.03-1.56), with increased risk for certain SPCs: colorectal (SIR 1.29; 95% CI 1.03-1.61), pancreatic (SIR 1.64; 95% CI 1.05-2.55), and thyroid (SIR 5.58; 95% CI 1.04-30.05) (Allen et al). Additionally, men diagnosed with breast cancer before 50 years of age were observed to have increased SPC risk compared with men who were older than 50 years at breast cancer onset (SIR 1.50 vs 1.14; P = .040).

This study highlights the importance of genetic assessment for men diagnosed with breast cancer, so they can be appropriately counseled on subsequent cancer risk. It also stimulates thinking regarding other potential contributing factors to the observed increased SPC risk among male breast cancer survivors, including the effect of various treatments, hormonal influences, and significant family history.

Studies have shown that older women derive a survival benefit with adjuvant chemotherapy; however, they may be at increased risk of experiencing toxicities owing to physical functioning and comorbidities.⁴ A comprehensive geriatric assessment is key, and it is also beneficial for identifying which patients have a higher likelihood of clinical decline after chemotherapy.

A prospective study including 295 robust women age ≥ 65 years with stage I-III breast cancer treated with chemotherapy showed that 26% had a chemotherapy-induced decline in frailty status; patients with high interleukin-6 (IL-6) and C-reactive protein (CRP) inflammatory markers before chemotherapy had a more than threefold odds of experiencing a chemotherapy-induced decline in frailty compared with those with low IL-6 and CRP (odds ratio 3.52; 95% CI 1.55-8.01; P = .003) (Ji et al).

These findings support the relationship between inflammation, aging, and chemotherapy-induced functional decline. Further research is warranted to identify whether there are specific drugs that are implicated, methods to enhance anti-inflammatory effects, and any downstream effect on breast cancer outcomes of these patients.

Additional References

1. Swain SM, Miles D, Kim SB, et al; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): End-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519-530. Doi: 10.1016/S1470-2045(19)30863-0
2. Ma SJ, Oladeru OT, Singh AK. Association of endocrine therapy with overall survival in women with small, hormone receptor-positive, ERBB2-negative breast cancer. JAMA Netw Open. 2020;3:e2013973. Doi: 10.1001/jamanetworkopen.2020.13973
3. Pritzlaff M, Summerour P, McFarland R, et al. Male breast cancer in a multi-gene panel testing cohort: Insights and unexpected results. Breast Cancer Res Treat. 2017;161:575-586. Doi: 10.1007/s10549-016-4085-4
4. Tamirisa N, Lin H, Shen Y, et al. Association of chemotherapy with survival in elderly patients with multiple comorbidities and estrogen receptor-positive, node-positive breast cancer. JAMA Oncol. 2020;6:1548-155 Doi: 10.1001/jamaoncol.2020.2388

A total of 126 patients were included in the full analysis set; median progression-free survival (PFS) was 18.8 months, overall response rate was 64.3%, and the safety profile was similar to prior studies. The median PFS in this observational study was comparable to a median PFS of 16.9 months in the CLEOPTRA study among 88 patients with prior (neo)adjuvant trastuzumab. HELENA also demonstrated similar PFS results for the hormone receptor (HR)-negative and HR-positive (HR+) subgroups (19.4 months vs 18.2 months), as well as for patients with nonvisceral and visceral metastases (20.5 months vs 18.0 months). These findings provide further support for use of the THP regimen as first-line treatment in the real-world setting for patients with HER2+ MBC and prior receipt of trastuzumab.

Adjuvant endocrine therapy (ET) is associated with a survival benefit for early-stage HR+ breast cancer; however, the absolute degree of benefit depends on various clinicopathologic features.² Although it generally has a manageable toxicity profile, some side effects carry more significant consequences (thromboembolism, endometrial carcinoma, osteoporosis), and some of the more common ones can affect routine quality of life (hot flashes, vaginal dryness, arthralgia).

A retrospective observational study including 5545 patients with pT1a-b estrogen receptor-positive (ER+) breast cancer demonstrated improvements in disease-free survival (DFS) and recurrence-free survival (RFS) among those who received ET vs those who did not receive ET after 5 and 7 years of follow-up (DFS: increases of 2.5% and 3.3%; RFS: increases of 1.9% and 4.3%) (Houvenaeghel et al). Among all patients, absence of ET was associated with decreased DFS (hazard ratio [HR] 1.275; P = .047) but no difference in RFS or OS. Patients with pT1a-b ER+ grade 2-3 tumors (n = 2363) experienced decreased DFS (HR 1.502, P = .049) without ET; however, those with pT1a-b ER+ grade 1 tumors did not experience a negative effect on DFS without ET.

These results provide further support for the survival improvements seen with adjuvant ET — although the relative benefit may be fairly modest — and that ET omission is a relevant consideration in patients with comorbidities or tolerance issues, particularly those with pT1a-b grade 1 tumors.

Advancements in breast cancer therapies have led to improvements in survival outcomes, and it is therefore increasingly essential to recognize risks for other cancer types in breast cancer survivors. Male breast cancer is rare, and although clinical management for the most part mirrors that of female breast cancer, it is important to be aware of potential differences in this population, including risks for subsequent non-breast primary cancers.³

A meta-analysis including eight retrospective cohort studies with male breast cancer survivors reported the standardized incidence ratio (SIR), which compares the incidence of non-breast second primary cancers (SPC) among men with first primary breast cancer vs the expected incidence of non-breast primary cancers in the general male population. The summary SIR estimate was 1.27 (95% CI 1.03-1.56), with increased risk for certain SPCs: colorectal (SIR 1.29; 95% CI 1.03-1.61), pancreatic (SIR 1.64; 95% CI 1.05-2.55), and thyroid (SIR 5.58; 95% CI 1.04-30.05) (Allen et al). Additionally, men diagnosed with breast cancer before 50 years of age were observed to have increased SPC risk compared with men who were older than 50 years at breast cancer onset (SIR 1.50 vs 1.14; P = .040).

This study highlights the importance of genetic assessment for men diagnosed with breast cancer, so they can be appropriately counseled on subsequent cancer risk. It also stimulates thinking regarding other potential contributing factors to the observed increased SPC risk among male breast cancer survivors, including the effect of various treatments, hormonal influences, and significant family history.

Studies have shown that older women derive a survival benefit with adjuvant chemotherapy; however, they may be at increased risk of experiencing toxicities owing to physical functioning and comorbidities.⁴ A comprehensive geriatric assessment is key, and it is also beneficial for identifying which patients have a higher likelihood of clinical decline after chemotherapy.

A prospective study including 295 robust women age ≥ 65 years with stage I-III breast cancer treated with chemotherapy showed that 26% had a chemotherapy-induced decline in frailty status; patients with high interleukin-6 (IL-6) and C-reactive protein (CRP) inflammatory markers before chemotherapy had a more than threefold odds of experiencing a chemotherapy-induced decline in frailty compared with those with low IL-6 and CRP (odds ratio 3.52; 95% CI 1.55-8.01; P = .003) (Ji et al).

These findings support the relationship between inflammation, aging, and chemotherapy-induced functional decline. Further research is warranted to identify whether there are specific drugs that are implicated, methods to enhance anti-inflammatory effects, and any downstream effect on breast cancer outcomes of these patients.

Additional References

1. Swain SM, Miles D, Kim SB, et al; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): End-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519-530. Doi: 10.1016/S1470-2045(19)30863-0
2. Ma SJ, Oladeru OT, Singh AK. Association of endocrine therapy with overall survival in women with small, hormone receptor-positive, ERBB2-negative breast cancer. JAMA Netw Open. 2020;3:e2013973. Doi: 10.1001/jamanetworkopen.2020.13973
3. Pritzlaff M, Summerour P, McFarland R, et al. Male breast cancer in a multi-gene panel testing cohort: Insights and unexpected results. Breast Cancer Res Treat. 2017;161:575-586. Doi: 10.1007/s10549-016-4085-4
4. Tamirisa N, Lin H, Shen Y, et al. Association of chemotherapy with survival in elderly patients with multiple comorbidities and estrogen receptor-positive, node-positive breast cancer. JAMA Oncol. 2020;6:1548-155 Doi: 10.1001/jamaoncol.2020.2388

Still, some patients seek alternative or adjunctive treatment approaches, owing to a desire to identify the root cause of disease, their aversion toward Western medicine, or fear of adverse events. Yepes-Nuñez and colleagues performed a systematic review and meta-analysis including 23 studies of benefits and harms of allergen immunotherapy for AD. I had the privilege of participating in this study and can testify to the astronomical amount of work that went into comprehensively identifying all of the relevant studies and synthesizing the data. We found that adjunctive subcutaneous or sublingual allergen immunotherapy, particularly for house dust mites, led to modest but generally delayed improvements of AD severity, itch, and quality of life, and less definitive effects on sleep disturbance and AD flares. Overall, both were well tolerated, though subcutaneous immunotherapy was associated with more adverse events than sublingual immunotherapy. Allergen immunotherapy requires a significant investment of time by patients and was only modestly effective. Nevertheless, it may be a reasonable approach to consider in select patients with AD.

