Opinion

Becker’s nevus

The history and physical exam are most consistent with Becker’s nevus, also known as Becker’s melanosis. This is a benign cutaneous hamartoma, usually found in males, characterized by a large, irregularly shaped brown patch, often with hypertrichosis.¹ Becker’s nevus can be congenital but is more commonly noticed in late childhood or early adolescence, with thickening, increased pigmentation, and hair growth. Becker’s nevus is considered an overgrowth of epidermal pigment cells and hair follicles and is thought to be attributable to postzygotic mutations (with ACTB mutations most reported).¹ It is often located unilaterally on the upper trunk but is occasionally present elsewhere on the body. Acne may occasionally develop within the nevus, which is believed to be triggered by puberty-associated androgens.¹ The lesion tends to persist indefinitely but has no propensity for malignant transformation.

Becker’s nevus is generally an isolated skin lesion without other anomalies. However, in rare instances, it may be associated with ipsilateral breast hypoplasia or hypoplastic defects of the muscle, skin, or skeleton, which is known as Becker’s nevus syndrome.² Treatment is not medically warranted for an isolated Becker’s nevus but may be pursued for cosmetic reasons. Although treatment is generally discouraged because of variable success, laser hair removal and laser therapy may be pursued to address the hypertrichosis and hyperpigmentation, respectively.
 

What is on the differential?

A café-au-lait macule (CALM) is a light- to dark-brown, oval lesion that commonly presents at birth or in early childhood. CALMs vary widely in size from less than 1.5 cm to more than 20 cm in diameter. They are asymptomatic and grow in proportion to the individual over time.³ Becker’s nevus can be distinguished from CALMs by the development of hypertrichosis, typical location and course, and other skin changes within the nevus.

Postinflammatory hyperpigmentation (PIH) is characterized by asymptomatic, darkened macules or patches that are brown to blue-gray in color. It is one of the most common causes of hyperpigmentation, particularly in skin of color, and can take months to years to resolve. PIH is caused by increased melanin production in response to a cutaneous inflammatory process, such as a drug reaction, allergy, mechanical or thermal injury, infection, phototoxicity, or an underlying skin condition.³ Our patient’s history with the lack of an inciting inflammatory process is more consistent with Becker’s nevus.

Erythema ab igne is a cutaneous reaction to heat that presents as a hyperpigmented patch with a reticular or mottled configuration and superficial venular telangiectasia. The lesion is initially erythematous and progresses to a pale pink to purplish dark-brown color.⁴ Causes include long-term use of a heating pad, laptop, electric blanket, or a hot water bottle. The absence of prolonged heat exposure in our patient’s history does not favor erythema ab igne.

Pigmentary mosaicism is characterized by a distinctive pattern of hyperpigmentation that follows the lines of ectodermal embryologic development, known as the lines of Blaschko.⁵ This condition is also known as linear and whorled nevoid hypermelanosis because of its streaky or swirl-like pattern. Pigmentary mosaicism can be present at birth or appear within the first few weeks of life. It is caused by genetic heterogeneity in neuroectodermal cells, which results in skin with areas of varying colors. Pigmentary mosaicism is unlikely in this case as our patient’s lesion does not follow the lines of Blaschko.
 

Ms. Laborada is a pediatric dermatology research associate in the division of pediatric and adolescent dermatology at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Eichenfield is the vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego, and Rady Children’s Hospital. Ms. Laborada and Dr. Eichenfield have no relevant financial disclosures.

References

1. Atzmony L et al. J Cutan Pathol. 2020;47(8):681-5.

2. Danarti R et al. J Am Acad Dermatol. 2004;51(6):965-9.

3. Paller A and Mancini AJ. “Hurwitz Clinical Pediatric Dermatology: A textbook of skin disorders of childhood and adolescence” 4th ed. Philadelphia: Elsevier Saunders, 2011.

4. Patel DP. JAMA Dermatol. 2017;153(7):685.

5. Kromann AB et al. Orphanet J Rare Dis. 2018;13(1):39.

Becker’s nevus

The history and physical exam are most consistent with Becker’s nevus, also known as Becker’s melanosis. This is a benign cutaneous hamartoma, usually found in males, characterized by a large, irregularly shaped brown patch, often with hypertrichosis.¹ Becker’s nevus can be congenital but is more commonly noticed in late childhood or early adolescence, with thickening, increased pigmentation, and hair growth. Becker’s nevus is considered an overgrowth of epidermal pigment cells and hair follicles and is thought to be attributable to postzygotic mutations (with ACTB mutations most reported).¹ It is often located unilaterally on the upper trunk but is occasionally present elsewhere on the body. Acne may occasionally develop within the nevus, which is believed to be triggered by puberty-associated androgens.¹ The lesion tends to persist indefinitely but has no propensity for malignant transformation.

Becker’s nevus is generally an isolated skin lesion without other anomalies. However, in rare instances, it may be associated with ipsilateral breast hypoplasia or hypoplastic defects of the muscle, skin, or skeleton, which is known as Becker’s nevus syndrome.² Treatment is not medically warranted for an isolated Becker’s nevus but may be pursued for cosmetic reasons. Although treatment is generally discouraged because of variable success, laser hair removal and laser therapy may be pursued to address the hypertrichosis and hyperpigmentation, respectively.
 

What is on the differential?

A café-au-lait macule (CALM) is a light- to dark-brown, oval lesion that commonly presents at birth or in early childhood. CALMs vary widely in size from less than 1.5 cm to more than 20 cm in diameter. They are asymptomatic and grow in proportion to the individual over time.³ Becker’s nevus can be distinguished from CALMs by the development of hypertrichosis, typical location and course, and other skin changes within the nevus.

Postinflammatory hyperpigmentation (PIH) is characterized by asymptomatic, darkened macules or patches that are brown to blue-gray in color. It is one of the most common causes of hyperpigmentation, particularly in skin of color, and can take months to years to resolve. PIH is caused by increased melanin production in response to a cutaneous inflammatory process, such as a drug reaction, allergy, mechanical or thermal injury, infection, phototoxicity, or an underlying skin condition.³ Our patient’s history with the lack of an inciting inflammatory process is more consistent with Becker’s nevus.

Erythema ab igne is a cutaneous reaction to heat that presents as a hyperpigmented patch with a reticular or mottled configuration and superficial venular telangiectasia. The lesion is initially erythematous and progresses to a pale pink to purplish dark-brown color.⁴ Causes include long-term use of a heating pad, laptop, electric blanket, or a hot water bottle. The absence of prolonged heat exposure in our patient’s history does not favor erythema ab igne.

Pigmentary mosaicism is characterized by a distinctive pattern of hyperpigmentation that follows the lines of ectodermal embryologic development, known as the lines of Blaschko.⁵ This condition is also known as linear and whorled nevoid hypermelanosis because of its streaky or swirl-like pattern. Pigmentary mosaicism can be present at birth or appear within the first few weeks of life. It is caused by genetic heterogeneity in neuroectodermal cells, which results in skin with areas of varying colors. Pigmentary mosaicism is unlikely in this case as our patient’s lesion does not follow the lines of Blaschko.
 

Ms. Laborada is a pediatric dermatology research associate in the division of pediatric and adolescent dermatology at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Eichenfield is the vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego, and Rady Children’s Hospital. Ms. Laborada and Dr. Eichenfield have no relevant financial disclosures.

References

1. Atzmony L et al. J Cutan Pathol. 2020;47(8):681-5.

2. Danarti R et al. J Am Acad Dermatol. 2004;51(6):965-9.

3. Paller A and Mancini AJ. “Hurwitz Clinical Pediatric Dermatology: A textbook of skin disorders of childhood and adolescence” 4th ed. Philadelphia: Elsevier Saunders, 2011.

4. Patel DP. JAMA Dermatol. 2017;153(7):685.

5. Kromann AB et al. Orphanet J Rare Dis. 2018;13(1):39.

Becker’s nevus

The history and physical exam are most consistent with Becker’s nevus, also known as Becker’s melanosis. This is a benign cutaneous hamartoma, usually found in males, characterized by a large, irregularly shaped brown patch, often with hypertrichosis.¹ Becker’s nevus can be congenital but is more commonly noticed in late childhood or early adolescence, with thickening, increased pigmentation, and hair growth. Becker’s nevus is considered an overgrowth of epidermal pigment cells and hair follicles and is thought to be attributable to postzygotic mutations (with ACTB mutations most reported).¹ It is often located unilaterally on the upper trunk but is occasionally present elsewhere on the body. Acne may occasionally develop within the nevus, which is believed to be triggered by puberty-associated androgens.¹ The lesion tends to persist indefinitely but has no propensity for malignant transformation.

Becker’s nevus is generally an isolated skin lesion without other anomalies. However, in rare instances, it may be associated with ipsilateral breast hypoplasia or hypoplastic defects of the muscle, skin, or skeleton, which is known as Becker’s nevus syndrome.² Treatment is not medically warranted for an isolated Becker’s nevus but may be pursued for cosmetic reasons. Although treatment is generally discouraged because of variable success, laser hair removal and laser therapy may be pursued to address the hypertrichosis and hyperpigmentation, respectively.
 

What is on the differential?

A café-au-lait macule (CALM) is a light- to dark-brown, oval lesion that commonly presents at birth or in early childhood. CALMs vary widely in size from less than 1.5 cm to more than 20 cm in diameter. They are asymptomatic and grow in proportion to the individual over time.³ Becker’s nevus can be distinguished from CALMs by the development of hypertrichosis, typical location and course, and other skin changes within the nevus.

Postinflammatory hyperpigmentation (PIH) is characterized by asymptomatic, darkened macules or patches that are brown to blue-gray in color. It is one of the most common causes of hyperpigmentation, particularly in skin of color, and can take months to years to resolve. PIH is caused by increased melanin production in response to a cutaneous inflammatory process, such as a drug reaction, allergy, mechanical or thermal injury, infection, phototoxicity, or an underlying skin condition.³ Our patient’s history with the lack of an inciting inflammatory process is more consistent with Becker’s nevus.

Erythema ab igne is a cutaneous reaction to heat that presents as a hyperpigmented patch with a reticular or mottled configuration and superficial venular telangiectasia. The lesion is initially erythematous and progresses to a pale pink to purplish dark-brown color.⁴ Causes include long-term use of a heating pad, laptop, electric blanket, or a hot water bottle. The absence of prolonged heat exposure in our patient’s history does not favor erythema ab igne.

Pigmentary mosaicism is characterized by a distinctive pattern of hyperpigmentation that follows the lines of ectodermal embryologic development, known as the lines of Blaschko.⁵ This condition is also known as linear and whorled nevoid hypermelanosis because of its streaky or swirl-like pattern. Pigmentary mosaicism can be present at birth or appear within the first few weeks of life. It is caused by genetic heterogeneity in neuroectodermal cells, which results in skin with areas of varying colors. Pigmentary mosaicism is unlikely in this case as our patient’s lesion does not follow the lines of Blaschko.
 

Ms. Laborada is a pediatric dermatology research associate in the division of pediatric and adolescent dermatology at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Eichenfield is the vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego, and Rady Children’s Hospital. Ms. Laborada and Dr. Eichenfield have no relevant financial disclosures.

References

1. Atzmony L et al. J Cutan Pathol. 2020;47(8):681-5.

2. Danarti R et al. J Am Acad Dermatol. 2004;51(6):965-9.

3. Paller A and Mancini AJ. “Hurwitz Clinical Pediatric Dermatology: A textbook of skin disorders of childhood and adolescence” 4th ed. Philadelphia: Elsevier Saunders, 2011.

