INTRODUCTION

Lymphadenopathy in Chronic Lymphocytic Leukemia (CLL) is a very common feature. However, sudden increase in lymphadenopathy or other symptoms like weight loss should be evaluated for possible metastatic malignancy. We describe a CLL patient with diffuse mediastinal lymphadenopathy who was diagnosed with metastatic bladder cancer without a primary bladder tumor mass on imaging.

CASE DESCRIPTION

A 60-year-old man with a 60 pack-year smoking history, alcoholic cirrhosis, and a 5-year history of stage 1 CLL presented with 3 months of progressive shortness of breath; persistent cough; chills; hemoptysis; and a steady weight loss of 35 lbs. Notably, he had no bladder symptoms. Initial labs showed leukocytosis of 35.8k with a lymphocytic predominance. Screening low-dose chest CT was positive for diffuse mediastinal lymphadenopathy. Subsequent PET/CT revealed numerous hypermetabolic lymph nodes in the neck, mediastinum, left hilum, and right periaortic abdominal region. CT Chest, Abdomen, Pelvis revealed progressive lymphadenopathy as seen in prior imaging, stable pulmonary nodules up to 4 mm in size, and splenomegaly. No distant primary sites, including of the bladder, were identified. Mediastinal lymph node biopsy confirmed metastatic poorly differentiated carcinoma with immunohistochemical staining negative for p40, p63, CK20, TTF-1, Napsin A, CDX2, CA19- 9, Calretinin, and D2-40 and positive for CK7, GATA3, Ber-EP4, and Uroplakin, supporting bladder as primary origin. Urology deferred a cystoscopy given his lack of urinary symptoms and positive biopsy and was started on Carboplatin/Gemcitabine for his metastatic disease. He was ineligible for Cisplatin given his cirrhosis and hearing impairment.

DISCUSSION

In patients with CLL, new onset mediastinal lymphadenopathy is concerning for disease progression and possible transformation to a diffuse b-cell lymphoma. However, this symptom has a broad differential, including primary lung carcinomas, sarcomas, and metastatic disease. While our patient’s PET/CT and pan-CT failed to identify a distant primary site, maintaining a low clinical suspicion for metastatic disease and doing a thorough work-up was paramount. Only through immunohistochemical staining were we able to diagnosis this patient with urothelial carcinoma.

CONCLUSIONS

Biopsy with immunohistochemical staining and maintaining a low suspicion for worsening lymphadenopathy can identify unusually presenting urothelial carcinomas in CLL patients.

INTRODUCTION

Lymphadenopathy in Chronic Lymphocytic Leukemia (CLL) is a very common feature. However, sudden increase in lymphadenopathy or other symptoms like weight loss should be evaluated for possible metastatic malignancy. We describe a CLL patient with diffuse mediastinal lymphadenopathy who was diagnosed with metastatic bladder cancer without a primary bladder tumor mass on imaging.

CASE DESCRIPTION

A 60-year-old man with a 60 pack-year smoking history, alcoholic cirrhosis, and a 5-year history of stage 1 CLL presented with 3 months of progressive shortness of breath; persistent cough; chills; hemoptysis; and a steady weight loss of 35 lbs. Notably, he had no bladder symptoms. Initial labs showed leukocytosis of 35.8k with a lymphocytic predominance. Screening low-dose chest CT was positive for diffuse mediastinal lymphadenopathy. Subsequent PET/CT revealed numerous hypermetabolic lymph nodes in the neck, mediastinum, left hilum, and right periaortic abdominal region. CT Chest, Abdomen, Pelvis revealed progressive lymphadenopathy as seen in prior imaging, stable pulmonary nodules up to 4 mm in size, and splenomegaly. No distant primary sites, including of the bladder, were identified. Mediastinal lymph node biopsy confirmed metastatic poorly differentiated carcinoma with immunohistochemical staining negative for p40, p63, CK20, TTF-1, Napsin A, CDX2, CA19- 9, Calretinin, and D2-40 and positive for CK7, GATA3, Ber-EP4, and Uroplakin, supporting bladder as primary origin. Urology deferred a cystoscopy given his lack of urinary symptoms and positive biopsy and was started on Carboplatin/Gemcitabine for his metastatic disease. He was ineligible for Cisplatin given his cirrhosis and hearing impairment.