Benjamin Franklin famously stated that "an ounce of prevention is worth a pound of cure." Likewise, while successful treatment of AD is great, how can we advise patients and caregivers of children who are at high risk for AD? To answer this question, Voigt and Lele performed a systematic review and meta-analysis of 11 randomized controlled trials examining the efficacy of Lactobacillus rhamnosus at preventing AD in children when taken by mothers during pregnancy. They found that L. rhamnosus significantly reduced the risk of developing AD within 2 years, marginally significantly reduced risk at 4-5 years, and significantly reduced risk at 6-7 years, but no significant risk differences were observed at 10-11 years. The authors concluded that use of L. rhamnosus with or without other probiotics during pregnancy reduces the incidence of childhood AD at least up to age 7 years.

Wang and colleagues conducted an observational study of the relationship of home environment exposures with atopic disease, including AD, in 17,881 offspring from Iceland, Norway, Sweden, Denmark, and Estonia who had undergone two follow-up investigations every 10 years. They found that AD was associated with parent-reported visible mold and dampness/mold at home, living in an apartment, and living in newer buildings. Avoidance of these environmental exposures could possibly decrease the risk of developing AD, although future confirmatory studies are needed.

For each of these treatment/prevention approaches, the magnitude of benefit is not very large. Thus, these approaches do not replace our armamentarium of treatments and avoidance strategies for AD. Rather, they can be used complementarily as low-risk add-on interventions with a potential upside.

Still, some patients seek alternative or adjunctive treatment approaches, owing to a desire to identify the root cause of disease, their aversion toward Western medicine, or fear of adverse events. Yepes-Nuñez and colleagues performed a systematic review and meta-analysis including 23 studies of benefits and harms of allergen immunotherapy for AD. I had the privilege of participating in this study and can testify to the astronomical amount of work that went into comprehensively identifying all of the relevant studies and synthesizing the data. We found that adjunctive subcutaneous or sublingual allergen immunotherapy, particularly for house dust mites, led to modest but generally delayed improvements of AD severity, itch, and quality of life, and less definitive effects on sleep disturbance and AD flares. Overall, both were well tolerated, though subcutaneous immunotherapy was associated with more adverse events than sublingual immunotherapy. Allergen immunotherapy requires a significant investment of time by patients and was only modestly effective. Nevertheless, it may be a reasonable approach to consider in select patients with AD.

Benjamin Franklin famously stated that "an ounce of prevention is worth a pound of cure." Likewise, while successful treatment of AD is great, how can we advise patients and caregivers of children who are at high risk for AD? To answer this question, Voigt and Lele performed a systematic review and meta-analysis of 11 randomized controlled trials examining the efficacy of Lactobacillus rhamnosus at preventing AD in children when taken by mothers during pregnancy. They found that L. rhamnosus significantly reduced the risk of developing AD within 2 years, marginally significantly reduced risk at 4-5 years, and significantly reduced risk at 6-7 years, but no significant risk differences were observed at 10-11 years. The authors concluded that use of L. rhamnosus with or without other probiotics during pregnancy reduces the incidence of childhood AD at least up to age 7 years.

Wang and colleagues conducted an observational study of the relationship of home environment exposures with atopic disease, including AD, in 17,881 offspring from Iceland, Norway, Sweden, Denmark, and Estonia who had undergone two follow-up investigations every 10 years. They found that AD was associated with parent-reported visible mold and dampness/mold at home, living in an apartment, and living in newer buildings. Avoidance of these environmental exposures could possibly decrease the risk of developing AD, although future confirmatory studies are needed.

For each of these treatment/prevention approaches, the magnitude of benefit is not very large. Thus, these approaches do not replace our armamentarium of treatments and avoidance strategies for AD. Rather, they can be used complementarily as low-risk add-on interventions with a potential upside.

Still, some patients seek alternative or adjunctive treatment approaches, owing to a desire to identify the root cause of disease, their aversion toward Western medicine, or fear of adverse events. Yepes-Nuñez and colleagues performed a systematic review and meta-analysis including 23 studies of benefits and harms of allergen immunotherapy for AD. I had the privilege of participating in this study and can testify to the astronomical amount of work that went into comprehensively identifying all of the relevant studies and synthesizing the data. We found that adjunctive subcutaneous or sublingual allergen immunotherapy, particularly for house dust mites, led to modest but generally delayed improvements of AD severity, itch, and quality of life, and less definitive effects on sleep disturbance and AD flares. Overall, both were well tolerated, though subcutaneous immunotherapy was associated with more adverse events than sublingual immunotherapy. Allergen immunotherapy requires a significant investment of time by patients and was only modestly effective. Nevertheless, it may be a reasonable approach to consider in select patients with AD.

Benjamin Franklin famously stated that "an ounce of prevention is worth a pound of cure." Likewise, while successful treatment of AD is great, how can we advise patients and caregivers of children who are at high risk for AD? To answer this question, Voigt and Lele performed a systematic review and meta-analysis of 11 randomized controlled trials examining the efficacy of Lactobacillus rhamnosus at preventing AD in children when taken by mothers during pregnancy. They found that L. rhamnosus significantly reduced the risk of developing AD within 2 years, marginally significantly reduced risk at 4-5 years, and significantly reduced risk at 6-7 years, but no significant risk differences were observed at 10-11 years. The authors concluded that use of L. rhamnosus with or without other probiotics during pregnancy reduces the incidence of childhood AD at least up to age 7 years.

Wang and colleagues conducted an observational study of the relationship of home environment exposures with atopic disease, including AD, in 17,881 offspring from Iceland, Norway, Sweden, Denmark, and Estonia who had undergone two follow-up investigations every 10 years. They found that AD was associated with parent-reported visible mold and dampness/mold at home, living in an apartment, and living in newer buildings. Avoidance of these environmental exposures could possibly decrease the risk of developing AD, although future confirmatory studies are needed.

For each of these treatment/prevention approaches, the magnitude of benefit is not very large. Thus, these approaches do not replace our armamentarium of treatments and avoidance strategies for AD. Rather, they can be used complementarily as low-risk add-on interventions with a potential upside.

Heart failure (HF) patients with high serum levels of alpha-linolenic acid (ALA) had a better prognosis than those with the lowest levels, in an observational study.

ALA is an omega-3 fatty acid that is found mainly in plants, including flaxseed, chia, walnuts, or canola oil.

PxHere

Plant power

Dr. Sala-Vila and colleagues analyzed data and samples from 905 patients (mean age, 67; 32% women) with HF of different etiologies. ALA was assessed by gas chromatography in serum phospholipids, which reflect long-term dietary ALA intake and metabolism.

The primary outcome was a composite of all-cause death or first HF hospitalization. The secondary outcome was the composite of CV death or HF hospitalization.

After a median follow-up of 2.4 years, 140 all-cause deaths, 85 CV deaths, and 141 first HF hospitalizations occurred (composite of all-cause death and first HF hospitalization, 238; composite of CV death and HF hospitalization, 184).

Compared with patients at the lowest quartile of ALA in serum phospholipids, those at the three upper quartiles showed a 39% reduction in the risk of the primary endpoint (hazard ratio, 0.61).

Statistically significant reductions also were observed for all-cause death (HR, 0.58), CV death (HR, 0.51), first HF hospitalization (HR, 0.58), and the composite of CV death and HF hospitalization (HR, 0.58).

By contrast, nonstatistically significant associations were seen for fish-derived EPA, DHA, and the sum of EPA + DHA.

Limitations of the study include its observational nature; a relatively young cohort with reduced or mid-range ejection fraction and stage 2 chronic kidney disease; and no dietary data except for those regarding fatty acids.

“Controversial results from landmark recent trials on omega-3 might have translated into confusion/negative impact on the reputation of these fatty acids,” Dr. Sala-Vila noted. “Many factors affect how each participant responds to a certain intervention (precision nutrition), such as genetics, the microbiome, and the environment. In this regard, nutritional status – omega-3 background – is emerging as a key determinant.”
 

Randomized trials needed

JoAnn E. Manson, MD, MPH, DrPH, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, Boston, said the findings “are promising in the context of earlier research on omega-3s.”

Those studies include the landmark GISSI-HF trial, a randomized, controlled trial (RCT) that showed a small benefit of n-3 polyunsaturated fatty acids regarding hospital admissions and mortality among patients with chronic HF, and her team’s VITAL-HF study, which showed a significant reduction in recurrent HF hospitalization with marine omega-3 supplementation versus placebo.

“This may not be a causal association, and the authors acknowledge that they don’t have information on other dietary factors,” Dr. Manson said. “It may be that the foods that are leading to this higher blood level of ALA comprise the type of plant-based diet that’s been linked to lower risk of CVD, such as the Mediterranean diet. The findings also could be the result of other factors that aren’t fully controlled for in the analysis, or the participants could be more compliant with their medications.”

Nevertheless, she said, “it’s reasonable to recommend that people with a history of HF or who are at high risk of HF increase their intake of ALA-enriched foods, including canola oil, flaxseed oils, soybeans and soybean oils, and walnuts.”