4. Patel DP. JAMA Dermatol. 2017;153(7):685.

5. Kromann AB et al. Orphanet J Rare Dis. 2018;13(1):39.

Norovirus, as noted above, is now the most common cause of medically attended acute gastroenteritis (AGE) in the United States. Norovirus AGE resembles rotavirus AGE, but a bit heavier on the vomiting. What makes it scary is that it is a low-inoculum infection (as few as 16 virus particles can cause infection), and it survives for prolonged periods in food, 10% chlorinated water, and on environmental surfaces (J Med Virol 2008;80:1468-76); hence, the infamous outbreaks on cruise ships and daycare centers. So a vaccine would be very welcome. The two non-Chinese candidates GI.1/GII.4 vaccines are Takeda’s VLP vaccine and Vaxart’s oral adenovirus vector-based vaccine. 
Takeda’s is injectable. If VLP sounds familiar, VLPs make up the FDA-approved HPV vaccine we use. Two doses of various formulations were tested in a recent phase 2 study of 1- to 3- and 4- to 8-year-olds in Finland, Panama, and Colombia with no safety issues identified. The 1- to 3-year-olds responded somewhat better than 4- to 8-year-olds, and titers remained elevated up to day 210 (Vaccine. 2022 Jun 9;40[26]:3588-96).

A recently as yet unpublished phase 1b trial of Vaxart’s vaccine in 55- to 80-year-olds (NCT04854746) showed a dose-dependent response. IgA mucosal cell responses were similar to those in younger adults. Adverse event profiles were similar between vaccinees and placebo recipients. 

Progress continues for both vaccines, but we await efficacy trials. We are likely still years from a pediatric vaccine. My sense is that an oral vaccine would be more readily accepted into the pediatric schedule, but how to incorporate it and not cause issues with the rotavirus vaccine will need evaluation.

Christopher J. Harrison, MD, is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. He has no financial conflicts of interest.

Norovirus, as noted above, is now the most common cause of medically attended acute gastroenteritis (AGE) in the United States. Norovirus AGE resembles rotavirus AGE, but a bit heavier on the vomiting. What makes it scary is that it is a low-inoculum infection (as few as 16 virus particles can cause infection), and it survives for prolonged periods in food, 10% chlorinated water, and on environmental surfaces (J Med Virol 2008;80:1468-76); hence, the infamous outbreaks on cruise ships and daycare centers. So a vaccine would be very welcome. The two non-Chinese candidates GI.1/GII.4 vaccines are Takeda’s VLP vaccine and Vaxart’s oral adenovirus vector-based vaccine. 
Takeda’s is injectable. If VLP sounds familiar, VLPs make up the FDA-approved HPV vaccine we use. Two doses of various formulations were tested in a recent phase 2 study of 1- to 3- and 4- to 8-year-olds in Finland, Panama, and Colombia with no safety issues identified. The 1- to 3-year-olds responded somewhat better than 4- to 8-year-olds, and titers remained elevated up to day 210 (Vaccine. 2022 Jun 9;40[26]:3588-96).

A recently as yet unpublished phase 1b trial of Vaxart’s vaccine in 55- to 80-year-olds (NCT04854746) showed a dose-dependent response. IgA mucosal cell responses were similar to those in younger adults. Adverse event profiles were similar between vaccinees and placebo recipients. 

Progress continues for both vaccines, but we await efficacy trials. We are likely still years from a pediatric vaccine. My sense is that an oral vaccine would be more readily accepted into the pediatric schedule, but how to incorporate it and not cause issues with the rotavirus vaccine will need evaluation.

Christopher J. Harrison, MD, is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. He has no financial conflicts of interest.

Norovirus, as noted above, is now the most common cause of medically attended acute gastroenteritis (AGE) in the United States. Norovirus AGE resembles rotavirus AGE, but a bit heavier on the vomiting. What makes it scary is that it is a low-inoculum infection (as few as 16 virus particles can cause infection), and it survives for prolonged periods in food, 10% chlorinated water, and on environmental surfaces (J Med Virol 2008;80:1468-76); hence, the infamous outbreaks on cruise ships and daycare centers. So a vaccine would be very welcome. The two non-Chinese candidates GI.1/GII.4 vaccines are Takeda’s VLP vaccine and Vaxart’s oral adenovirus vector-based vaccine. 
Takeda’s is injectable. If VLP sounds familiar, VLPs make up the FDA-approved HPV vaccine we use. Two doses of various formulations were tested in a recent phase 2 study of 1- to 3- and 4- to 8-year-olds in Finland, Panama, and Colombia with no safety issues identified. The 1- to 3-year-olds responded somewhat better than 4- to 8-year-olds, and titers remained elevated up to day 210 (Vaccine. 2022 Jun 9;40[26]:3588-96).

A recently as yet unpublished phase 1b trial of Vaxart’s vaccine in 55- to 80-year-olds (NCT04854746) showed a dose-dependent response. IgA mucosal cell responses were similar to those in younger adults. Adverse event profiles were similar between vaccinees and placebo recipients. 

Progress continues for both vaccines, but we await efficacy trials. We are likely still years from a pediatric vaccine. My sense is that an oral vaccine would be more readily accepted into the pediatric schedule, but how to incorporate it and not cause issues with the rotavirus vaccine will need evaluation.

Christopher J. Harrison, MD, is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. He has no financial conflicts of interest.

In spring 2022 the World Health Organization did release the new guidelines (module 5) for the shorter (4 month) regimen for 3-month- to 16-year-olds with nonsevere pulmonary tuberculosis (TB) limited to one lobe that is also smear-negative and at least presumed to be due to drug-susceptible M. tuberculosis. This regimen is NOT for children with clinically significant airway obstruction, cavitary disease, miliary TB, complex pleural effusion, or peripheral lymph node involvement. The newly recommended regimen consists of 8 weeks as an “intensive phase” (isoniazid, rifampin, pyrazinamide, and ethambutol, per local guidance) followed by 8 weeks of a “continuation phase” (isoniazid and rifampin only). Of note, the Turkova study had shown nearly identical adverse event and adherence rates – 8% and 94% – for both the short- and traditional-length regimens. The onerous multidrug treatment of uncomplicated TB in most children has become less onerous.

Caveat: The newly recommended 4-month schedule (March 2022) of traditional TB drugs is not to be confused with rifapentine-moxifloxacin–based 4-month regimen recommended by the WHO in June 2021 (CDC added guidance February 2022). This rifapentine-based regimen had been okayed for patients 12 years or older weighing at least 40 kg and also with drug-susceptible pulmonary TB, but no extrapulmonary involvement.
The new shorter regimen shows the value of trials in non-U.S. countries. The careful work in Africa and India has borne fruit that makes things easier for families, providers, and public health organizations.

Christopher J. Harrison, MD, is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. He has no financial conflicts of interest.

In spring 2022 the World Health Organization did release the new guidelines (module 5) for the shorter (4 month) regimen for 3-month- to 16-year-olds with nonsevere pulmonary tuberculosis (TB) limited to one lobe that is also smear-negative and at least presumed to be due to drug-susceptible M. tuberculosis. This regimen is NOT for children with clinically significant airway obstruction, cavitary disease, miliary TB, complex pleural effusion, or peripheral lymph node involvement. The newly recommended regimen consists of 8 weeks as an “intensive phase” (isoniazid, rifampin, pyrazinamide, and ethambutol, per local guidance) followed by 8 weeks of a “continuation phase” (isoniazid and rifampin only). Of note, the Turkova study had shown nearly identical adverse event and adherence rates – 8% and 94% – for both the short- and traditional-length regimens. The onerous multidrug treatment of uncomplicated TB in most children has become less onerous.

Caveat: The newly recommended 4-month schedule (March 2022) of traditional TB drugs is not to be confused with rifapentine-moxifloxacin–based 4-month regimen recommended by the WHO in June 2021 (CDC added guidance February 2022). This rifapentine-based regimen had been okayed for patients 12 years or older weighing at least 40 kg and also with drug-susceptible pulmonary TB, but no extrapulmonary involvement.
The new shorter regimen shows the value of trials in non-U.S. countries. The careful work in Africa and India has borne fruit that makes things easier for families, providers, and public health organizations.

Christopher J. Harrison, MD, is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. He has no financial conflicts of interest.

In spring 2022 the World Health Organization did release the new guidelines (module 5) for the shorter (4 month) regimen for 3-month- to 16-year-olds with nonsevere pulmonary tuberculosis (TB) limited to one lobe that is also smear-negative and at least presumed to be due to drug-susceptible M. tuberculosis. This regimen is NOT for children with clinically significant airway obstruction, cavitary disease, miliary TB, complex pleural effusion, or peripheral lymph node involvement. The newly recommended regimen consists of 8 weeks as an “intensive phase” (isoniazid, rifampin, pyrazinamide, and ethambutol, per local guidance) followed by 8 weeks of a “continuation phase” (isoniazid and rifampin only). Of note, the Turkova study had shown nearly identical adverse event and adherence rates – 8% and 94% – for both the short- and traditional-length regimens. The onerous multidrug treatment of uncomplicated TB in most children has become less onerous.

Caveat: The newly recommended 4-month schedule (March 2022) of traditional TB drugs is not to be confused with rifapentine-moxifloxacin–based 4-month regimen recommended by the WHO in June 2021 (CDC added guidance February 2022). This rifapentine-based regimen had been okayed for patients 12 years or older weighing at least 40 kg and also with drug-susceptible pulmonary TB, but no extrapulmonary involvement.
The new shorter regimen shows the value of trials in non-U.S. countries. The careful work in Africa and India has borne fruit that makes things easier for families, providers, and public health organizations.

Christopher J. Harrison, MD, is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. He has no financial conflicts of interest.

The standard management for early-stage endometrial cancer involves surgery with hysterectomy, salpingectomy with or without oophorectomy, and staging lymph node sampling. Surgery serves as both a therapeutic and diagnostic intervention because surgical pathology results are in turn used to predict the likelihood of relapse and guide adjuvant therapy decisions. However, in some cases, surgical intervention is not feasible or desired, particularly if fertility preservation is a goal. Fortunately, there are nonsurgical options that are associated with favorable outcomes to offer these patients.

Endometrial cancer is associated with obesity attributable to causative mechanisms that promote endometrial hyperplasia, cellular proliferation, and heightened hormonal and growth factor signaling. Not only does obesity drive the development of endometrial cancer, but it also complicates the treatment of the disease. For example, endometrial cancer staging surgery is less successfully completed through a minimally invasive route as body mass index increases, primarily because of limitations in surgical exposure.¹ In fact, obesity can prevent surgery from being offered through any route. In addition to body habitus, determination of inoperability is also significantly influenced by the presence of coronary artery disease, hypertension, and diabetes.² Given that these comorbidities are more commonly experienced by women who are overweight, obesity creates a perfect storm of causative and complicating factors for optimal treatment.

While surgeons may determine the candidacy of patients for hysterectomy, patients themselves also drive this decision-making, particularly in the case of young patients who desire fertility preservation. Approximately 10% of patients with endometrial cancer are premenopausal, a number that is increasing over time. These women may have experienced infertility prior to their diagnosis, yet still strongly desire the attempt to conceive, particularly if they have suffered from anovulatory menstrual cycles or polycystic ovarian disease. Women with Lynch syndrome are at a higher risk for developing their cancer in premenopausal years. Therefore, it is critical that gynecologic oncologists consider nonsurgical remedies for these women and understand their potential for success.

Certain criteria should be met for women undergoing nonsurgical management of endometrial cancer, particularly if chosen electively for fertility preservation. Diagnosis should be obtained with a curettage specimen (rather than a pipelle) to optimize the accuracy of establishing tumor grade and to “debulk” the endometrial tissue. Pretreatment imaging is necessary to rule out distant metastatic disease. MRI is particularly helpful in approximating the depth of myometrial invasion of the malignancy and is recommended for patients desiring fertility preservation. Patients who have an endometrial cancer that is deeply invasive into the myometrium are poor candidates for fertility preservation and have a higher risk for metastatic disease, particularly to lymph nodes, and treatment decisions (such as surgery, or, if inoperable, radiation which treats nodal basins) should be considered for these women.