DISCUSSION

In patients with CLL, new onset mediastinal lymphadenopathy is concerning for disease progression and possible transformation to a diffuse b-cell lymphoma. However, this symptom has a broad differential, including primary lung carcinomas, sarcomas, and metastatic disease. While our patient’s PET/CT and pan-CT failed to identify a distant primary site, maintaining a low clinical suspicion for metastatic disease and doing a thorough work-up was paramount. Only through immunohistochemical staining were we able to diagnosis this patient with urothelial carcinoma.

CONCLUSIONS

Biopsy with immunohistochemical staining and maintaining a low suspicion for worsening lymphadenopathy can identify unusually presenting urothelial carcinomas in CLL patients.

INTRODUCTION

Lymphadenopathy in Chronic Lymphocytic Leukemia (CLL) is a very common feature. However, sudden increase in lymphadenopathy or other symptoms like weight loss should be evaluated for possible metastatic malignancy. We describe a CLL patient with diffuse mediastinal lymphadenopathy who was diagnosed with metastatic bladder cancer without a primary bladder tumor mass on imaging.

CASE DESCRIPTION

A 60-year-old man with a 60 pack-year smoking history, alcoholic cirrhosis, and a 5-year history of stage 1 CLL presented with 3 months of progressive shortness of breath; persistent cough; chills; hemoptysis; and a steady weight loss of 35 lbs. Notably, he had no bladder symptoms. Initial labs showed leukocytosis of 35.8k with a lymphocytic predominance. Screening low-dose chest CT was positive for diffuse mediastinal lymphadenopathy. Subsequent PET/CT revealed numerous hypermetabolic lymph nodes in the neck, mediastinum, left hilum, and right periaortic abdominal region. CT Chest, Abdomen, Pelvis revealed progressive lymphadenopathy as seen in prior imaging, stable pulmonary nodules up to 4 mm in size, and splenomegaly. No distant primary sites, including of the bladder, were identified. Mediastinal lymph node biopsy confirmed metastatic poorly differentiated carcinoma with immunohistochemical staining negative for p40, p63, CK20, TTF-1, Napsin A, CDX2, CA19- 9, Calretinin, and D2-40 and positive for CK7, GATA3, Ber-EP4, and Uroplakin, supporting bladder as primary origin. Urology deferred a cystoscopy given his lack of urinary symptoms and positive biopsy and was started on Carboplatin/Gemcitabine for his metastatic disease. He was ineligible for Cisplatin given his cirrhosis and hearing impairment.

DISCUSSION

In patients with CLL, new onset mediastinal lymphadenopathy is concerning for disease progression and possible transformation to a diffuse b-cell lymphoma. However, this symptom has a broad differential, including primary lung carcinomas, sarcomas, and metastatic disease. While our patient’s PET/CT and pan-CT failed to identify a distant primary site, maintaining a low clinical suspicion for metastatic disease and doing a thorough work-up was paramount. Only through immunohistochemical staining were we able to diagnosis this patient with urothelial carcinoma.

CONCLUSIONS

Biopsy with immunohistochemical staining and maintaining a low suspicion for worsening lymphadenopathy can identify unusually presenting urothelial carcinomas in CLL patients.

Throughout the 20th century, the management of ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing the conservative treatment of methotrexate and/or tubal surgery. I make this, seemingly obscure, reference to managing ectopic pregnancy to consider an analogous shift over time in the management of patients with cancer. Over the next decade, the number of people who have lived 5 or more years after their cancer diagnosis is projected to increase approximately 30%, to 16.3 million. Due to the improved survival rates following a cancer diagnosis,¹ revolutionary developments have been made in fertility preservation to obviate the impact of gonadotoxic therapy. We have evolved, however, from shielding and transposing ovaries to ovarian tissue cryopreservation,² with rapid implementation.