“I think the evidence is promising enough that an RCT of ALA in people with heart failure also would be reasonable,” she added.

Similarly, Abdallah Al-Mohammad, MD, of Northern General Hospital, Sheffield, England, writes in a related editorial that while a potential role for ALA in improving morbidity and mortality in HF patients cannot be substantiated yet, the findings “open the field to more questions” for which “the judge and jury ... shall be prospective randomized controlled trials.”

No commercial funding or relevant conflicts of interest were declared.

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

Heart failure (HF) patients with high serum levels of alpha-linolenic acid (ALA) had a better prognosis than those with the lowest levels, in an observational study.

ALA is an omega-3 fatty acid that is found mainly in plants, including flaxseed, chia, walnuts, or canola oil.

PxHere

Plant power

Dr. Sala-Vila and colleagues analyzed data and samples from 905 patients (mean age, 67; 32% women) with HF of different etiologies. ALA was assessed by gas chromatography in serum phospholipids, which reflect long-term dietary ALA intake and metabolism.

The primary outcome was a composite of all-cause death or first HF hospitalization. The secondary outcome was the composite of CV death or HF hospitalization.

After a median follow-up of 2.4 years, 140 all-cause deaths, 85 CV deaths, and 141 first HF hospitalizations occurred (composite of all-cause death and first HF hospitalization, 238; composite of CV death and HF hospitalization, 184).

Compared with patients at the lowest quartile of ALA in serum phospholipids, those at the three upper quartiles showed a 39% reduction in the risk of the primary endpoint (hazard ratio, 0.61).

Statistically significant reductions also were observed for all-cause death (HR, 0.58), CV death (HR, 0.51), first HF hospitalization (HR, 0.58), and the composite of CV death and HF hospitalization (HR, 0.58).

By contrast, nonstatistically significant associations were seen for fish-derived EPA, DHA, and the sum of EPA + DHA.

Limitations of the study include its observational nature; a relatively young cohort with reduced or mid-range ejection fraction and stage 2 chronic kidney disease; and no dietary data except for those regarding fatty acids.

“Controversial results from landmark recent trials on omega-3 might have translated into confusion/negative impact on the reputation of these fatty acids,” Dr. Sala-Vila noted. “Many factors affect how each participant responds to a certain intervention (precision nutrition), such as genetics, the microbiome, and the environment. In this regard, nutritional status – omega-3 background – is emerging as a key determinant.”
 

Randomized trials needed

JoAnn E. Manson, MD, MPH, DrPH, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, Boston, said the findings “are promising in the context of earlier research on omega-3s.”

Those studies include the landmark GISSI-HF trial, a randomized, controlled trial (RCT) that showed a small benefit of n-3 polyunsaturated fatty acids regarding hospital admissions and mortality among patients with chronic HF, and her team’s VITAL-HF study, which showed a significant reduction in recurrent HF hospitalization with marine omega-3 supplementation versus placebo.

“This may not be a causal association, and the authors acknowledge that they don’t have information on other dietary factors,” Dr. Manson said. “It may be that the foods that are leading to this higher blood level of ALA comprise the type of plant-based diet that’s been linked to lower risk of CVD, such as the Mediterranean diet. The findings also could be the result of other factors that aren’t fully controlled for in the analysis, or the participants could be more compliant with their medications.”

Nevertheless, she said, “it’s reasonable to recommend that people with a history of HF or who are at high risk of HF increase their intake of ALA-enriched foods, including canola oil, flaxseed oils, soybeans and soybean oils, and walnuts.”

“I think the evidence is promising enough that an RCT of ALA in people with heart failure also would be reasonable,” she added.

Similarly, Abdallah Al-Mohammad, MD, of Northern General Hospital, Sheffield, England, writes in a related editorial that while a potential role for ALA in improving morbidity and mortality in HF patients cannot be substantiated yet, the findings “open the field to more questions” for which “the judge and jury ... shall be prospective randomized controlled trials.”

No commercial funding or relevant conflicts of interest were declared.

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

Heart failure (HF) patients with high serum levels of alpha-linolenic acid (ALA) had a better prognosis than those with the lowest levels, in an observational study.

ALA is an omega-3 fatty acid that is found mainly in plants, including flaxseed, chia, walnuts, or canola oil.

PxHere

Plant power

Dr. Sala-Vila and colleagues analyzed data and samples from 905 patients (mean age, 67; 32% women) with HF of different etiologies. ALA was assessed by gas chromatography in serum phospholipids, which reflect long-term dietary ALA intake and metabolism.

The primary outcome was a composite of all-cause death or first HF hospitalization. The secondary outcome was the composite of CV death or HF hospitalization.

After a median follow-up of 2.4 years, 140 all-cause deaths, 85 CV deaths, and 141 first HF hospitalizations occurred (composite of all-cause death and first HF hospitalization, 238; composite of CV death and HF hospitalization, 184).

Compared with patients at the lowest quartile of ALA in serum phospholipids, those at the three upper quartiles showed a 39% reduction in the risk of the primary endpoint (hazard ratio, 0.61).

Statistically significant reductions also were observed for all-cause death (HR, 0.58), CV death (HR, 0.51), first HF hospitalization (HR, 0.58), and the composite of CV death and HF hospitalization (HR, 0.58).

By contrast, nonstatistically significant associations were seen for fish-derived EPA, DHA, and the sum of EPA + DHA.

Limitations of the study include its observational nature; a relatively young cohort with reduced or mid-range ejection fraction and stage 2 chronic kidney disease; and no dietary data except for those regarding fatty acids.

“Controversial results from landmark recent trials on omega-3 might have translated into confusion/negative impact on the reputation of these fatty acids,” Dr. Sala-Vila noted. “Many factors affect how each participant responds to a certain intervention (precision nutrition), such as genetics, the microbiome, and the environment. In this regard, nutritional status – omega-3 background – is emerging as a key determinant.”
 

Randomized trials needed

JoAnn E. Manson, MD, MPH, DrPH, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, Boston, said the findings “are promising in the context of earlier research on omega-3s.”

Those studies include the landmark GISSI-HF trial, a randomized, controlled trial (RCT) that showed a small benefit of n-3 polyunsaturated fatty acids regarding hospital admissions and mortality among patients with chronic HF, and her team’s VITAL-HF study, which showed a significant reduction in recurrent HF hospitalization with marine omega-3 supplementation versus placebo.

“This may not be a causal association, and the authors acknowledge that they don’t have information on other dietary factors,” Dr. Manson said. “It may be that the foods that are leading to this higher blood level of ALA comprise the type of plant-based diet that’s been linked to lower risk of CVD, such as the Mediterranean diet. The findings also could be the result of other factors that aren’t fully controlled for in the analysis, or the participants could be more compliant with their medications.”

Nevertheless, she said, “it’s reasonable to recommend that people with a history of HF or who are at high risk of HF increase their intake of ALA-enriched foods, including canola oil, flaxseed oils, soybeans and soybean oils, and walnuts.”

“I think the evidence is promising enough that an RCT of ALA in people with heart failure also would be reasonable,” she added.

Similarly, Abdallah Al-Mohammad, MD, of Northern General Hospital, Sheffield, England, writes in a related editorial that while a potential role for ALA in improving morbidity and mortality in HF patients cannot be substantiated yet, the findings “open the field to more questions” for which “the judge and jury ... shall be prospective randomized controlled trials.”

No commercial funding or relevant conflicts of interest were declared.

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

Although the nausea and vomiting associated with pregnancy are usually mild, they are more severe (hyperemesis gravidarum) in around one-third of women and require hospitalization in the first trimester for 0.3%-3.6% of these women in France. Given the diversity of practical care, a working group from the National College of French Gynecologists and Obstetricians (CNGOF) has established a consensus on the definition and management of these symptoms.

Definition and severity

Nausea and vomiting during pregnancy are defined as those emerging in the first trimester of pregnancy and for which there is no other etiology.

The severity of these symptoms should be assessed through weight loss from the beginning of the pregnancy, clinical signs of dehydration (thirst, skin turgor, hypotension, oliguria, etc.), and modified PUQE (Pregnancy-Unique Quantification of Emesis and Nausea) score. This is a three-question score rated from 0 to 15, available in the full text of the expert consensus.

Severe nausea and vomiting are not considered complicated when weight loss is < 5%, with no clinical signs of dehydration, and combined with a PUQE score of ≤ 6. In contrast, hyperemesis gravidarum is distinguished from nausea and vomiting during pregnancy by weight loss of ≥ 5 % or signs of dehydration or a PUQE score of ≥ 7.
 

Treating hyperemesis gravidarum

A laboratory workup should be ordered, along with an assay of blood potassium, blood sodium ions, and creatinine levels, as well as a complete dipstick urinalysis.

If symptoms persist or worsen despite well-managed treatment, an additional assessment is recommended, including an abdominal ultrasound and laboratory workup (white blood cell count, transaminases, lipase, CRP, TSH, T4).