Hormonal therapy has long been identified as a highly effective systemic therapy for endometrial cancers, particularly those that are low grade and express estrogen and progesterone receptors. Progesterone can be administered orally in preparations such as megestrol or medroxyprogesterone or “locally” with levonorgestrel-releasing intrauterine devices. Oral preparations are straightforward, typically low-cost agents. Likelihood of success is 50%-75%. However, the systemic side effects of these agents, which include increased venous thromboembolism risk and appetite stimulation, are particularly problematic in this population. Therefore, many providers prefer to place progestin-releasing intrauterine devices to “bypass” these side effects, avoid issues with adherence to dosing, and provide some preventative endometrial coverage after resolution of the cancer. Recent trials have observed elimination of endometrial cancer on repeat sampling in 67%-76% of cases.^3-5 This strategy may be more successful when it is paired with the addition of GnRH agonists.⁴

When hormonal therapy is chosen for primary endometrial cancer treatment, it is typically monitored for efficacy with repeat endometrial samplings, most commonly with pipelle biopsies to avoid displacement of an intrauterine device, though repeat D&C may be more effective in achieving a complete pathologic response to treatment. Most providers recommend resampling the endometrium at 3-month intervals until resolution of the malignancy has been documented, and thereafter if any new bleeding events develop. For women who have demonstrated resolution of carcinoma on repeat sampling, data are lacking to guide decision-making regarding resumption of conception efforts, ongoing surveillance, and completion hysterectomy after they finish childbearing. If malignancy continues to be identified after 6 months of hormonal therapy, consideration should be made of a more definitive treatment (such as surgery, if feasible, or radiation if not). Continued hormonal therapy can also be considered, as delayed responses remain common even 1 year after starting therapy.⁶ If hormonal therapy is prolonged for persistent disease, repeat MRI is recommended at 6 months to document lack of progression.

Radiation, preferably with both intracavitary and external beam treatment, is the most definitive intervention for inoperable early-stage endometrial cancer. Unfortunately, fertility is not preserved with this approach. However, for patients with high-grade tumors that are less likely to express hormone receptors or respond to hormonal therapies, this may be the only treatment option available. Typical treatment courses include 5 weeks of external beam radiation treatments, focused on treating the pelvis as a whole, including occult metastases not identified on imaging. Optimal therapy also includes placement of intracavitary radiation implants, such as Heymans capsules, to concentrate the dose at the uterine fundus, while minimizing toxicity to the adjacent bladder and bowel structures. While definitive radiation is considered inferior to a primary surgical effort, disease-specific survival can be observed in more than 80% of patients treated this way.⁷

While surgery remains the standard intervention for women with early-stage endometrial cancer, hormonal therapy or radiation remain viable options with high rates of success for women who are not surgical candidates or who desire fertility preservation.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Walker JL et al. J Clin Oncol. 2009;27(32):5331-6.

2. Ertel M et al. Ann Surg Oncol. 2021;28(13):8987-95.

3. Janda M et al. Gynecol Oncol. 2021;161(1):143-51.

4. Novikova OV et al. Gynecol Oncol. 2021;161(1):152-9.

5. Westin SN et al. Am J Obstet Gynecol. 2021;224(2):191.e1-15.

6. Cho A et al. Gynecol Oncol. 2021;160(2):413-17.

7. Dutta SW et al. Brachytherapy. 2017;16(3):526-33.

The standard management for early-stage endometrial cancer involves surgery with hysterectomy, salpingectomy with or without oophorectomy, and staging lymph node sampling. Surgery serves as both a therapeutic and diagnostic intervention because surgical pathology results are in turn used to predict the likelihood of relapse and guide adjuvant therapy decisions. However, in some cases, surgical intervention is not feasible or desired, particularly if fertility preservation is a goal. Fortunately, there are nonsurgical options that are associated with favorable outcomes to offer these patients.

Endometrial cancer is associated with obesity attributable to causative mechanisms that promote endometrial hyperplasia, cellular proliferation, and heightened hormonal and growth factor signaling. Not only does obesity drive the development of endometrial cancer, but it also complicates the treatment of the disease. For example, endometrial cancer staging surgery is less successfully completed through a minimally invasive route as body mass index increases, primarily because of limitations in surgical exposure.¹ In fact, obesity can prevent surgery from being offered through any route. In addition to body habitus, determination of inoperability is also significantly influenced by the presence of coronary artery disease, hypertension, and diabetes.² Given that these comorbidities are more commonly experienced by women who are overweight, obesity creates a perfect storm of causative and complicating factors for optimal treatment.

While surgeons may determine the candidacy of patients for hysterectomy, patients themselves also drive this decision-making, particularly in the case of young patients who desire fertility preservation. Approximately 10% of patients with endometrial cancer are premenopausal, a number that is increasing over time. These women may have experienced infertility prior to their diagnosis, yet still strongly desire the attempt to conceive, particularly if they have suffered from anovulatory menstrual cycles or polycystic ovarian disease. Women with Lynch syndrome are at a higher risk for developing their cancer in premenopausal years. Therefore, it is critical that gynecologic oncologists consider nonsurgical remedies for these women and understand their potential for success.

Certain criteria should be met for women undergoing nonsurgical management of endometrial cancer, particularly if chosen electively for fertility preservation. Diagnosis should be obtained with a curettage specimen (rather than a pipelle) to optimize the accuracy of establishing tumor grade and to “debulk” the endometrial tissue. Pretreatment imaging is necessary to rule out distant metastatic disease. MRI is particularly helpful in approximating the depth of myometrial invasion of the malignancy and is recommended for patients desiring fertility preservation. Patients who have an endometrial cancer that is deeply invasive into the myometrium are poor candidates for fertility preservation and have a higher risk for metastatic disease, particularly to lymph nodes, and treatment decisions (such as surgery, or, if inoperable, radiation which treats nodal basins) should be considered for these women.

Hormonal therapy has long been identified as a highly effective systemic therapy for endometrial cancers, particularly those that are low grade and express estrogen and progesterone receptors. Progesterone can be administered orally in preparations such as megestrol or medroxyprogesterone or “locally” with levonorgestrel-releasing intrauterine devices. Oral preparations are straightforward, typically low-cost agents. Likelihood of success is 50%-75%. However, the systemic side effects of these agents, which include increased venous thromboembolism risk and appetite stimulation, are particularly problematic in this population. Therefore, many providers prefer to place progestin-releasing intrauterine devices to “bypass” these side effects, avoid issues with adherence to dosing, and provide some preventative endometrial coverage after resolution of the cancer. Recent trials have observed elimination of endometrial cancer on repeat sampling in 67%-76% of cases.^3-5 This strategy may be more successful when it is paired with the addition of GnRH agonists.⁴

When hormonal therapy is chosen for primary endometrial cancer treatment, it is typically monitored for efficacy with repeat endometrial samplings, most commonly with pipelle biopsies to avoid displacement of an intrauterine device, though repeat D&C may be more effective in achieving a complete pathologic response to treatment. Most providers recommend resampling the endometrium at 3-month intervals until resolution of the malignancy has been documented, and thereafter if any new bleeding events develop. For women who have demonstrated resolution of carcinoma on repeat sampling, data are lacking to guide decision-making regarding resumption of conception efforts, ongoing surveillance, and completion hysterectomy after they finish childbearing. If malignancy continues to be identified after 6 months of hormonal therapy, consideration should be made of a more definitive treatment (such as surgery, if feasible, or radiation if not). Continued hormonal therapy can also be considered, as delayed responses remain common even 1 year after starting therapy.⁶ If hormonal therapy is prolonged for persistent disease, repeat MRI is recommended at 6 months to document lack of progression.

Radiation, preferably with both intracavitary and external beam treatment, is the most definitive intervention for inoperable early-stage endometrial cancer. Unfortunately, fertility is not preserved with this approach. However, for patients with high-grade tumors that are less likely to express hormone receptors or respond to hormonal therapies, this may be the only treatment option available. Typical treatment courses include 5 weeks of external beam radiation treatments, focused on treating the pelvis as a whole, including occult metastases not identified on imaging. Optimal therapy also includes placement of intracavitary radiation implants, such as Heymans capsules, to concentrate the dose at the uterine fundus, while minimizing toxicity to the adjacent bladder and bowel structures. While definitive radiation is considered inferior to a primary surgical effort, disease-specific survival can be observed in more than 80% of patients treated this way.⁷

While surgery remains the standard intervention for women with early-stage endometrial cancer, hormonal therapy or radiation remain viable options with high rates of success for women who are not surgical candidates or who desire fertility preservation.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Walker JL et al. J Clin Oncol. 2009;27(32):5331-6.

2. Ertel M et al. Ann Surg Oncol. 2021;28(13):8987-95.

3. Janda M et al. Gynecol Oncol. 2021;161(1):143-51.

4. Novikova OV et al. Gynecol Oncol. 2021;161(1):152-9.

5. Westin SN et al. Am J Obstet Gynecol. 2021;224(2):191.e1-15.

6. Cho A et al. Gynecol Oncol. 2021;160(2):413-17.

7. Dutta SW et al. Brachytherapy. 2017;16(3):526-33.

The standard management for early-stage endometrial cancer involves surgery with hysterectomy, salpingectomy with or without oophorectomy, and staging lymph node sampling. Surgery serves as both a therapeutic and diagnostic intervention because surgical pathology results are in turn used to predict the likelihood of relapse and guide adjuvant therapy decisions. However, in some cases, surgical intervention is not feasible or desired, particularly if fertility preservation is a goal. Fortunately, there are nonsurgical options that are associated with favorable outcomes to offer these patients.

Endometrial cancer is associated with obesity attributable to causative mechanisms that promote endometrial hyperplasia, cellular proliferation, and heightened hormonal and growth factor signaling. Not only does obesity drive the development of endometrial cancer, but it also complicates the treatment of the disease. For example, endometrial cancer staging surgery is less successfully completed through a minimally invasive route as body mass index increases, primarily because of limitations in surgical exposure.¹ In fact, obesity can prevent surgery from being offered through any route. In addition to body habitus, determination of inoperability is also significantly influenced by the presence of coronary artery disease, hypertension, and diabetes.² Given that these comorbidities are more commonly experienced by women who are overweight, obesity creates a perfect storm of causative and complicating factors for optimal treatment.

While surgeons may determine the candidacy of patients for hysterectomy, patients themselves also drive this decision-making, particularly in the case of young patients who desire fertility preservation. Approximately 10% of patients with endometrial cancer are premenopausal, a number that is increasing over time. These women may have experienced infertility prior to their diagnosis, yet still strongly desire the attempt to conceive, particularly if they have suffered from anovulatory menstrual cycles or polycystic ovarian disease. Women with Lynch syndrome are at a higher risk for developing their cancer in premenopausal years. Therefore, it is critical that gynecologic oncologists consider nonsurgical remedies for these women and understand their potential for success.

Certain criteria should be met for women undergoing nonsurgical management of endometrial cancer, particularly if chosen electively for fertility preservation. Diagnosis should be obtained with a curettage specimen (rather than a pipelle) to optimize the accuracy of establishing tumor grade and to “debulk” the endometrial tissue. Pretreatment imaging is necessary to rule out distant metastatic disease. MRI is particularly helpful in approximating the depth of myometrial invasion of the malignancy and is recommended for patients desiring fertility preservation. Patients who have an endometrial cancer that is deeply invasive into the myometrium are poor candidates for fertility preservation and have a higher risk for metastatic disease, particularly to lymph nodes, and treatment decisions (such as surgery, or, if inoperable, radiation which treats nodal basins) should be considered for these women.

Hormonal therapy has long been identified as a highly effective systemic therapy for endometrial cancers, particularly those that are low grade and express estrogen and progesterone receptors. Progesterone can be administered orally in preparations such as megestrol or medroxyprogesterone or “locally” with levonorgestrel-releasing intrauterine devices. Oral preparations are straightforward, typically low-cost agents. Likelihood of success is 50%-75%. However, the systemic side effects of these agents, which include increased venous thromboembolism risk and appetite stimulation, are particularly problematic in this population. Therefore, many providers prefer to place progestin-releasing intrauterine devices to “bypass” these side effects, avoid issues with adherence to dosing, and provide some preventative endometrial coverage after resolution of the cancer. Recent trials have observed elimination of endometrial cancer on repeat sampling in 67%-76% of cases.^3-5 This strategy may be more successful when it is paired with the addition of GnRH agonists.⁴

When hormonal therapy is chosen for primary endometrial cancer treatment, it is typically monitored for efficacy with repeat endometrial samplings, most commonly with pipelle biopsies to avoid displacement of an intrauterine device, though repeat D&C may be more effective in achieving a complete pathologic response to treatment. Most providers recommend resampling the endometrium at 3-month intervals until resolution of the malignancy has been documented, and thereafter if any new bleeding events develop. For women who have demonstrated resolution of carcinoma on repeat sampling, data are lacking to guide decision-making regarding resumption of conception efforts, ongoing surveillance, and completion hysterectomy after they finish childbearing. If malignancy continues to be identified after 6 months of hormonal therapy, consideration should be made of a more definitive treatment (such as surgery, if feasible, or radiation if not). Continued hormonal therapy can also be considered, as delayed responses remain common even 1 year after starting therapy.⁶ If hormonal therapy is prolonged for persistent disease, repeat MRI is recommended at 6 months to document lack of progression.

Radiation, preferably with both intracavitary and external beam treatment, is the most definitive intervention for inoperable early-stage endometrial cancer. Unfortunately, fertility is not preserved with this approach. However, for patients with high-grade tumors that are less likely to express hormone receptors or respond to hormonal therapies, this may be the only treatment option available. Typical treatment courses include 5 weeks of external beam radiation treatments, focused on treating the pelvis as a whole, including occult metastases not identified on imaging. Optimal therapy also includes placement of intracavitary radiation implants, such as Heymans capsules, to concentrate the dose at the uterine fundus, while minimizing toxicity to the adjacent bladder and bowel structures. While definitive radiation is considered inferior to a primary surgical effort, disease-specific survival can be observed in more than 80% of patients treated this way.⁷

While surgery remains the standard intervention for women with early-stage endometrial cancer, hormonal therapy or radiation remain viable options with high rates of success for women who are not surgical candidates or who desire fertility preservation.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Walker JL et al. J Clin Oncol. 2009;27(32):5331-6.

2. Ertel M et al. Ann Surg Oncol. 2021;28(13):8987-95.

3. Janda M et al. Gynecol Oncol. 2021;161(1):143-51.

4. Novikova OV et al. Gynecol Oncol. 2021;161(1):152-9.

5. Westin SN et al. Am J Obstet Gynecol. 2021;224(2):191.e1-15.

6. Cho A et al. Gynecol Oncol. 2021;160(2):413-17.

7. Dutta SW et al. Brachytherapy. 2017;16(3):526-33.

On March 13, most of the United States and Canada will advance the clock an hour to be on Daylight Saving Time. Most other countries in the Northern Hemisphere will do the same within a few weeks; and many countries across the Southern Hemisphere turn the clock back an hour around the same time. A friend of mine, who spent time on Capitol Hill, once told me that whether it’s adjusting to Daylight Saving Time (and losing an hour of sleep) or switching back to Standard Time (and picking up an hour), large numbers of Americans call their member of Congress every season to complain.

Why are so many of us annoyed by the semi-annual resetting of clocks? It turns out that there are biological reasons for our discomfort with time changes. Those reasons also come into play when we change time zones as we travel, when we work on the night shift, or when we live at higher latitudes, where depressive symptoms from seasonal affective disorder (SAD) can plague us as the period of daylight progressively shortens in winter.
 

Our internal clock(s)

Each of us has a biological master clock keeping track of where we are in our 24-hour day, making ongoing time-of-day-appropriate physical and neurologic adjustments. We refer to those automatic adjustments as “circadian” rhythms – from the Latin, for “around a day” rhythms.

©Thinglass/thinkstockphotos.com

One of the most important regulated functions that is influenced by this time keeping is our sleep-wake cycle. Our brain’s hypothalamus has a kind of “master clock” that receives inputs directly from our eyes, which is how our brain sets our daily cycle period at about 24 hours.

This master clock turns on a tiny structure in our brains, called the pineal gland, to release more of a sleep-inducing chemical, called melatonin, about the same time every evening. The level of melatonin slowly increases to reach maximum deep sleep in the night, then slowly declines as you advance toward morning awakening. The shift from darkness to daylight in the morning, causing your initial morning awakening, releases the excitatory neuromodulator norepinephrine, which, with other chemicals, “turns on the lights” in your brain.

That works well most of the time – but no one told your brain that you were going to arbitrarily go to bed an hour earlier (or in the fall, later) on Circadian Rhythm Time!

We also obviously shift the time on the mechanical clock – requiring a reset of the brain’s master clock – when we travel across time zones or work the night shift. That type of desynchronization of our master clock from the mechanical clock puts our waking and sleeping behaviors out of sync with the production of brain chemicals that affect our alertness and mood. The result may be that you find yourself tired, but not sleepy, and often grumpy or even depressed. As an example, on average, people who work the night shift are just a little bit more anxious and depressed than people who get up to rise and shine with the sun every morning.
 

Seasonal affective disorder

An extreme example of this desynchronization of the master clock can manifest as SAD. SAD is a type of depression that’s related to seasonal transitions. The most commonly cited cases of SAD are for the fall-to-winter transition. In North America, its prevalence is significantly influenced by the distance of one’s place of residence from the equator – with about 12 times the impact in Alaska versus Florida. Of note, a weaker effect of latitude has been recorded in Europe, where more settled populations have had thousands of years to biologically and culturally adapt to their seasonal patterns.

What can we do about our clocks being messed with?

The most common treatment for SAD is light therapy, in which patients sit or work under artificial lights in an early-morning period, to try to advance the chemical signaling that controls sleeping and waking. Alas, light therapy doesn’t work for everyone.

Another approach, with or without the lights, is to engage in activities early in the day that produce brain chemicals to contribute to bright and cheerful waking. Those “raring-to-go” brain chemicals include norepinephrine (produced when you encounter novelty and are just having fun), acetylcholine (produced when you are carefully paying attention and are in a learning and remembering mode), serotonin (produced when you are feeling positive and just a little bit euphoric), and dopamine (produced when you feel happy and all is right with the world).

In fact, you would benefit from creating the habit of starting every day with activity that wakes up your brain. I begin my day with computerized brain exercises that are attentionally demanding, filled with novelty, and richly neurologically rewarding. I then take a brisk morning walk in which I vary my path for the sake of novelty (pumping norepinephrine), pay close attention to my surroundings (pumping acetylcholine and serotonin), and delight in all of the wonderful things out there in my world (pumping dopamine). My dog Doug enjoys this process of waking up brain and body almost as much as I do! Of course, there are a thousand other stimulating things that could help you get your day off to a lively start.

If you anticipate feeling altered by a time change, you could also think about preparing for it in advance. If it’s the semi-annual 1-hour change that throws you off kilter, you might adjust your bedtime by 10 minutes a day for the week before. If you are traveling 12 time zones (and flipping night and day), you may need to make larger adjustments over the preceding couple of weeks. Generally, without that preparation, it takes about 1 day per time zone crossed to naturally adjust your circadian rhythms.

If you’re a little lazier, like me, you might also adjust to jet lag by not forgetting to take along your little bottle of melatonin tablets, to give your pineal gland a little help. Still, that pineal gland will work hard to tell you to take a nap every day – just when you’ll probably want to be wide awake.

And if, after reading this column, you find yourself still annoyed by the upcoming 1-hour time change, you might just look around at what’s happening out there in the world and decide that your troubles are very small by comparison, and that you should delight in the “extra” hour of sunshine each evening!

Dr. Merzenich is professor emeritus, department of neuroscience, at the University of California, San Francisco. He reported serving in various positions and speaking for Posit Science and Stronger Brain, and has also received funding from the National Institutes of Health. A version of this article first appeared on Medscape.com.

On March 13, most of the United States and Canada will advance the clock an hour to be on Daylight Saving Time. Most other countries in the Northern Hemisphere will do the same within a few weeks; and many countries across the Southern Hemisphere turn the clock back an hour around the same time. A friend of mine, who spent time on Capitol Hill, once told me that whether it’s adjusting to Daylight Saving Time (and losing an hour of sleep) or switching back to Standard Time (and picking up an hour), large numbers of Americans call their member of Congress every season to complain.

Why are so many of us annoyed by the semi-annual resetting of clocks? It turns out that there are biological reasons for our discomfort with time changes. Those reasons also come into play when we change time zones as we travel, when we work on the night shift, or when we live at higher latitudes, where depressive symptoms from seasonal affective disorder (SAD) can plague us as the period of daylight progressively shortens in winter.
 

Our internal clock(s)

Each of us has a biological master clock keeping track of where we are in our 24-hour day, making ongoing time-of-day-appropriate physical and neurologic adjustments. We refer to those automatic adjustments as “circadian” rhythms – from the Latin, for “around a day” rhythms.

©Thinglass/thinkstockphotos.com

One of the most important regulated functions that is influenced by this time keeping is our sleep-wake cycle. Our brain’s hypothalamus has a kind of “master clock” that receives inputs directly from our eyes, which is how our brain sets our daily cycle period at about 24 hours.

This master clock turns on a tiny structure in our brains, called the pineal gland, to release more of a sleep-inducing chemical, called melatonin, about the same time every evening. The level of melatonin slowly increases to reach maximum deep sleep in the night, then slowly declines as you advance toward morning awakening. The shift from darkness to daylight in the morning, causing your initial morning awakening, releases the excitatory neuromodulator norepinephrine, which, with other chemicals, “turns on the lights” in your brain.

That works well most of the time – but no one told your brain that you were going to arbitrarily go to bed an hour earlier (or in the fall, later) on Circadian Rhythm Time!

We also obviously shift the time on the mechanical clock – requiring a reset of the brain’s master clock – when we travel across time zones or work the night shift. That type of desynchronization of our master clock from the mechanical clock puts our waking and sleeping behaviors out of sync with the production of brain chemicals that affect our alertness and mood. The result may be that you find yourself tired, but not sleepy, and often grumpy or even depressed. As an example, on average, people who work the night shift are just a little bit more anxious and depressed than people who get up to rise and shine with the sun every morning.
 

Seasonal affective disorder

An extreme example of this desynchronization of the master clock can manifest as SAD. SAD is a type of depression that’s related to seasonal transitions. The most commonly cited cases of SAD are for the fall-to-winter transition. In North America, its prevalence is significantly influenced by the distance of one’s place of residence from the equator – with about 12 times the impact in Alaska versus Florida. Of note, a weaker effect of latitude has been recorded in Europe, where more settled populations have had thousands of years to biologically and culturally adapt to their seasonal patterns.

What can we do about our clocks being messed with?

The most common treatment for SAD is light therapy, in which patients sit or work under artificial lights in an early-morning period, to try to advance the chemical signaling that controls sleeping and waking. Alas, light therapy doesn’t work for everyone.

Another approach, with or without the lights, is to engage in activities early in the day that produce brain chemicals to contribute to bright and cheerful waking. Those “raring-to-go” brain chemicals include norepinephrine (produced when you encounter novelty and are just having fun), acetylcholine (produced when you are carefully paying attention and are in a learning and remembering mode), serotonin (produced when you are feeling positive and just a little bit euphoric), and dopamine (produced when you feel happy and all is right with the world).

In fact, you would benefit from creating the habit of starting every day with activity that wakes up your brain. I begin my day with computerized brain exercises that are attentionally demanding, filled with novelty, and richly neurologically rewarding. I then take a brisk morning walk in which I vary my path for the sake of novelty (pumping norepinephrine), pay close attention to my surroundings (pumping acetylcholine and serotonin), and delight in all of the wonderful things out there in my world (pumping dopamine). My dog Doug enjoys this process of waking up brain and body almost as much as I do! Of course, there are a thousand other stimulating things that could help you get your day off to a lively start.

If you anticipate feeling altered by a time change, you could also think about preparing for it in advance. If it’s the semi-annual 1-hour change that throws you off kilter, you might adjust your bedtime by 10 minutes a day for the week before. If you are traveling 12 time zones (and flipping night and day), you may need to make larger adjustments over the preceding couple of weeks. Generally, without that preparation, it takes about 1 day per time zone crossed to naturally adjust your circadian rhythms.