Hospitalization is proposed when at least one of the following criteria is met: weight loss ≥ 10%, one or more clinical signs of dehydration, PUQE score of ≥ 13, hypokalemia < 3.0 mmol/L, hyponatremia < 120 mmol/L, elevated serum creatinine > 100 micromol/L, or resistance to treatment.
 

Which treatment?

Prenatal vitamins and iron supplementation should be stopped, as the latter seems to make symptoms worse. This step should be taken without stopping folic acid supplementation.

Women are free to adapt their diets and lifestyles according to their symptoms, since no such changes have been reported to improve symptoms.

If the PUQE score is < 6, even in the absence of proof of their benefit, ginger or B6 vitamin can be used. The same applies to acupressure, acupuncture, and electrical stimulation, which should only be considered in women without complications. Aromatherapy is not to be used, because of the potential risks associated with essential oils, and as no efficacy has been demonstrated.

It is proposed that drugs or combinations of drugs associated with the least severe and least frequent side effects should always be chosen in the absence of superiority of one class over another.

To prevent Gayet Wernicke encephalopathy, vitamin B1 must be administered systematically for hyperemesis gravidarum needing parenteral rehydration. Psychological support should be offered to all patients with hyperemesis gravidarum because of the negative impact of this pathology on mental well-being. Patients should be informed that there are patient associations involved in supporting these women and their families.

A version of this article first appeared on Medscape.com and was translated from Univadis France.

Although the nausea and vomiting associated with pregnancy are usually mild, they are more severe (hyperemesis gravidarum) in around one-third of women and require hospitalization in the first trimester for 0.3%-3.6% of these women in France. Given the diversity of practical care, a working group from the National College of French Gynecologists and Obstetricians (CNGOF) has established a consensus on the definition and management of these symptoms.

Definition and severity

Nausea and vomiting during pregnancy are defined as those emerging in the first trimester of pregnancy and for which there is no other etiology.

The severity of these symptoms should be assessed through weight loss from the beginning of the pregnancy, clinical signs of dehydration (thirst, skin turgor, hypotension, oliguria, etc.), and modified PUQE (Pregnancy-Unique Quantification of Emesis and Nausea) score. This is a three-question score rated from 0 to 15, available in the full text of the expert consensus.

Severe nausea and vomiting are not considered complicated when weight loss is < 5%, with no clinical signs of dehydration, and combined with a PUQE score of ≤ 6. In contrast, hyperemesis gravidarum is distinguished from nausea and vomiting during pregnancy by weight loss of ≥ 5 % or signs of dehydration or a PUQE score of ≥ 7.
 

Treating hyperemesis gravidarum

A laboratory workup should be ordered, along with an assay of blood potassium, blood sodium ions, and creatinine levels, as well as a complete dipstick urinalysis.

If symptoms persist or worsen despite well-managed treatment, an additional assessment is recommended, including an abdominal ultrasound and laboratory workup (white blood cell count, transaminases, lipase, CRP, TSH, T4).

Hospitalization is proposed when at least one of the following criteria is met: weight loss ≥ 10%, one or more clinical signs of dehydration, PUQE score of ≥ 13, hypokalemia < 3.0 mmol/L, hyponatremia < 120 mmol/L, elevated serum creatinine > 100 micromol/L, or resistance to treatment.
 

Which treatment?

Prenatal vitamins and iron supplementation should be stopped, as the latter seems to make symptoms worse. This step should be taken without stopping folic acid supplementation.

Women are free to adapt their diets and lifestyles according to their symptoms, since no such changes have been reported to improve symptoms.

If the PUQE score is < 6, even in the absence of proof of their benefit, ginger or B6 vitamin can be used. The same applies to acupressure, acupuncture, and electrical stimulation, which should only be considered in women without complications. Aromatherapy is not to be used, because of the potential risks associated with essential oils, and as no efficacy has been demonstrated.

It is proposed that drugs or combinations of drugs associated with the least severe and least frequent side effects should always be chosen in the absence of superiority of one class over another.

To prevent Gayet Wernicke encephalopathy, vitamin B1 must be administered systematically for hyperemesis gravidarum needing parenteral rehydration. Psychological support should be offered to all patients with hyperemesis gravidarum because of the negative impact of this pathology on mental well-being. Patients should be informed that there are patient associations involved in supporting these women and their families.

A version of this article first appeared on Medscape.com and was translated from Univadis France.

Although the nausea and vomiting associated with pregnancy are usually mild, they are more severe (hyperemesis gravidarum) in around one-third of women and require hospitalization in the first trimester for 0.3%-3.6% of these women in France. Given the diversity of practical care, a working group from the National College of French Gynecologists and Obstetricians (CNGOF) has established a consensus on the definition and management of these symptoms.

Definition and severity

Nausea and vomiting during pregnancy are defined as those emerging in the first trimester of pregnancy and for which there is no other etiology.

The severity of these symptoms should be assessed through weight loss from the beginning of the pregnancy, clinical signs of dehydration (thirst, skin turgor, hypotension, oliguria, etc.), and modified PUQE (Pregnancy-Unique Quantification of Emesis and Nausea) score. This is a three-question score rated from 0 to 15, available in the full text of the expert consensus.

Severe nausea and vomiting are not considered complicated when weight loss is < 5%, with no clinical signs of dehydration, and combined with a PUQE score of ≤ 6. In contrast, hyperemesis gravidarum is distinguished from nausea and vomiting during pregnancy by weight loss of ≥ 5 % or signs of dehydration or a PUQE score of ≥ 7.
 

Treating hyperemesis gravidarum

A laboratory workup should be ordered, along with an assay of blood potassium, blood sodium ions, and creatinine levels, as well as a complete dipstick urinalysis.

If symptoms persist or worsen despite well-managed treatment, an additional assessment is recommended, including an abdominal ultrasound and laboratory workup (white blood cell count, transaminases, lipase, CRP, TSH, T4).

Hospitalization is proposed when at least one of the following criteria is met: weight loss ≥ 10%, one or more clinical signs of dehydration, PUQE score of ≥ 13, hypokalemia < 3.0 mmol/L, hyponatremia < 120 mmol/L, elevated serum creatinine > 100 micromol/L, or resistance to treatment.
 

Which treatment?

Prenatal vitamins and iron supplementation should be stopped, as the latter seems to make symptoms worse. This step should be taken without stopping folic acid supplementation.

Women are free to adapt their diets and lifestyles according to their symptoms, since no such changes have been reported to improve symptoms.

If the PUQE score is < 6, even in the absence of proof of their benefit, ginger or B6 vitamin can be used. The same applies to acupressure, acupuncture, and electrical stimulation, which should only be considered in women without complications. Aromatherapy is not to be used, because of the potential risks associated with essential oils, and as no efficacy has been demonstrated.

It is proposed that drugs or combinations of drugs associated with the least severe and least frequent side effects should always be chosen in the absence of superiority of one class over another.

To prevent Gayet Wernicke encephalopathy, vitamin B1 must be administered systematically for hyperemesis gravidarum needing parenteral rehydration. Psychological support should be offered to all patients with hyperemesis gravidarum because of the negative impact of this pathology on mental well-being. Patients should be informed that there are patient associations involved in supporting these women and their families.

A version of this article first appeared on Medscape.com and was translated from Univadis France.

Menopause appears to be an independent risk factor for relapse in women with schizophrenia spectrum disorders (SSDs), new research suggests.
 

Investigators studied a cohort of close to 62,000 people with SSDs, stratifying individuals by sex and age, and found that starting between the ages of 45 and 50 years – when the menopausal transition is underway – women were more frequently hospitalized for psychosis, compared with men and women younger than 45 years.

In addition, the protective effect of antipsychotic medication was highest in women younger than 45 years and lowest in women aged 45 years or older, even at higher doses.

“Women with schizophrenia who are older than 45 are a vulnerable group for relapse, and higher doses of antipsychotics are not the answer,” lead author Iris Sommer, MD, PhD, professor, department of neuroscience, University Medical Center of Groningen, the Netherlands, told this news organization.

The study was published online in Schizophrenia Bulletin.
 

Vulnerable period

There is an association between estrogen levels and disease severity throughout the life stages of women with SSDs, with lower estrogen levels associated with psychosis, for example, during low estrogenic phases of the menstrual cycle, the investigators note.

“After menopause, estrogen levels remain low, which is associated with a deterioration in the clinical course; therefore, women with SSD have sex-specific psychiatric needs that differ according to their life stage,” they add.

“Estrogens inhibit an important liver enzyme (cytochrome P-450 [CYP1A2]), which leads to higher blood levels of several antipsychotics like olanzapine and clozapine,” said Dr. Sommer. In addition, estrogens make the stomach less acidic, “leading to easier resorption of medication.”

As a clinician, Dr. Sommer said that she has “often witnessed a worsening of symptoms [of psychosis] after menopause.” As a researcher, she “knew that estrogens can have ameliorating effects on brain health, especially in schizophrenia.”

She and her colleagues were motivated to research the issue because there is a “remarkable paucity” of quantitative data on a “vulnerable period that all women with schizophrenia will experience.”
 