If you’re a little lazier, like me, you might also adjust to jet lag by not forgetting to take along your little bottle of melatonin tablets, to give your pineal gland a little help. Still, that pineal gland will work hard to tell you to take a nap every day – just when you’ll probably want to be wide awake.

And if, after reading this column, you find yourself still annoyed by the upcoming 1-hour time change, you might just look around at what’s happening out there in the world and decide that your troubles are very small by comparison, and that you should delight in the “extra” hour of sunshine each evening!

Dr. Merzenich is professor emeritus, department of neuroscience, at the University of California, San Francisco. He reported serving in various positions and speaking for Posit Science and Stronger Brain, and has also received funding from the National Institutes of Health. A version of this article first appeared on Medscape.com.

On March 13, most of the United States and Canada will advance the clock an hour to be on Daylight Saving Time. Most other countries in the Northern Hemisphere will do the same within a few weeks; and many countries across the Southern Hemisphere turn the clock back an hour around the same time. A friend of mine, who spent time on Capitol Hill, once told me that whether it’s adjusting to Daylight Saving Time (and losing an hour of sleep) or switching back to Standard Time (and picking up an hour), large numbers of Americans call their member of Congress every season to complain.

Why are so many of us annoyed by the semi-annual resetting of clocks? It turns out that there are biological reasons for our discomfort with time changes. Those reasons also come into play when we change time zones as we travel, when we work on the night shift, or when we live at higher latitudes, where depressive symptoms from seasonal affective disorder (SAD) can plague us as the period of daylight progressively shortens in winter.
 

Our internal clock(s)

Each of us has a biological master clock keeping track of where we are in our 24-hour day, making ongoing time-of-day-appropriate physical and neurologic adjustments. We refer to those automatic adjustments as “circadian” rhythms – from the Latin, for “around a day” rhythms.

©Thinglass/thinkstockphotos.com

One of the most important regulated functions that is influenced by this time keeping is our sleep-wake cycle. Our brain’s hypothalamus has a kind of “master clock” that receives inputs directly from our eyes, which is how our brain sets our daily cycle period at about 24 hours.

This master clock turns on a tiny structure in our brains, called the pineal gland, to release more of a sleep-inducing chemical, called melatonin, about the same time every evening. The level of melatonin slowly increases to reach maximum deep sleep in the night, then slowly declines as you advance toward morning awakening. The shift from darkness to daylight in the morning, causing your initial morning awakening, releases the excitatory neuromodulator norepinephrine, which, with other chemicals, “turns on the lights” in your brain.

That works well most of the time – but no one told your brain that you were going to arbitrarily go to bed an hour earlier (or in the fall, later) on Circadian Rhythm Time!

We also obviously shift the time on the mechanical clock – requiring a reset of the brain’s master clock – when we travel across time zones or work the night shift. That type of desynchronization of our master clock from the mechanical clock puts our waking and sleeping behaviors out of sync with the production of brain chemicals that affect our alertness and mood. The result may be that you find yourself tired, but not sleepy, and often grumpy or even depressed. As an example, on average, people who work the night shift are just a little bit more anxious and depressed than people who get up to rise and shine with the sun every morning.
 

Seasonal affective disorder

An extreme example of this desynchronization of the master clock can manifest as SAD. SAD is a type of depression that’s related to seasonal transitions. The most commonly cited cases of SAD are for the fall-to-winter transition. In North America, its prevalence is significantly influenced by the distance of one’s place of residence from the equator – with about 12 times the impact in Alaska versus Florida. Of note, a weaker effect of latitude has been recorded in Europe, where more settled populations have had thousands of years to biologically and culturally adapt to their seasonal patterns.

What can we do about our clocks being messed with?

The most common treatment for SAD is light therapy, in which patients sit or work under artificial lights in an early-morning period, to try to advance the chemical signaling that controls sleeping and waking. Alas, light therapy doesn’t work for everyone.

Another approach, with or without the lights, is to engage in activities early in the day that produce brain chemicals to contribute to bright and cheerful waking. Those “raring-to-go” brain chemicals include norepinephrine (produced when you encounter novelty and are just having fun), acetylcholine (produced when you are carefully paying attention and are in a learning and remembering mode), serotonin (produced when you are feeling positive and just a little bit euphoric), and dopamine (produced when you feel happy and all is right with the world).

In fact, you would benefit from creating the habit of starting every day with activity that wakes up your brain. I begin my day with computerized brain exercises that are attentionally demanding, filled with novelty, and richly neurologically rewarding. I then take a brisk morning walk in which I vary my path for the sake of novelty (pumping norepinephrine), pay close attention to my surroundings (pumping acetylcholine and serotonin), and delight in all of the wonderful things out there in my world (pumping dopamine). My dog Doug enjoys this process of waking up brain and body almost as much as I do! Of course, there are a thousand other stimulating things that could help you get your day off to a lively start.

If you anticipate feeling altered by a time change, you could also think about preparing for it in advance. If it’s the semi-annual 1-hour change that throws you off kilter, you might adjust your bedtime by 10 minutes a day for the week before. If you are traveling 12 time zones (and flipping night and day), you may need to make larger adjustments over the preceding couple of weeks. Generally, without that preparation, it takes about 1 day per time zone crossed to naturally adjust your circadian rhythms.

If you’re a little lazier, like me, you might also adjust to jet lag by not forgetting to take along your little bottle of melatonin tablets, to give your pineal gland a little help. Still, that pineal gland will work hard to tell you to take a nap every day – just when you’ll probably want to be wide awake.

And if, after reading this column, you find yourself still annoyed by the upcoming 1-hour time change, you might just look around at what’s happening out there in the world and decide that your troubles are very small by comparison, and that you should delight in the “extra” hour of sunshine each evening!

Dr. Merzenich is professor emeritus, department of neuroscience, at the University of California, San Francisco. He reported serving in various positions and speaking for Posit Science and Stronger Brain, and has also received funding from the National Institutes of Health. A version of this article first appeared on Medscape.com.

Magnetic Resonance Imaging has long been the standard for diagnosing and surveilling multiple sclerosis (MS), and new guidelines provide updates on the use of MRI for the diagnosis, prognosis, and treatment monitoring of MS.

MS affects approximately one million people in the United States. As family physicians, these guidelines are important to know, because we are often the ones who make the initial diagnosis of MS. Similarly, if we order the wrong imaging study, we can miss making an accurate diagnosis.

The new guidelines (MAGNIMS), which were sponsored by the Consortium of Multiple Sclerosis Centres, were published in August. The documents offers detailed guidance on the use of standardized MRI protocols as well as the use of IV gadolinium contrast agents, including in children and pregnant patients.

It is advised to use 3-D techniques (as opposed to two-dimensional) and it is noted that this is becoming more clinically available. Sagittal 3-D T2-weighted fluid-attenuated inversion recovery (FLAIR) is the core sequence considered for MS diagnosis and monitoring because of its high sensitivity. High-quality 2-D pulse sequences can be used alternatively when 3-D FLAIR is not available.

When 3 T scanners are not available, 1.5 T scanners are sufficient. However, 3 T scanners do have a higher detection rate for MS lesions. In evaluating the imaging, T2 lesion counts, gadolinium lesion counts, and interval changes should be reported.

The use of GBCAs (gadolinium-based contrast agents) is needed to diagnose MS and rule out other diseases. The time between injection of contrast should ideally be 10 minutes but no less than 5. Optic nerve MRI is recommended only in patients with atypical symptoms, such as new visual symptoms. Spinal cord MRI is also not routinely advised unless it is needed for prognosis.

When the initial MRI does not meet the full criteria of MS, brain MRI should be repeated every 6-12 months in suspected cases. The same modality should be used each time. After treatment is started, it is recommended to perform MRI without GBCAs for 3 months and annual follow ups. The use of GBCAs-free MRIs for routine follow up is a new recommendation compared to previous ones. However, if the use of GBCAs would change the management, then they should be utilized for monitoring.

The same imaging standards are recommended in pediatric patients. Spinal cord MRI should be utilized in kids with spinal cord symptoms or inconclusive brain MRI. Similar scan frequency is recommended as in adults. MRI is not contraindicated during pregnancy but should be decided on an individual basis. Standard protocols should be used as well as a magnetic field strength of 1.5 T. GBCAs should not be used during pregnancy. There are no limitations in the postpartum period.

The complete set of guidelines is quite extensive and adds to the previous guidelines published in 2017. They were first published in The Lancet Neurology.

While most of these patients will be referred to neurologists, as the primary care physician it is our responsibility to know all aspects of our patients’ diseases and treatments. While we may not be actively treating MS in these patients, we need to know their medications, how they interact with others, and how their disease is progressing

Additionally, we may be the ones asked to order MRIs for monitoring. It is imperative that we know the guidelines for how to do this.

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

Magnetic Resonance Imaging has long been the standard for diagnosing and surveilling multiple sclerosis (MS), and new guidelines provide updates on the use of MRI for the diagnosis, prognosis, and treatment monitoring of MS.

MS affects approximately one million people in the United States. As family physicians, these guidelines are important to know, because we are often the ones who make the initial diagnosis of MS. Similarly, if we order the wrong imaging study, we can miss making an accurate diagnosis.

The new guidelines (MAGNIMS), which were sponsored by the Consortium of Multiple Sclerosis Centres, were published in August. The documents offers detailed guidance on the use of standardized MRI protocols as well as the use of IV gadolinium contrast agents, including in children and pregnant patients.

It is advised to use 3-D techniques (as opposed to two-dimensional) and it is noted that this is becoming more clinically available. Sagittal 3-D T2-weighted fluid-attenuated inversion recovery (FLAIR) is the core sequence considered for MS diagnosis and monitoring because of its high sensitivity. High-quality 2-D pulse sequences can be used alternatively when 3-D FLAIR is not available.

When 3 T scanners are not available, 1.5 T scanners are sufficient. However, 3 T scanners do have a higher detection rate for MS lesions. In evaluating the imaging, T2 lesion counts, gadolinium lesion counts, and interval changes should be reported.

The use of GBCAs (gadolinium-based contrast agents) is needed to diagnose MS and rule out other diseases. The time between injection of contrast should ideally be 10 minutes but no less than 5. Optic nerve MRI is recommended only in patients with atypical symptoms, such as new visual symptoms. Spinal cord MRI is also not routinely advised unless it is needed for prognosis.

When the initial MRI does not meet the full criteria of MS, brain MRI should be repeated every 6-12 months in suspected cases. The same modality should be used each time. After treatment is started, it is recommended to perform MRI without GBCAs for 3 months and annual follow ups. The use of GBCAs-free MRIs for routine follow up is a new recommendation compared to previous ones. However, if the use of GBCAs would change the management, then they should be utilized for monitoring.

The same imaging standards are recommended in pediatric patients. Spinal cord MRI should be utilized in kids with spinal cord symptoms or inconclusive brain MRI. Similar scan frequency is recommended as in adults. MRI is not contraindicated during pregnancy but should be decided on an individual basis. Standard protocols should be used as well as a magnetic field strength of 1.5 T. GBCAs should not be used during pregnancy. There are no limitations in the postpartum period.

The complete set of guidelines is quite extensive and adds to the previous guidelines published in 2017. They were first published in The Lancet Neurology.

While most of these patients will be referred to neurologists, as the primary care physician it is our responsibility to know all aspects of our patients’ diseases and treatments. While we may not be actively treating MS in these patients, we need to know their medications, how they interact with others, and how their disease is progressing

Additionally, we may be the ones asked to order MRIs for monitoring. It is imperative that we know the guidelines for how to do this.

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

Magnetic Resonance Imaging has long been the standard for diagnosing and surveilling multiple sclerosis (MS), and new guidelines provide updates on the use of MRI for the diagnosis, prognosis, and treatment monitoring of MS.

MS affects approximately one million people in the United States. As family physicians, these guidelines are important to know, because we are often the ones who make the initial diagnosis of MS. Similarly, if we order the wrong imaging study, we can miss making an accurate diagnosis.

The new guidelines (MAGNIMS), which were sponsored by the Consortium of Multiple Sclerosis Centres, were published in August. The documents offers detailed guidance on the use of standardized MRI protocols as well as the use of IV gadolinium contrast agents, including in children and pregnant patients.

It is advised to use 3-D techniques (as opposed to two-dimensional) and it is noted that this is becoming more clinically available. Sagittal 3-D T2-weighted fluid-attenuated inversion recovery (FLAIR) is the core sequence considered for MS diagnosis and monitoring because of its high sensitivity. High-quality 2-D pulse sequences can be used alternatively when 3-D FLAIR is not available.

When 3 T scanners are not available, 1.5 T scanners are sufficient. However, 3 T scanners do have a higher detection rate for MS lesions. In evaluating the imaging, T2 lesion counts, gadolinium lesion counts, and interval changes should be reported.

The use of GBCAs (gadolinium-based contrast agents) is needed to diagnose MS and rule out other diseases. The time between injection of contrast should ideally be 10 minutes but no less than 5. Optic nerve MRI is recommended only in patients with atypical symptoms, such as new visual symptoms. Spinal cord MRI is also not routinely advised unless it is needed for prognosis.

When the initial MRI does not meet the full criteria of MS, brain MRI should be repeated every 6-12 months in suspected cases. The same modality should be used each time. After treatment is started, it is recommended to perform MRI without GBCAs for 3 months and annual follow ups. The use of GBCAs-free MRIs for routine follow up is a new recommendation compared to previous ones. However, if the use of GBCAs would change the management, then they should be utilized for monitoring.

The same imaging standards are recommended in pediatric patients. Spinal cord MRI should be utilized in kids with spinal cord symptoms or inconclusive brain MRI. Similar scan frequency is recommended as in adults. MRI is not contraindicated during pregnancy but should be decided on an individual basis. Standard protocols should be used as well as a magnetic field strength of 1.5 T. GBCAs should not be used during pregnancy. There are no limitations in the postpartum period.

The complete set of guidelines is quite extensive and adds to the previous guidelines published in 2017. They were first published in The Lancet Neurology.

While most of these patients will be referred to neurologists, as the primary care physician it is our responsibility to know all aspects of our patients’ diseases and treatments. While we may not be actively treating MS in these patients, we need to know their medications, how they interact with others, and how their disease is progressing

Additionally, we may be the ones asked to order MRIs for monitoring. It is imperative that we know the guidelines for how to do this.

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

Pain management is a huge part of how we in palliative care help patients – and most of the time, I think we do it well, but in the regulatory environment of the opioid epidemic, getting opioid prescriptions filled in a timely manner with the clinician’s drug of choice can feel like a Sisyphean task.

A patient – let’s call her Joan – calls me in distress. She is a 62-year-old woman with widespread metastatic breast cancer. Her pain is mainly due to bone metastases, but she also has discomfort due to the cancer’s invasion of the thin membranes that line her lungs and abdomen.

She was started on a combination opioid and acetaminophen tablet about 2 months ago by her oncologist, but is now requiring it around the clock, nearing the ceiling dose for this particular medication.

Given that her pain is escalating, Joan and I discuss starting a long-acting opioid to better manage the peak and trough effect of short-acting opioids, which can make a patient feel that the pain is relieved only for a few hours at a time, with sharp spikes throughout the day that mandate the next dose of short-acting opioid. This tethers the patient to the clock, having to take as many as six or eight doses of medication per day, and can be very disruptive to daily life.

Sarah F. D’Ambruoso, NP, is a palliative care nurse practitioner in Santa Monica, Calif.

Pain management is a huge part of how we in palliative care help patients – and most of the time, I think we do it well, but in the regulatory environment of the opioid epidemic, getting opioid prescriptions filled in a timely manner with the clinician’s drug of choice can feel like a Sisyphean task.

A patient – let’s call her Joan – calls me in distress. She is a 62-year-old woman with widespread metastatic breast cancer. Her pain is mainly due to bone metastases, but she also has discomfort due to the cancer’s invasion of the thin membranes that line her lungs and abdomen.

She was started on a combination opioid and acetaminophen tablet about 2 months ago by her oncologist, but is now requiring it around the clock, nearing the ceiling dose for this particular medication.

Given that her pain is escalating, Joan and I discuss starting a long-acting opioid to better manage the peak and trough effect of short-acting opioids, which can make a patient feel that the pain is relieved only for a few hours at a time, with sharp spikes throughout the day that mandate the next dose of short-acting opioid. This tethers the patient to the clock, having to take as many as six or eight doses of medication per day, and can be very disruptive to daily life.

Sarah F. D’Ambruoso, NP, is a palliative care nurse practitioner in Santa Monica, Calif.

Pain management is a huge part of how we in palliative care help patients – and most of the time, I think we do it well, but in the regulatory environment of the opioid epidemic, getting opioid prescriptions filled in a timely manner with the clinician’s drug of choice can feel like a Sisyphean task.

A patient – let’s call her Joan – calls me in distress. She is a 62-year-old woman with widespread metastatic breast cancer. Her pain is mainly due to bone metastases, but she also has discomfort due to the cancer’s invasion of the thin membranes that line her lungs and abdomen.

She was started on a combination opioid and acetaminophen tablet about 2 months ago by her oncologist, but is now requiring it around the clock, nearing the ceiling dose for this particular medication.

Given that her pain is escalating, Joan and I discuss starting a long-acting opioid to better manage the peak and trough effect of short-acting opioids, which can make a patient feel that the pain is relieved only for a few hours at a time, with sharp spikes throughout the day that mandate the next dose of short-acting opioid. This tethers the patient to the clock, having to take as many as six or eight doses of medication per day, and can be very disruptive to daily life.

Sarah F. D’Ambruoso, NP, is a palliative care nurse practitioner in Santa Monica, Calif.

This has been an unfortunate, but not an atypical year, for the children in Maine whose lives have intersected with the state’s Department of Health and Human Services. In 2021, 25 children died of abuse and neglect or in homes with prior involvement with the child protective system. Four cases not included in that number are currently listed as homicides. At a recent legislative hearing the grandmother of one of those victims told her story to the lawmaker.

Her grandson was removed from his mother’s custody at 3 months of age after a 2-year-old sibling overdosed on methadone. Father and grandmother became his caregivers but when the father was arrested the child was returned to the mother’s custody by a judge despite the pleas of the child’s court-appointed guardian. The child eventually returned to the care of his paternal aunt and father, but when the father was arrested again the then 3-year-old was returned to his mother. Within months he was dead with multiple fractures, including to his spine and with internal and intracranial bleeding (Overton P. Maine’s child welfare system failed a 3-year old who died, grandmother tells lawmakers. 2022 Feb 11. Portland Press Herald).

The grandmother questioned the legislators why a vulnerable child would be returned to the care of a woman with such an extensive history of involvement with the Department of Health and Human Services. While there may have been errors of judgment on the part of department staff, in large part the answer lies in the system’s emphasis on reunification. Like apple pie, motherhood, and more recently fatherhood, have been viewed as something deserving of our unquestioning efforts to preserve.

This is not a recent trend. Some of the most frustrating cases over my 40 years of practice involved the failure of the courts and in some cases social workers to place a child’s welfare in the proper perspective as court schedules and custody decisions were made. Too often the reunification of “the family” seemed to trump the needs of the child. Fortunately, I’m unaware of any of my patients who died as the result of these untimely and poorly made decisions. However, many of my patients lived in unsettled conditions never sure what the next week would bring while the system focused on giving an adult whose life was a mess one more chance to demonstrate his or her ability to parent.

Of course, there are occasions in which child protective workers have been too hasty in pulling a child from his or her parents. But, in my experience those cases pale next to the number of times in which children were exposed to home environments that threatened their psychological health and development. Yes, there are bad foster homes. Many foster homes might do a better job if they were working in a system that put a higher value on the emotional needs and safety of the children in making its custody decisions.

We have a governor here in Maine who has worked hard to do the right thing during the pandemic and has made child health a focus. However, her recent proposed appropriations bill appears to continue the focus on reunification by funneling money into programs such as family reunion training and coaching as well as a parent mentorship program. Certainly, one can’t argue that these kind of programs might be helpful to some families. On the other hand, we can’t let these programs create the impression that an intact family is our primary goal. Not every family is repairable, at least on a time schedule compatible with the emotional and health needs of the children.

I wouldn’t be surprised to learn that many of you have experienced a similar frustration when decisions based on an unrealistic goal of family reunification have put your patients at risk.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

This has been an unfortunate, but not an atypical year, for the children in Maine whose lives have intersected with the state’s Department of Health and Human Services. In 2021, 25 children died of abuse and neglect or in homes with prior involvement with the child protective system. Four cases not included in that number are currently listed as homicides. At a recent legislative hearing the grandmother of one of those victims told her story to the lawmaker.

Her grandson was removed from his mother’s custody at 3 months of age after a 2-year-old sibling overdosed on methadone. Father and grandmother became his caregivers but when the father was arrested the child was returned to the mother’s custody by a judge despite the pleas of the child’s court-appointed guardian. The child eventually returned to the care of his paternal aunt and father, but when the father was arrested again the then 3-year-old was returned to his mother. Within months he was dead with multiple fractures, including to his spine and with internal and intracranial bleeding (Overton P. Maine’s child welfare system failed a 3-year old who died, grandmother tells lawmakers. 2022 Feb 11. Portland Press Herald).

The grandmother questioned the legislators why a vulnerable child would be returned to the care of a woman with such an extensive history of involvement with the Department of Health and Human Services. While there may have been errors of judgment on the part of department staff, in large part the answer lies in the system’s emphasis on reunification. Like apple pie, motherhood, and more recently fatherhood, have been viewed as something deserving of our unquestioning efforts to preserve.

This is not a recent trend. Some of the most frustrating cases over my 40 years of practice involved the failure of the courts and in some cases social workers to place a child’s welfare in the proper perspective as court schedules and custody decisions were made. Too often the reunification of “the family” seemed to trump the needs of the child. Fortunately, I’m unaware of any of my patients who died as the result of these untimely and poorly made decisions. However, many of my patients lived in unsettled conditions never sure what the next week would bring while the system focused on giving an adult whose life was a mess one more chance to demonstrate his or her ability to parent.

Of course, there are occasions in which child protective workers have been too hasty in pulling a child from his or her parents. But, in my experience those cases pale next to the number of times in which children were exposed to home environments that threatened their psychological health and development. Yes, there are bad foster homes. Many foster homes might do a better job if they were working in a system that put a higher value on the emotional needs and safety of the children in making its custody decisions.

We have a governor here in Maine who has worked hard to do the right thing during the pandemic and has made child health a focus. However, her recent proposed appropriations bill appears to continue the focus on reunification by funneling money into programs such as family reunion training and coaching as well as a parent mentorship program. Certainly, one can’t argue that these kind of programs might be helpful to some families. On the other hand, we can’t let these programs create the impression that an intact family is our primary goal. Not every family is repairable, at least on a time schedule compatible with the emotional and health needs of the children.

I wouldn’t be surprised to learn that many of you have experienced a similar frustration when decisions based on an unrealistic goal of family reunification have put your patients at risk.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

This has been an unfortunate, but not an atypical year, for the children in Maine whose lives have intersected with the state’s Department of Health and Human Services. In 2021, 25 children died of abuse and neglect or in homes with prior involvement with the child protective system. Four cases not included in that number are currently listed as homicides. At a recent legislative hearing the grandmother of one of those victims told her story to the lawmaker.

Her grandson was removed from his mother’s custody at 3 months of age after a 2-year-old sibling overdosed on methadone. Father and grandmother became his caregivers but when the father was arrested the child was returned to the mother’s custody by a judge despite the pleas of the child’s court-appointed guardian. The child eventually returned to the care of his paternal aunt and father, but when the father was arrested again the then 3-year-old was returned to his mother. Within months he was dead with multiple fractures, including to his spine and with internal and intracranial bleeding (Overton P. Maine’s child welfare system failed a 3-year old who died, grandmother tells lawmakers. 2022 Feb 11. Portland Press Herald).