Detailed, quantitative data

The researchers sought to provide “detailed, quantitative data on life-stage dependent clinical changes occurring in women with SSD, using an intra-individual design to prevent confounding.”

They drew on data from a nationwide, register-based cohort study of all hospitalized patients with SSD between 1972 and 2014 in Finland (n = 61,889), with follow-up from Jan. 1, 1996, to Dec. 31, 2017.

People were stratified according to age (younger than 45 years and 45 years or older), with the same person contributing person-time to both age groups. The cohort was also subdivided into 5-year age groups, starting at age 20 years and ending at age 69 years.

The primary outcome measure was relapse (that is, inpatient hospitalization because of psychosis).

The researchers focused specifically on monotherapies, excluding time periods when two or more antipsychotics were used concomitantly. They also looked at antipsychotic nonuse periods.

Antipsychotic monotherapies were categorized into defined daily doses per day (DDDs/d):

• less than 0.4
• 0.4 to 0.6
• 0.6 to 0.9
• 0.9 to less than 1.1
• 1.1 to less than 1.4
• 1.4 to less than 1.6
• 1.6 or more

The researchers restricted the main analyses to the four most frequently used oral antipsychotic monotherapies: clozapine, olanzapine, quetiapine, and risperidone.
 

The turning tide

The cohort consisted of more men than women (31,104 vs. 30,785, respectively), with a mean (standard deviation) age of 49.8 (16.6) years in women vs. 43.6 (14.8) in men.

Among both sexes, olanzapine was the most prescribed antipsychotic (roughly one-quarter of patients). In women, the next most common antipsychotic was risperidone, followed by quetiapine and clozapine, whereas in men, the second most common antipsychotic was clozapine, followed by risperidone and quetiapine.

When the researchers compared men and women younger than 45 years, there were “few consistent differences” in proportions hospitalized for psychosis.

Starting at age 45 years and continuing through the oldest age group (65-69 years), higher proportions of women were hospitalized for psychosis, compared with their male peers (all Ps < .00001). 

Women 45 or older had significantly higher risk for relapse associated with standard dose use, compared with the other groups.

When the researchers compared men and women older and younger than 45 years, women younger than 45 years showed lower adjusted hazard ratios (aHRs) at doses between of 0.6-0.9 DDDs/d, whereas for doses over 1.1 DDDs/d, women aged 45 years or older showed “remarkably higher” aHRs, compared with women younger than 45 years and men aged 45 years or older, with a difference that increased with increasing dose.

In women, the efficacy of the antipsychotics was decreased at these DDDs/d.

“We ... showed that antipsychotic monotherapy is most effective in preventing relapse in women below 45, as compared to women above that age, and also as compared to men of all ages,” the authors summarize. But after age 45 years, “the tide seems to turn for women,” compared with younger women and with men of the same age group.

One of several study limitations was the use of age as an estimation of menopausal status, they note.
 

Don’t just raise the dose

Commenting on the research, Mary Seeman, MD, professor emerita, department of psychiatry, University of Toronto, noted the study corroborates her group’s findings regarding the effect of menopause on antipsychotic response.

“When the efficacy of previously effective antipsychotic doses wanes at menopause, raising the dose is not the treatment of choice because it increases the risk of weight gain, cardiovascular, and cerebrovascular events,” said Dr. Seeman, who was not involved with the current research.

“Changing to an antipsychotic that is less affected by estrogen loss may work better,” she continued, noting that amisulpride and aripiprazole “work well post menopause.”

Additional interventions may include changing to a depot or skin-patch antipsychotic that “obviates first-pass metabolism,” adding hormone replacement or a selective estrogen receptor modulator or including phytoestrogens (bioidenticals) in the diet.

The study yields research recommendations, including comparing the effectiveness of different antipsychotics in postmenopausal women with SSDs, recruiting pre- and postmenopausal women in trials of antipsychotic drugs, and stratifying by hormonal status when analyzing results of antipsychotic trials, Dr. Seeman said.

This work was supported by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and the Academy of Finland. The Dutch Medical Research Association supported Dr. Sommer. Dr. Sommer declares no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Seeman declares no relevant financial relationships.

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

Menopause appears to be an independent risk factor for relapse in women with schizophrenia spectrum disorders (SSDs), new research suggests.
 

Investigators studied a cohort of close to 62,000 people with SSDs, stratifying individuals by sex and age, and found that starting between the ages of 45 and 50 years – when the menopausal transition is underway – women were more frequently hospitalized for psychosis, compared with men and women younger than 45 years.

In addition, the protective effect of antipsychotic medication was highest in women younger than 45 years and lowest in women aged 45 years or older, even at higher doses.

“Women with schizophrenia who are older than 45 are a vulnerable group for relapse, and higher doses of antipsychotics are not the answer,” lead author Iris Sommer, MD, PhD, professor, department of neuroscience, University Medical Center of Groningen, the Netherlands, told this news organization.

The study was published online in Schizophrenia Bulletin.
 

Vulnerable period

There is an association between estrogen levels and disease severity throughout the life stages of women with SSDs, with lower estrogen levels associated with psychosis, for example, during low estrogenic phases of the menstrual cycle, the investigators note.

“After menopause, estrogen levels remain low, which is associated with a deterioration in the clinical course; therefore, women with SSD have sex-specific psychiatric needs that differ according to their life stage,” they add.

“Estrogens inhibit an important liver enzyme (cytochrome P-450 [CYP1A2]), which leads to higher blood levels of several antipsychotics like olanzapine and clozapine,” said Dr. Sommer. In addition, estrogens make the stomach less acidic, “leading to easier resorption of medication.”

As a clinician, Dr. Sommer said that she has “often witnessed a worsening of symptoms [of psychosis] after menopause.” As a researcher, she “knew that estrogens can have ameliorating effects on brain health, especially in schizophrenia.”

She and her colleagues were motivated to research the issue because there is a “remarkable paucity” of quantitative data on a “vulnerable period that all women with schizophrenia will experience.”
 

Detailed, quantitative data

The researchers sought to provide “detailed, quantitative data on life-stage dependent clinical changes occurring in women with SSD, using an intra-individual design to prevent confounding.”

They drew on data from a nationwide, register-based cohort study of all hospitalized patients with SSD between 1972 and 2014 in Finland (n = 61,889), with follow-up from Jan. 1, 1996, to Dec. 31, 2017.

People were stratified according to age (younger than 45 years and 45 years or older), with the same person contributing person-time to both age groups. The cohort was also subdivided into 5-year age groups, starting at age 20 years and ending at age 69 years.

The primary outcome measure was relapse (that is, inpatient hospitalization because of psychosis).

The researchers focused specifically on monotherapies, excluding time periods when two or more antipsychotics were used concomitantly. They also looked at antipsychotic nonuse periods.

Antipsychotic monotherapies were categorized into defined daily doses per day (DDDs/d):

• less than 0.4
• 0.4 to 0.6
• 0.6 to 0.9
• 0.9 to less than 1.1
• 1.1 to less than 1.4
• 1.4 to less than 1.6
• 1.6 or more

The researchers restricted the main analyses to the four most frequently used oral antipsychotic monotherapies: clozapine, olanzapine, quetiapine, and risperidone.
 

The turning tide

The cohort consisted of more men than women (31,104 vs. 30,785, respectively), with a mean (standard deviation) age of 49.8 (16.6) years in women vs. 43.6 (14.8) in men.

Among both sexes, olanzapine was the most prescribed antipsychotic (roughly one-quarter of patients). In women, the next most common antipsychotic was risperidone, followed by quetiapine and clozapine, whereas in men, the second most common antipsychotic was clozapine, followed by risperidone and quetiapine.

When the researchers compared men and women younger than 45 years, there were “few consistent differences” in proportions hospitalized for psychosis.

Starting at age 45 years and continuing through the oldest age group (65-69 years), higher proportions of women were hospitalized for psychosis, compared with their male peers (all Ps < .00001). 

Women 45 or older had significantly higher risk for relapse associated with standard dose use, compared with the other groups.

When the researchers compared men and women older and younger than 45 years, women younger than 45 years showed lower adjusted hazard ratios (aHRs) at doses between of 0.6-0.9 DDDs/d, whereas for doses over 1.1 DDDs/d, women aged 45 years or older showed “remarkably higher” aHRs, compared with women younger than 45 years and men aged 45 years or older, with a difference that increased with increasing dose.

In women, the efficacy of the antipsychotics was decreased at these DDDs/d.

“We ... showed that antipsychotic monotherapy is most effective in preventing relapse in women below 45, as compared to women above that age, and also as compared to men of all ages,” the authors summarize. But after age 45 years, “the tide seems to turn for women,” compared with younger women and with men of the same age group.

One of several study limitations was the use of age as an estimation of menopausal status, they note.
 

Don’t just raise the dose

Commenting on the research, Mary Seeman, MD, professor emerita, department of psychiatry, University of Toronto, noted the study corroborates her group’s findings regarding the effect of menopause on antipsychotic response.

“When the efficacy of previously effective antipsychotic doses wanes at menopause, raising the dose is not the treatment of choice because it increases the risk of weight gain, cardiovascular, and cerebrovascular events,” said Dr. Seeman, who was not involved with the current research.