The grandmother questioned the legislators why a vulnerable child would be returned to the care of a woman with such an extensive history of involvement with the Department of Health and Human Services. While there may have been errors of judgment on the part of department staff, in large part the answer lies in the system’s emphasis on reunification. Like apple pie, motherhood, and more recently fatherhood, have been viewed as something deserving of our unquestioning efforts to preserve.

This is not a recent trend. Some of the most frustrating cases over my 40 years of practice involved the failure of the courts and in some cases social workers to place a child’s welfare in the proper perspective as court schedules and custody decisions were made. Too often the reunification of “the family” seemed to trump the needs of the child. Fortunately, I’m unaware of any of my patients who died as the result of these untimely and poorly made decisions. However, many of my patients lived in unsettled conditions never sure what the next week would bring while the system focused on giving an adult whose life was a mess one more chance to demonstrate his or her ability to parent.

Of course, there are occasions in which child protective workers have been too hasty in pulling a child from his or her parents. But, in my experience those cases pale next to the number of times in which children were exposed to home environments that threatened their psychological health and development. Yes, there are bad foster homes. Many foster homes might do a better job if they were working in a system that put a higher value on the emotional needs and safety of the children in making its custody decisions.

We have a governor here in Maine who has worked hard to do the right thing during the pandemic and has made child health a focus. However, her recent proposed appropriations bill appears to continue the focus on reunification by funneling money into programs such as family reunion training and coaching as well as a parent mentorship program. Certainly, one can’t argue that these kind of programs might be helpful to some families. On the other hand, we can’t let these programs create the impression that an intact family is our primary goal. Not every family is repairable, at least on a time schedule compatible with the emotional and health needs of the children.

I wouldn’t be surprised to learn that many of you have experienced a similar frustration when decisions based on an unrealistic goal of family reunification have put your patients at risk.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Mr. Jones has had multiple sclerosis (MS) since 2008. Initially it was pretty active, though I was able to bring it under control with drug A. He didn’t like the side effects, or the shots, but at that time options for MS treatment were kind of limited.

When the oral agents came out he switched to drug B. He still had some side effects on it, which he didn’t like, but his insurance didn’t cover the other oral agent that was available. So he soldiered on.

Then, in late 2019, he had an episode of optic neuritis, and a repeat MRI showed that in the last 2 years he’d had an uptick in demyelinating plaques. So, in early 2020, he switched to drug C.

Drug C has, to date, been pretty good. He’s had no side effects or relapses, and a recent brain MRI was stable.

Of course, drug C ain’t cheap. Its price isn’t even listed on ePocrates or GoodRx. So my staff and I have to do all kinds of paperwork and hoop-jumping to get it covered each year.

So in late 2021 we started the annual process, which doesn’t happen overnight. We finally received notice he’d been approved – until March 1, 2022. Only 3 months.

Given the alacrity with which these companies seem to work, we began the new authorization paperwork almost as soon as we got the last one in mid-January. This time we didn’t hear back, and every time we called they told us the application was “under review.” In the meantime, Mr. Jones’ supply of pills, which are pretty critical to his health and well-being, was gradually decreasing.

Recently, out of the blue, a 1-month supply of drug C showed up in his mailbox, along with a bill for $3,000. Mr. Jones is a career waiter at a local restaurant, and had no way to pay for this. So my staff went to work on the phones, and after a few hours got it in writing that it was being covered as a bridging supply under the manufacturer’s assistance program. Okay. That crises was averted. (I have no idea if the insurance really pays $3,000/month. Like buying a car, there can be a big difference between a drug’s asking price and what’s really paid for it).

The next morning, however, we got a note from his insurance company saying the medical reviewer had decided he didn’t need drug C, and wanted him to go back to drug B. After all, it was cheaper. I called the reviewer and argued with him. I told him he’d clinically worsened on drug B, not to mention the side effects. The reviewer said I should have mentioned that in my notes. I pointed out that it was in my notes, which had been sent along with the forms I’d filled out. He didn’t answer that, just said he’d have them fax me an appeal form.

The appeal form showed up about an hour later, so I took some time out of my weekend to fill it out. Then I faxed it back, along with (as they requested) chart notes and MRI reports dating back to 2008. Which was a lot.

So now we’ll see what happens.

Do other countries have this sort of thing? Or is this a product of the bizarre patchwork that makes up the American health care system? Different insurance companies, different subplans, and regional sub-subplans, and so on, each with a different set of rules, forms, and obstacle courses to navigate.

For all their glitzy TV commercials showing smiling, happy, multigenerational families, all looking to be in glowing health from the medical care they’re receiving, they seem to be pretty determined to keep Mr. Jones from receiving a drug that’s allowing him to continue working as a waiter 50-60 hours per week. Without it, he’d likely be unable to work and, at some point, would have to file for disability. Probably would eventually need increasingly high-cost items, going to a cane, then a walker, then a wheelchair, then a power wheelchair. ER visits, things that. In the long run, those would cost a helluva lot more than drug C.

Of course, that may be part of their game, too. Maybe they figure he’ll end up dropping off their insurance as he worsens, and then their shareholders don’t have to pay for his bad luck. I hope I’m wrong in thinking that, but such is the nature of business. And health insurance is a HUGE business.

So now I’ve faxed in the appeal forms, and can move on, for the time being, to the needs of other patients (not to mention spending time with my family). But Mr. Jones’ pill supply will run out on April 1, 2022, and I still have no idea what will happen then.

Neither does he. And for him, that’s pretty scary.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Mr. Jones has had multiple sclerosis (MS) since 2008. Initially it was pretty active, though I was able to bring it under control with drug A. He didn’t like the side effects, or the shots, but at that time options for MS treatment were kind of limited.

When the oral agents came out he switched to drug B. He still had some side effects on it, which he didn’t like, but his insurance didn’t cover the other oral agent that was available. So he soldiered on.

Then, in late 2019, he had an episode of optic neuritis, and a repeat MRI showed that in the last 2 years he’d had an uptick in demyelinating plaques. So, in early 2020, he switched to drug C.

Drug C has, to date, been pretty good. He’s had no side effects or relapses, and a recent brain MRI was stable.

Of course, drug C ain’t cheap. Its price isn’t even listed on ePocrates or GoodRx. So my staff and I have to do all kinds of paperwork and hoop-jumping to get it covered each year.

So in late 2021 we started the annual process, which doesn’t happen overnight. We finally received notice he’d been approved – until March 1, 2022. Only 3 months.

Given the alacrity with which these companies seem to work, we began the new authorization paperwork almost as soon as we got the last one in mid-January. This time we didn’t hear back, and every time we called they told us the application was “under review.” In the meantime, Mr. Jones’ supply of pills, which are pretty critical to his health and well-being, was gradually decreasing.

Recently, out of the blue, a 1-month supply of drug C showed up in his mailbox, along with a bill for $3,000. Mr. Jones is a career waiter at a local restaurant, and had no way to pay for this. So my staff went to work on the phones, and after a few hours got it in writing that it was being covered as a bridging supply under the manufacturer’s assistance program. Okay. That crises was averted. (I have no idea if the insurance really pays $3,000/month. Like buying a car, there can be a big difference between a drug’s asking price and what’s really paid for it).

The next morning, however, we got a note from his insurance company saying the medical reviewer had decided he didn’t need drug C, and wanted him to go back to drug B. After all, it was cheaper. I called the reviewer and argued with him. I told him he’d clinically worsened on drug B, not to mention the side effects. The reviewer said I should have mentioned that in my notes. I pointed out that it was in my notes, which had been sent along with the forms I’d filled out. He didn’t answer that, just said he’d have them fax me an appeal form.

The appeal form showed up about an hour later, so I took some time out of my weekend to fill it out. Then I faxed it back, along with (as they requested) chart notes and MRI reports dating back to 2008. Which was a lot.

So now we’ll see what happens.

Do other countries have this sort of thing? Or is this a product of the bizarre patchwork that makes up the American health care system? Different insurance companies, different subplans, and regional sub-subplans, and so on, each with a different set of rules, forms, and obstacle courses to navigate.

For all their glitzy TV commercials showing smiling, happy, multigenerational families, all looking to be in glowing health from the medical care they’re receiving, they seem to be pretty determined to keep Mr. Jones from receiving a drug that’s allowing him to continue working as a waiter 50-60 hours per week. Without it, he’d likely be unable to work and, at some point, would have to file for disability. Probably would eventually need increasingly high-cost items, going to a cane, then a walker, then a wheelchair, then a power wheelchair. ER visits, things that. In the long run, those would cost a helluva lot more than drug C.

Of course, that may be part of their game, too. Maybe they figure he’ll end up dropping off their insurance as he worsens, and then their shareholders don’t have to pay for his bad luck. I hope I’m wrong in thinking that, but such is the nature of business. And health insurance is a HUGE business.

So now I’ve faxed in the appeal forms, and can move on, for the time being, to the needs of other patients (not to mention spending time with my family). But Mr. Jones’ pill supply will run out on April 1, 2022, and I still have no idea what will happen then.

Neither does he. And for him, that’s pretty scary.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Mr. Jones has had multiple sclerosis (MS) since 2008. Initially it was pretty active, though I was able to bring it under control with drug A. He didn’t like the side effects, or the shots, but at that time options for MS treatment were kind of limited.

When the oral agents came out he switched to drug B. He still had some side effects on it, which he didn’t like, but his insurance didn’t cover the other oral agent that was available. So he soldiered on.

Then, in late 2019, he had an episode of optic neuritis, and a repeat MRI showed that in the last 2 years he’d had an uptick in demyelinating plaques. So, in early 2020, he switched to drug C.

Drug C has, to date, been pretty good. He’s had no side effects or relapses, and a recent brain MRI was stable.

Of course, drug C ain’t cheap. Its price isn’t even listed on ePocrates or GoodRx. So my staff and I have to do all kinds of paperwork and hoop-jumping to get it covered each year.

So in late 2021 we started the annual process, which doesn’t happen overnight. We finally received notice he’d been approved – until March 1, 2022. Only 3 months.

Given the alacrity with which these companies seem to work, we began the new authorization paperwork almost as soon as we got the last one in mid-January. This time we didn’t hear back, and every time we called they told us the application was “under review.” In the meantime, Mr. Jones’ supply of pills, which are pretty critical to his health and well-being, was gradually decreasing.

Recently, out of the blue, a 1-month supply of drug C showed up in his mailbox, along with a bill for $3,000. Mr. Jones is a career waiter at a local restaurant, and had no way to pay for this. So my staff went to work on the phones, and after a few hours got it in writing that it was being covered as a bridging supply under the manufacturer’s assistance program. Okay. That crises was averted. (I have no idea if the insurance really pays $3,000/month. Like buying a car, there can be a big difference between a drug’s asking price and what’s really paid for it).

The next morning, however, we got a note from his insurance company saying the medical reviewer had decided he didn’t need drug C, and wanted him to go back to drug B. After all, it was cheaper. I called the reviewer and argued with him. I told him he’d clinically worsened on drug B, not to mention the side effects. The reviewer said I should have mentioned that in my notes. I pointed out that it was in my notes, which had been sent along with the forms I’d filled out. He didn’t answer that, just said he’d have them fax me an appeal form.

The appeal form showed up about an hour later, so I took some time out of my weekend to fill it out. Then I faxed it back, along with (as they requested) chart notes and MRI reports dating back to 2008. Which was a lot.

So now we’ll see what happens.

Do other countries have this sort of thing? Or is this a product of the bizarre patchwork that makes up the American health care system? Different insurance companies, different subplans, and regional sub-subplans, and so on, each with a different set of rules, forms, and obstacle courses to navigate.

For all their glitzy TV commercials showing smiling, happy, multigenerational families, all looking to be in glowing health from the medical care they’re receiving, they seem to be pretty determined to keep Mr. Jones from receiving a drug that’s allowing him to continue working as a waiter 50-60 hours per week. Without it, he’d likely be unable to work and, at some point, would have to file for disability. Probably would eventually need increasingly high-cost items, going to a cane, then a walker, then a wheelchair, then a power wheelchair. ER visits, things that. In the long run, those would cost a helluva lot more than drug C.

Of course, that may be part of their game, too. Maybe they figure he’ll end up dropping off their insurance as he worsens, and then their shareholders don’t have to pay for his bad luck. I hope I’m wrong in thinking that, but such is the nature of business. And health insurance is a HUGE business.

So now I’ve faxed in the appeal forms, and can move on, for the time being, to the needs of other patients (not to mention spending time with my family). But Mr. Jones’ pill supply will run out on April 1, 2022, and I still have no idea what will happen then.

Neither does he. And for him, that’s pretty scary.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

In the field of lung cancer, and more broadly in oncology, many of our biggest advances in 2021 have come as clinically meaningful improvements in surrogate endpoints – disease-free survival, progression-free survival, and sometimes even pathologic complete response rate.

I have historically been most compelled to consider new findings to be practice-changing when they improve overall survival or quality of life – the endpoints that translate to direct benefits for patients. However, I also feel it is appropriate to call surrogate endpoints practice-changing when they can predict improvements in overall survival or quality of life.

Take the PACIFIC trial, which assessed maintenance durvalumab after concurrent chemoradiation for unresectable stage III non–small cell lung cancer (NSCLC).

Back in 2017, I was initially unconvinced by the interim phase 3 data that were presented in a press release that highlighted the disease-free survival benefit. However, after examining additional data more closely, I saw the dramatic improvement in time to distant relapse or death was overwhelmingly likely to predict an improvement in overall survival – a benefit that the data subsequently bore out.

More recently, the disease-free survival results for adjuvant osimertinib in resected endothelial growth factor receptor mutation–positive NSCLC and adjuvant atezolizumab in resected programmed death-ligand 1–positive stage II-IIIA NSCLC have led to excitement about Food and Drug Administration approvals for these therapies. Although there is reason to be cautious about the likelihood of an overall survival benefit with either therapy – particularly for patients with low programmed death-ligand 1 who receive atezolizumab – I think that the results are promising enough to discuss these treatment options with appropriate patients.

Some argue, however, that overall survival is not necessarily a critical goal and that certain surrogate endpoints are inherently beneficial. Patients and oncologists may, for instance, view delaying disease progression as a win, even if overall survival remains the same.

I appreciate the view that favorable scan results are an achievement, even without a survival benefit. Patients appreciate the good news, and it is gratifying for us to deliver it. However, what remains unspoken is whether the benefit can be provided at a reasonable value given the financial costs associated with the new treatment.

In the United States, we consider the physician-patient relationship to be autonomous and even revered, but we conveniently ignore the fact that both are deciding on treatments that are funded by people who are not represented in the room. And in a health care system that fails to cover basic cancer care needs as well as other critical, high-value interventions for both the uninsured and underinsured, we should acknowledge that our decisions redirect limited resources from others.

Is it the best use of $10,000 per month for a new drug that improves disease-free survival but not overall survival? Given the cost of so many of these newer treatments, we should expect more than indirect, inferred benefits for patients.

At the same time, we also have to remain vigilant and reflect on whether we are echoing the marketing messages of the companies selling these treatments. Having recently watched the excellent Hulu series Dopesick, which realistically portrays the medical community’s egregious overuse of Oxycontin at the behest of Purdue Pharmaceuticals, it is striking to see how effectively the pharmaceutical industry can co-opt stakeholders. Very few physicians or patients have expertise in health care policy with broad societal perspective, yet subspecialists offer edicts as if society should dedicate unlimited resources first and foremost to our career focus or personal cause.

I certainly appreciate the appeal of surrogate endpoints in a world in which we hope to offer novel therapies to patients in a timely fashion. In the next few years, some of our most promising data in oncology will demand that we consider whether surrogate endpoints are practice-changing. We are facing a fundamental question: Are we using these surrogate endpoints to predict overall survival or quality of life or do these endpoints stand on their own as practice-changing metrics?

We need to acknowledge that our primary clinical focus is not the only one that deserves our attention, particularly when our treatment decisions are, in fact, spending other people’s money. We should be asking not whether we prefer to deliver good news after a scan, but whether that alone is enough to justify the high cost of a new treatment without an overall survival benefit.

Dr. West disclosed serving as a director, officer, partner, employee, adviser, consultant, or trustee for Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, and Merck; serving as a speaker or a member of a speakers bureau for Ariad/Takeda, AstraZeneca, and Genentech/Roche; and receiving income from Eli Lilly. A version of this article first appeared on Medscape.com.

In the field of lung cancer, and more broadly in oncology, many of our biggest advances in 2021 have come as clinically meaningful improvements in surrogate endpoints – disease-free survival, progression-free survival, and sometimes even pathologic complete response rate.

I have historically been most compelled to consider new findings to be practice-changing when they improve overall survival or quality of life – the endpoints that translate to direct benefits for patients. However, I also feel it is appropriate to call surrogate endpoints practice-changing when they can predict improvements in overall survival or quality of life.

Take the PACIFIC trial, which assessed maintenance durvalumab after concurrent chemoradiation for unresectable stage III non–small cell lung cancer (NSCLC).

Back in 2017, I was initially unconvinced by the interim phase 3 data that were presented in a press release that highlighted the disease-free survival benefit. However, after examining additional data more closely, I saw the dramatic improvement in time to distant relapse or death was overwhelmingly likely to predict an improvement in overall survival – a benefit that the data subsequently bore out.

More recently, the disease-free survival results for adjuvant osimertinib in resected endothelial growth factor receptor mutation–positive NSCLC and adjuvant atezolizumab in resected programmed death-ligand 1–positive stage II-IIIA NSCLC have led to excitement about Food and Drug Administration approvals for these therapies. Although there is reason to be cautious about the likelihood of an overall survival benefit with either therapy – particularly for patients with low programmed death-ligand 1 who receive atezolizumab – I think that the results are promising enough to discuss these treatment options with appropriate patients.

Some argue, however, that overall survival is not necessarily a critical goal and that certain surrogate endpoints are inherently beneficial. Patients and oncologists may, for instance, view delaying disease progression as a win, even if overall survival remains the same.

I appreciate the view that favorable scan results are an achievement, even without a survival benefit. Patients appreciate the good news, and it is gratifying for us to deliver it. However, what remains unspoken is whether the benefit can be provided at a reasonable value given the financial costs associated with the new treatment.

In the United States, we consider the physician-patient relationship to be autonomous and even revered, but we conveniently ignore the fact that both are deciding on treatments that are funded by people who are not represented in the room. And in a health care system that fails to cover basic cancer care needs as well as other critical, high-value interventions for both the uninsured and underinsured, we should acknowledge that our decisions redirect limited resources from others.

Is it the best use of $10,000 per month for a new drug that improves disease-free survival but not overall survival? Given the cost of so many of these newer treatments, we should expect more than indirect, inferred benefits for patients.

At the same time, we also have to remain vigilant and reflect on whether we are echoing the marketing messages of the companies selling these treatments. Having recently watched the excellent Hulu series Dopesick, which realistically portrays the medical community’s egregious overuse of Oxycontin at the behest of Purdue Pharmaceuticals, it is striking to see how effectively the pharmaceutical industry can co-opt stakeholders. Very few physicians or patients have expertise in health care policy with broad societal perspective, yet subspecialists offer edicts as if society should dedicate unlimited resources first and foremost to our career focus or personal cause.

I certainly appreciate the appeal of surrogate endpoints in a world in which we hope to offer novel therapies to patients in a timely fashion. In the next few years, some of our most promising data in oncology will demand that we consider whether surrogate endpoints are practice-changing. We are facing a fundamental question: Are we using these surrogate endpoints to predict overall survival or quality of life or do these endpoints stand on their own as practice-changing metrics?

We need to acknowledge that our primary clinical focus is not the only one that deserves our attention, particularly when our treatment decisions are, in fact, spending other people’s money. We should be asking not whether we prefer to deliver good news after a scan, but whether that alone is enough to justify the high cost of a new treatment without an overall survival benefit.

Dr. West disclosed serving as a director, officer, partner, employee, adviser, consultant, or trustee for Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, and Merck; serving as a speaker or a member of a speakers bureau for Ariad/Takeda, AstraZeneca, and Genentech/Roche; and receiving income from Eli Lilly. A version of this article first appeared on Medscape.com.

In the field of lung cancer, and more broadly in oncology, many of our biggest advances in 2021 have come as clinically meaningful improvements in surrogate endpoints – disease-free survival, progression-free survival, and sometimes even pathologic complete response rate.

I have historically been most compelled to consider new findings to be practice-changing when they improve overall survival or quality of life – the endpoints that translate to direct benefits for patients. However, I also feel it is appropriate to call surrogate endpoints practice-changing when they can predict improvements in overall survival or quality of life.

Take the PACIFIC trial, which assessed maintenance durvalumab after concurrent chemoradiation for unresectable stage III non–small cell lung cancer (NSCLC).

Back in 2017, I was initially unconvinced by the interim phase 3 data that were presented in a press release that highlighted the disease-free survival benefit. However, after examining additional data more closely, I saw the dramatic improvement in time to distant relapse or death was overwhelmingly likely to predict an improvement in overall survival – a benefit that the data subsequently bore out.

More recently, the disease-free survival results for adjuvant osimertinib in resected endothelial growth factor receptor mutation–positive NSCLC and adjuvant atezolizumab in resected programmed death-ligand 1–positive stage II-IIIA NSCLC have led to excitement about Food and Drug Administration approvals for these therapies. Although there is reason to be cautious about the likelihood of an overall survival benefit with either therapy – particularly for patients with low programmed death-ligand 1 who receive atezolizumab – I think that the results are promising enough to discuss these treatment options with appropriate patients.

Some argue, however, that overall survival is not necessarily a critical goal and that certain surrogate endpoints are inherently beneficial. Patients and oncologists may, for instance, view delaying disease progression as a win, even if overall survival remains the same.

I appreciate the view that favorable scan results are an achievement, even without a survival benefit. Patients appreciate the good news, and it is gratifying for us to deliver it. However, what remains unspoken is whether the benefit can be provided at a reasonable value given the financial costs associated with the new treatment.

In the United States, we consider the physician-patient relationship to be autonomous and even revered, but we conveniently ignore the fact that both are deciding on treatments that are funded by people who are not represented in the room. And in a health care system that fails to cover basic cancer care needs as well as other critical, high-value interventions for both the uninsured and underinsured, we should acknowledge that our decisions redirect limited resources from others.

Is it the best use of $10,000 per month for a new drug that improves disease-free survival but not overall survival? Given the cost of so many of these newer treatments, we should expect more than indirect, inferred benefits for patients.

At the same time, we also have to remain vigilant and reflect on whether we are echoing the marketing messages of the companies selling these treatments. Having recently watched the excellent Hulu series Dopesick, which realistically portrays the medical community’s egregious overuse of Oxycontin at the behest of Purdue Pharmaceuticals, it is striking to see how effectively the pharmaceutical industry can co-opt stakeholders. Very few physicians or patients have expertise in health care policy with broad societal perspective, yet subspecialists offer edicts as if society should dedicate unlimited resources first and foremost to our career focus or personal cause.

I certainly appreciate the appeal of surrogate endpoints in a world in which we hope to offer novel therapies to patients in a timely fashion. In the next few years, some of our most promising data in oncology will demand that we consider whether surrogate endpoints are practice-changing. We are facing a fundamental question: Are we using these surrogate endpoints to predict overall survival or quality of life or do these endpoints stand on their own as practice-changing metrics?

We need to acknowledge that our primary clinical focus is not the only one that deserves our attention, particularly when our treatment decisions are, in fact, spending other people’s money. We should be asking not whether we prefer to deliver good news after a scan, but whether that alone is enough to justify the high cost of a new treatment without an overall survival benefit.

Dr. West disclosed serving as a director, officer, partner, employee, adviser, consultant, or trustee for Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, and Merck; serving as a speaker or a member of a speakers bureau for Ariad/Takeda, AstraZeneca, and Genentech/Roche; and receiving income from Eli Lilly. A version of this article first appeared on Medscape.com.