“Changing to an antipsychotic that is less affected by estrogen loss may work better,” she continued, noting that amisulpride and aripiprazole “work well post menopause.”

Additional interventions may include changing to a depot or skin-patch antipsychotic that “obviates first-pass metabolism,” adding hormone replacement or a selective estrogen receptor modulator or including phytoestrogens (bioidenticals) in the diet.

The study yields research recommendations, including comparing the effectiveness of different antipsychotics in postmenopausal women with SSDs, recruiting pre- and postmenopausal women in trials of antipsychotic drugs, and stratifying by hormonal status when analyzing results of antipsychotic trials, Dr. Seeman said.

This work was supported by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and the Academy of Finland. The Dutch Medical Research Association supported Dr. Sommer. Dr. Sommer declares no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Seeman declares no relevant financial relationships.

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

Menopause appears to be an independent risk factor for relapse in women with schizophrenia spectrum disorders (SSDs), new research suggests.
 

Investigators studied a cohort of close to 62,000 people with SSDs, stratifying individuals by sex and age, and found that starting between the ages of 45 and 50 years – when the menopausal transition is underway – women were more frequently hospitalized for psychosis, compared with men and women younger than 45 years.

In addition, the protective effect of antipsychotic medication was highest in women younger than 45 years and lowest in women aged 45 years or older, even at higher doses.

“Women with schizophrenia who are older than 45 are a vulnerable group for relapse, and higher doses of antipsychotics are not the answer,” lead author Iris Sommer, MD, PhD, professor, department of neuroscience, University Medical Center of Groningen, the Netherlands, told this news organization.

The study was published online in Schizophrenia Bulletin.
 

Vulnerable period

There is an association between estrogen levels and disease severity throughout the life stages of women with SSDs, with lower estrogen levels associated with psychosis, for example, during low estrogenic phases of the menstrual cycle, the investigators note.

“After menopause, estrogen levels remain low, which is associated with a deterioration in the clinical course; therefore, women with SSD have sex-specific psychiatric needs that differ according to their life stage,” they add.

“Estrogens inhibit an important liver enzyme (cytochrome P-450 [CYP1A2]), which leads to higher blood levels of several antipsychotics like olanzapine and clozapine,” said Dr. Sommer. In addition, estrogens make the stomach less acidic, “leading to easier resorption of medication.”

As a clinician, Dr. Sommer said that she has “often witnessed a worsening of symptoms [of psychosis] after menopause.” As a researcher, she “knew that estrogens can have ameliorating effects on brain health, especially in schizophrenia.”

She and her colleagues were motivated to research the issue because there is a “remarkable paucity” of quantitative data on a “vulnerable period that all women with schizophrenia will experience.”
 

Detailed, quantitative data

The researchers sought to provide “detailed, quantitative data on life-stage dependent clinical changes occurring in women with SSD, using an intra-individual design to prevent confounding.”

They drew on data from a nationwide, register-based cohort study of all hospitalized patients with SSD between 1972 and 2014 in Finland (n = 61,889), with follow-up from Jan. 1, 1996, to Dec. 31, 2017.

People were stratified according to age (younger than 45 years and 45 years or older), with the same person contributing person-time to both age groups. The cohort was also subdivided into 5-year age groups, starting at age 20 years and ending at age 69 years.

The primary outcome measure was relapse (that is, inpatient hospitalization because of psychosis).

The researchers focused specifically on monotherapies, excluding time periods when two or more antipsychotics were used concomitantly. They also looked at antipsychotic nonuse periods.

Antipsychotic monotherapies were categorized into defined daily doses per day (DDDs/d):

• less than 0.4
• 0.4 to 0.6
• 0.6 to 0.9
• 0.9 to less than 1.1
• 1.1 to less than 1.4
• 1.4 to less than 1.6
• 1.6 or more

The researchers restricted the main analyses to the four most frequently used oral antipsychotic monotherapies: clozapine, olanzapine, quetiapine, and risperidone.
 

The turning tide

The cohort consisted of more men than women (31,104 vs. 30,785, respectively), with a mean (standard deviation) age of 49.8 (16.6) years in women vs. 43.6 (14.8) in men.

Among both sexes, olanzapine was the most prescribed antipsychotic (roughly one-quarter of patients). In women, the next most common antipsychotic was risperidone, followed by quetiapine and clozapine, whereas in men, the second most common antipsychotic was clozapine, followed by risperidone and quetiapine.

When the researchers compared men and women younger than 45 years, there were “few consistent differences” in proportions hospitalized for psychosis.

Starting at age 45 years and continuing through the oldest age group (65-69 years), higher proportions of women were hospitalized for psychosis, compared with their male peers (all Ps < .00001). 

Women 45 or older had significantly higher risk for relapse associated with standard dose use, compared with the other groups.

When the researchers compared men and women older and younger than 45 years, women younger than 45 years showed lower adjusted hazard ratios (aHRs) at doses between of 0.6-0.9 DDDs/d, whereas for doses over 1.1 DDDs/d, women aged 45 years or older showed “remarkably higher” aHRs, compared with women younger than 45 years and men aged 45 years or older, with a difference that increased with increasing dose.

In women, the efficacy of the antipsychotics was decreased at these DDDs/d.

“We ... showed that antipsychotic monotherapy is most effective in preventing relapse in women below 45, as compared to women above that age, and also as compared to men of all ages,” the authors summarize. But after age 45 years, “the tide seems to turn for women,” compared with younger women and with men of the same age group.

One of several study limitations was the use of age as an estimation of menopausal status, they note.
 

Don’t just raise the dose

Commenting on the research, Mary Seeman, MD, professor emerita, department of psychiatry, University of Toronto, noted the study corroborates her group’s findings regarding the effect of menopause on antipsychotic response.

“When the efficacy of previously effective antipsychotic doses wanes at menopause, raising the dose is not the treatment of choice because it increases the risk of weight gain, cardiovascular, and cerebrovascular events,” said Dr. Seeman, who was not involved with the current research.

“Changing to an antipsychotic that is less affected by estrogen loss may work better,” she continued, noting that amisulpride and aripiprazole “work well post menopause.”

Additional interventions may include changing to a depot or skin-patch antipsychotic that “obviates first-pass metabolism,” adding hormone replacement or a selective estrogen receptor modulator or including phytoestrogens (bioidenticals) in the diet.

The study yields research recommendations, including comparing the effectiveness of different antipsychotics in postmenopausal women with SSDs, recruiting pre- and postmenopausal women in trials of antipsychotic drugs, and stratifying by hormonal status when analyzing results of antipsychotic trials, Dr. Seeman said.

This work was supported by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and the Academy of Finland. The Dutch Medical Research Association supported Dr. Sommer. Dr. Sommer declares no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Seeman declares no relevant financial relationships.

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

The phase 2 FIGHT trial¹ evaluated the role of bemarituzumab, an anti-FGFR2 antibody, in combination with chemotherapy during first-line treatment of advanced gastroesophageal adenocarcinoma. The primary endpoint of this trial was progression-free survival (PFS). This trial enrolled 155 patients with upper gastrointestinal tumors with FGFR2b overexpression (defined as at least 2+ by immunohistochemistry) or amplification on next-generation sequencing. About 30% of patients with HER2 nonpositive tumors (ie, those that would not qualify for treatment with the targeted agent trastuzumab) were eligible for participation. In the FIGHT trial, patients were randomized in a 1:1 ratio to receive either standard chemotherapy (folinic acid, fluorouracil, and oxaliplatin [FOLFOX]) or chemotherapy plus bemarituzumab. Patients in the experimental group were allowed to receive one dose of standard FOLFOX chemotherapy while biomarker testing was ongoing.

With a median follow-up time of 10.9 moths, PFS was numerically prolonged in the bemarituzumab group (9.5 vs 7.4 months), but it did not reach statistical significance (P = .073). Overall survival (OS) was improved in the experimental group (not reached vs 12.9 months; P = .027). With a longer follow-up of 12.5 months, in post hoc exploratory analysis, OS was significantly longer in the experimental group (19.2 vs 13.5 months; hazard ratio 0.60, P = .027). The rate of serious adverse events was similar between the two groups. However, it is important to note ocular toxicities associated with bemarituzumab treatment. Corneal adverse events were seen in 67% of patients in the experimental group, with 24% of patients experiencing grade 3 events. Moreover, 26% of patients discontinued bemarituzumab because of corneal adverse events.

Overall, this phase 2 trial demonstrated that FGFR2b is emerging as an important biomarker and target in patients with advanced gastroesophageal adenocarcinoma. Ongoing phase 3 trials (FORTITUDE-101 with FOLFOX [NCT05052801] and FORTITUDE-102 with FOLFOX and nivolumab [NCT05111626]) hopefully will confirm the early results seen in the FIGHT trial. Awareness and early attention to treatment-associated toxicities will be critical for the potential future incorporation of bemarituzumab into clinical practice.

A study by Ramos‐Santillan and colleagues explored whether the order of treatment modalities matter in the management of early-stage gastric cancer. Typically, perioperative chemotherapy (both neoadjuvant and adjuvant) is used during treatment of early-stage gastric cancer, which is usually defined as at least cT2N0 or cTxN+ disease. In this study, multivariable Cox regression analyses were performed on propensity score-matched cohorts. The study analyzed outcomes of 11,984 patients who were identified using the US National Cancer Database and treated between 2005 and 2014. The results revealed that patients who had stage I disease had better outcomes with upfront resection followed by adjuvant therapy. Patients with stage III disease did better with a neoadjuvant approach, whereas patients with stage II disease had similar outcomes regardless of chemotherapy timing. This research has the limitations inherent to the retrospective nature of the analysis and lack of prospective enrollment and controls. However, it does suggest that there may be a fraction of patients who should be treated with upfront resection. For incorporation of this change into standard practice, the question of therapy sequencing should be answered in a randomized prospective trial that incorporates the most updated systemic therapy (fluorouracil, leucovorin, oxaliplatin, and docetaxel [FLOT]) into its design.

Chemotherapy continues to play a critical role during first-line treatment of advanced esophageal and gastric adenocarcinoma. Triple chemotherapy regimens have been known to have increased efficacy in this setting, but their use has been limited by associated toxicities. A study by Nguyen and colleagues evaluated the TCX regimen (paclitaxel, carboplatin, and capecitabine) during first-line treatment of advanced gastric cancer. This regimen is similar to other triple chemotherapy regimens, such as FLOT and DCF (docetaxel, cisplatin, and fluorouracil), which have proven activity in this disease. This prospective phase 2 trial enrolled 83 patients. The median PFS (9.3 months) and OS (17 months) compared favorably with historical references. The regimen had expected adverse events, with cytopenias and fatigue being the most frequently reported. On the basis of the reported safety and efficacy, TCX has potential to be used as a chemotherapy backbone in future trials, but larger trials are needed to confirm the phase 2 trial results.

References

Wainberg ZA, Enzinger PC, Kang YK, et al. Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): A randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. 2022 Oct 13. Doi: 10.1016/S1470-2045(22)00603-9

The phase 2 FIGHT trial¹ evaluated the role of bemarituzumab, an anti-FGFR2 antibody, in combination with chemotherapy during first-line treatment of advanced gastroesophageal adenocarcinoma. The primary endpoint of this trial was progression-free survival (PFS). This trial enrolled 155 patients with upper gastrointestinal tumors with FGFR2b overexpression (defined as at least 2+ by immunohistochemistry) or amplification on next-generation sequencing. About 30% of patients with HER2 nonpositive tumors (ie, those that would not qualify for treatment with the targeted agent trastuzumab) were eligible for participation. In the FIGHT trial, patients were randomized in a 1:1 ratio to receive either standard chemotherapy (folinic acid, fluorouracil, and oxaliplatin [FOLFOX]) or chemotherapy plus bemarituzumab. Patients in the experimental group were allowed to receive one dose of standard FOLFOX chemotherapy while biomarker testing was ongoing.

With a median follow-up time of 10.9 moths, PFS was numerically prolonged in the bemarituzumab group (9.5 vs 7.4 months), but it did not reach statistical significance (P = .073). Overall survival (OS) was improved in the experimental group (not reached vs 12.9 months; P = .027). With a longer follow-up of 12.5 months, in post hoc exploratory analysis, OS was significantly longer in the experimental group (19.2 vs 13.5 months; hazard ratio 0.60, P = .027). The rate of serious adverse events was similar between the two groups. However, it is important to note ocular toxicities associated with bemarituzumab treatment. Corneal adverse events were seen in 67% of patients in the experimental group, with 24% of patients experiencing grade 3 events. Moreover, 26% of patients discontinued bemarituzumab because of corneal adverse events.

Overall, this phase 2 trial demonstrated that FGFR2b is emerging as an important biomarker and target in patients with advanced gastroesophageal adenocarcinoma. Ongoing phase 3 trials (FORTITUDE-101 with FOLFOX [NCT05052801] and FORTITUDE-102 with FOLFOX and nivolumab [NCT05111626]) hopefully will confirm the early results seen in the FIGHT trial. Awareness and early attention to treatment-associated toxicities will be critical for the potential future incorporation of bemarituzumab into clinical practice.

A study by Ramos‐Santillan and colleagues explored whether the order of treatment modalities matter in the management of early-stage gastric cancer. Typically, perioperative chemotherapy (both neoadjuvant and adjuvant) is used during treatment of early-stage gastric cancer, which is usually defined as at least cT2N0 or cTxN+ disease. In this study, multivariable Cox regression analyses were performed on propensity score-matched cohorts. The study analyzed outcomes of 11,984 patients who were identified using the US National Cancer Database and treated between 2005 and 2014. The results revealed that patients who had stage I disease had better outcomes with upfront resection followed by adjuvant therapy. Patients with stage III disease did better with a neoadjuvant approach, whereas patients with stage II disease had similar outcomes regardless of chemotherapy timing. This research has the limitations inherent to the retrospective nature of the analysis and lack of prospective enrollment and controls. However, it does suggest that there may be a fraction of patients who should be treated with upfront resection. For incorporation of this change into standard practice, the question of therapy sequencing should be answered in a randomized prospective trial that incorporates the most updated systemic therapy (fluorouracil, leucovorin, oxaliplatin, and docetaxel [FLOT]) into its design.

Chemotherapy continues to play a critical role during first-line treatment of advanced esophageal and gastric adenocarcinoma. Triple chemotherapy regimens have been known to have increased efficacy in this setting, but their use has been limited by associated toxicities. A study by Nguyen and colleagues evaluated the TCX regimen (paclitaxel, carboplatin, and capecitabine) during first-line treatment of advanced gastric cancer. This regimen is similar to other triple chemotherapy regimens, such as FLOT and DCF (docetaxel, cisplatin, and fluorouracil), which have proven activity in this disease. This prospective phase 2 trial enrolled 83 patients. The median PFS (9.3 months) and OS (17 months) compared favorably with historical references. The regimen had expected adverse events, with cytopenias and fatigue being the most frequently reported. On the basis of the reported safety and efficacy, TCX has potential to be used as a chemotherapy backbone in future trials, but larger trials are needed to confirm the phase 2 trial results.

References

Wainberg ZA, Enzinger PC, Kang YK, et al. Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): A randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. 2022 Oct 13. Doi: 10.1016/S1470-2045(22)00603-9

The phase 2 FIGHT trial¹ evaluated the role of bemarituzumab, an anti-FGFR2 antibody, in combination with chemotherapy during first-line treatment of advanced gastroesophageal adenocarcinoma. The primary endpoint of this trial was progression-free survival (PFS). This trial enrolled 155 patients with upper gastrointestinal tumors with FGFR2b overexpression (defined as at least 2+ by immunohistochemistry) or amplification on next-generation sequencing. About 30% of patients with HER2 nonpositive tumors (ie, those that would not qualify for treatment with the targeted agent trastuzumab) were eligible for participation. In the FIGHT trial, patients were randomized in a 1:1 ratio to receive either standard chemotherapy (folinic acid, fluorouracil, and oxaliplatin [FOLFOX]) or chemotherapy plus bemarituzumab. Patients in the experimental group were allowed to receive one dose of standard FOLFOX chemotherapy while biomarker testing was ongoing.

With a median follow-up time of 10.9 moths, PFS was numerically prolonged in the bemarituzumab group (9.5 vs 7.4 months), but it did not reach statistical significance (P = .073). Overall survival (OS) was improved in the experimental group (not reached vs 12.9 months; P = .027). With a longer follow-up of 12.5 months, in post hoc exploratory analysis, OS was significantly longer in the experimental group (19.2 vs 13.5 months; hazard ratio 0.60, P = .027). The rate of serious adverse events was similar between the two groups. However, it is important to note ocular toxicities associated with bemarituzumab treatment. Corneal adverse events were seen in 67% of patients in the experimental group, with 24% of patients experiencing grade 3 events. Moreover, 26% of patients discontinued bemarituzumab because of corneal adverse events.

Overall, this phase 2 trial demonstrated that FGFR2b is emerging as an important biomarker and target in patients with advanced gastroesophageal adenocarcinoma. Ongoing phase 3 trials (FORTITUDE-101 with FOLFOX [NCT05052801] and FORTITUDE-102 with FOLFOX and nivolumab [NCT05111626]) hopefully will confirm the early results seen in the FIGHT trial. Awareness and early attention to treatment-associated toxicities will be critical for the potential future incorporation of bemarituzumab into clinical practice.

A study by Ramos‐Santillan and colleagues explored whether the order of treatment modalities matter in the management of early-stage gastric cancer. Typically, perioperative chemotherapy (both neoadjuvant and adjuvant) is used during treatment of early-stage gastric cancer, which is usually defined as at least cT2N0 or cTxN+ disease. In this study, multivariable Cox regression analyses were performed on propensity score-matched cohorts. The study analyzed outcomes of 11,984 patients who were identified using the US National Cancer Database and treated between 2005 and 2014. The results revealed that patients who had stage I disease had better outcomes with upfront resection followed by adjuvant therapy. Patients with stage III disease did better with a neoadjuvant approach, whereas patients with stage II disease had similar outcomes regardless of chemotherapy timing. This research has the limitations inherent to the retrospective nature of the analysis and lack of prospective enrollment and controls. However, it does suggest that there may be a fraction of patients who should be treated with upfront resection. For incorporation of this change into standard practice, the question of therapy sequencing should be answered in a randomized prospective trial that incorporates the most updated systemic therapy (fluorouracil, leucovorin, oxaliplatin, and docetaxel [FLOT]) into its design.

Chemotherapy continues to play a critical role during first-line treatment of advanced esophageal and gastric adenocarcinoma. Triple chemotherapy regimens have been known to have increased efficacy in this setting, but their use has been limited by associated toxicities. A study by Nguyen and colleagues evaluated the TCX regimen (paclitaxel, carboplatin, and capecitabine) during first-line treatment of advanced gastric cancer. This regimen is similar to other triple chemotherapy regimens, such as FLOT and DCF (docetaxel, cisplatin, and fluorouracil), which have proven activity in this disease. This prospective phase 2 trial enrolled 83 patients. The median PFS (9.3 months) and OS (17 months) compared favorably with historical references. The regimen had expected adverse events, with cytopenias and fatigue being the most frequently reported. On the basis of the reported safety and efficacy, TCX has potential to be used as a chemotherapy backbone in future trials, but larger trials are needed to confirm the phase 2 trial results.

References

Wainberg ZA, Enzinger PC, Kang YK, et al. Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): A randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. 2022 Oct 13. Doi: 10.1016/S1470-2045(22)00603-9

Once again, I have been given the distinct honor of analyzing two of the most provocative studies in colorectal cancer this month for Clinical Edge. The first study I will examine was done by Khamzina and colleagues and attempts to define the optimal time to perform surgery after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. In this retrospective analysis, 770 patients who received long-course chemoradiotherapy for rectal cancer followed by total mesorectal excision (TME) were analyzed by how long the interval was between completion of radiation and surgery. Patients were separated into two groups: 6-8 weeks (n = 502) vs >8 weeks (n = 268). Though the pathologic complete response rates and 5-year disease-free survival rates were not significantly different between the two groups, tumor regression grade was significantly better in the >8 weeks arm (P = .004). This result confirms many previous studies that demonstrate continued tumor shrinkage months after completion of chemoradiotherapy and may provide an explanation of why the OPRA trial demonstrated a higher TME-free rate in the chemoradiotherapy-then-chemotherapy arm than it did in the induction chemotherapy-then-chemoradiotherapy arm (53% vs 41%).

Schaefer and colleagues looked at the potential prognostic markers for efficacy of transarterial radioembolization (TARE) with ⁹⁰Y resin microspheres in the treatment of liver-dominant metastatic colorectal cancer (mCRC). Their study evaluated 237 patients with liver-dominant mCRC from the prospective observational CIRSE Registry for SIR-Spheres Therapy (CIRT) study who were scheduled to receive TARE with ⁹⁰Y resin microspheres. For these patients, the aspartate transaminase-to-platelet ratio index (APRI), international normalized ratio (INR), and albumin-bilirubin (ALBI) grade were measured prior to treatment to potentially detect values that might be associated with differential outcomes from TARE. An APRI > 0.40 independently predicted worse overall survival (OS) (hazard ratio [HR] 2.25; P < .0001), progression-free survival (PFS) (HR 1.42; P = .0416), and hepatic PFS (HR 1.50; P = .0207). The other independent predictors for worse OS and hepatic PFS were an INR value of < 1 (HR 1.66; P = .0091) and ALBI grade 3 (HR 5.29; P = .0075), respectively. It is very difficult to make much out of this study save to say that poorer liver function at baseline (at least with respect to APRI and ALBI) predicts worse outcomes after TARE, which is none too controversial an opinion. That said, APRI and ALBI may be able to provide an extra measure of granularity to determine who might be more of a marginal candidate for TARE than would categorization according to Child-Pugh score alone. Saving these patients from a potentially morbid procedure would be a significant benefit.

Once again, I have been given the distinct honor of analyzing two of the most provocative studies in colorectal cancer this month for Clinical Edge. The first study I will examine was done by Khamzina and colleagues and attempts to define the optimal time to perform surgery after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. In this retrospective analysis, 770 patients who received long-course chemoradiotherapy for rectal cancer followed by total mesorectal excision (TME) were analyzed by how long the interval was between completion of radiation and surgery. Patients were separated into two groups: 6-8 weeks (n = 502) vs >8 weeks (n = 268). Though the pathologic complete response rates and 5-year disease-free survival rates were not significantly different between the two groups, tumor regression grade was significantly better in the >8 weeks arm (P = .004). This result confirms many previous studies that demonstrate continued tumor shrinkage months after completion of chemoradiotherapy and may provide an explanation of why the OPRA trial demonstrated a higher TME-free rate in the chemoradiotherapy-then-chemotherapy arm than it did in the induction chemotherapy-then-chemoradiotherapy arm (53% vs 41%).

Schaefer and colleagues looked at the potential prognostic markers for efficacy of transarterial radioembolization (TARE) with ⁹⁰Y resin microspheres in the treatment of liver-dominant metastatic colorectal cancer (mCRC). Their study evaluated 237 patients with liver-dominant mCRC from the prospective observational CIRSE Registry for SIR-Spheres Therapy (CIRT) study who were scheduled to receive TARE with ⁹⁰Y resin microspheres. For these patients, the aspartate transaminase-to-platelet ratio index (APRI), international normalized ratio (INR), and albumin-bilirubin (ALBI) grade were measured prior to treatment to potentially detect values that might be associated with differential outcomes from TARE. An APRI > 0.40 independently predicted worse overall survival (OS) (hazard ratio [HR] 2.25; P < .0001), progression-free survival (PFS) (HR 1.42; P = .0416), and hepatic PFS (HR 1.50; P = .0207). The other independent predictors for worse OS and hepatic PFS were an INR value of < 1 (HR 1.66; P = .0091) and ALBI grade 3 (HR 5.29; P = .0075), respectively. It is very difficult to make much out of this study save to say that poorer liver function at baseline (at least with respect to APRI and ALBI) predicts worse outcomes after TARE, which is none too controversial an opinion. That said, APRI and ALBI may be able to provide an extra measure of granularity to determine who might be more of a marginal candidate for TARE than would categorization according to Child-Pugh score alone. Saving these patients from a potentially morbid procedure would be a significant benefit.

Once again, I have been given the distinct honor of analyzing two of the most provocative studies in colorectal cancer this month for Clinical Edge. The first study I will examine was done by Khamzina and colleagues and attempts to define the optimal time to perform surgery after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. In this retrospective analysis, 770 patients who received long-course chemoradiotherapy for rectal cancer followed by total mesorectal excision (TME) were analyzed by how long the interval was between completion of radiation and surgery. Patients were separated into two groups: 6-8 weeks (n = 502) vs >8 weeks (n = 268). Though the pathologic complete response rates and 5-year disease-free survival rates were not significantly different between the two groups, tumor regression grade was significantly better in the >8 weeks arm (P = .004). This result confirms many previous studies that demonstrate continued tumor shrinkage months after completion of chemoradiotherapy and may provide an explanation of why the OPRA trial demonstrated a higher TME-free rate in the chemoradiotherapy-then-chemotherapy arm than it did in the induction chemotherapy-then-chemoradiotherapy arm (53% vs 41%).

Schaefer and colleagues looked at the potential prognostic markers for efficacy of transarterial radioembolization (TARE) with ⁹⁰Y resin microspheres in the treatment of liver-dominant metastatic colorectal cancer (mCRC). Their study evaluated 237 patients with liver-dominant mCRC from the prospective observational CIRSE Registry for SIR-Spheres Therapy (CIRT) study who were scheduled to receive TARE with ⁹⁰Y resin microspheres. For these patients, the aspartate transaminase-to-platelet ratio index (APRI), international normalized ratio (INR), and albumin-bilirubin (ALBI) grade were measured prior to treatment to potentially detect values that might be associated with differential outcomes from TARE. An APRI > 0.40 independently predicted worse overall survival (OS) (hazard ratio [HR] 2.25; P < .0001), progression-free survival (PFS) (HR 1.42; P = .0416), and hepatic PFS (HR 1.50; P = .0207). The other independent predictors for worse OS and hepatic PFS were an INR value of < 1 (HR 1.66; P = .0091) and ALBI grade 3 (HR 5.29; P = .0075), respectively. It is very difficult to make much out of this study save to say that poorer liver function at baseline (at least with respect to APRI and ALBI) predicts worse outcomes after TARE, which is none too controversial an opinion. That said, APRI and ALBI may be able to provide an extra measure of granularity to determine who might be more of a marginal candidate for TARE than would categorization according to Child-Pugh score alone. Saving these patients from a potentially morbid procedure would be a significant benefit.