While advances in reproductive cryopreservation have allowed for the delay, or even potential “prevention” of infertility, assisted reproductive technology (ART) cannot yet claim a “cure” in ensuring procreation. Nevertheless, fertility preservation is a burgeoning field that has transitioned from an experimental label to a standard of care in 2012, as designated by the American Society for Reproductive Medicine (ASRM).³ From the original intention of offering oocyte cryopreservation to women at risk of ovarian failure from impending gonadotoxic cancer treatment, fertility preservation has accelerated to include freezing for nonmedical reasons—eg, planned oocyte cryopreservation (POC), or “social” egg freezing, to ovarian tissue cryopreservation to accommodate the expediency needed for the treatment of certain cancer treatments. Additionally, across the United States, the number of donor egg banks, which allow women an easily accessible option, is rivaling enduring sperm banks. Due to the advanced methodology of vitrification and growing demand for the technology due to increasing IVF cycles, cryopreservation has become a specialized area of reproductive medicine, and a target of venture capital and private equity commercialization. This article will review the latest techniques, appropriate counseling, and cost/benefit ratio of fertility preservation, with an emphasis on POC.

CASE 1 Fertility preservation options for patient with breast cancer

A 37-year-old woman with newly diagnosed hormone receptor−positive breast cancer is referred for a fertility preservation consultation prior to initiating treatment. Her oncologist plans chemotherapy, followed by radiation and a minimum of 5 years of tamoxifen therapy.

What is the best consultation approach for this patient?

Consultation involves understanding several factors

The consultation approach to this patient involves ascertaining her medical, social, and family history, along with her reproductive plans.

Medical history. For the medical component, we must focus on her diagnosis, anticipated treatment with timeline, risks of gonadal toxicity with planned treatments, her current medical stability, and prognosis for expected survival.

Social history. Her age, relationship status, and desired family size address her social history.

Family history. Given that her cancer affects the breast, there is the risk of genetic susceptibility and potential for embryo testing for the BRCA gene.

Reproductive plans. These include her and her partner’s, if applicable, number of desired children and their risk factors for infertility.

Regarding the reproductive timeline, the antihormonal therapy that may be required for her treatment may improve overall survival, but it would delay the time to pregnancy. Consequently, the pursuit of fertility preservation prior to cancer treatment is a multidisciplinary approach that can involve medical oncology, radiation oncology, REI, medical genetics, and often, psychology. Fortunately, evidence continues to support fertility preservation, with or without hormonal ovarian stimulation, for patients with breast cancer. Data, with up to 5 years of follow-up, has indicated that it is safe.⁴

Continue to: Oncofertility...

To address the need to maximize the reproductive potential of patients with newly diagnosed cancer, the field of oncofertility combines the specialties of oncology and reproductive medicine. The reproductive risk of cancer treatment is gonadotoxicity, with subsequent iatrogenic primary ovarian insufficiency (POI) and infertility. Alkylating agents (including cyclosphosphamide) have the highest risk for amenorrhea, while antimetabolites (including methotrexate, 5–fluorouracil) have the lowest risk.⁵ Treating bone marrow/stem cell transplantation using high-dose alkylating agents, with or without whole body irradiation, results in ≥80% amenorrhea. The minimum radiation dose to induce ovarian failure decreases with advancing age, from 18.4 Gy at age 10 years to 6 Gy at age 40 years, due to biologically diminishing ovarian reserve and an increase in the radiosensitivity of oocytes.⁶ An online tool—using varying factors including age, chemotherapy dose, prior treatment, smoking, and baseline diminished ovarian reserve—is available to help predict the chance of ovarian failure following chemotherapy.⁷

Cryopreservation to the rescue

Since 2012, when ASRM removed the experimental designation on oocyte cryopreservation (OC), the number of cycles offered for fertility preservation has increased dramatically (FIGURE),⁸ initially being used for patients with cancer and now also including women desiring POC.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a matter of routine when patients with infertility utilize frozen eggs from a donor. While there remains debate over better live birth rates with frozen eggs versus fresh eggs, clinic experience may be a critical factor.¹⁰

Ovarian tissue cryopreservation. In addition to the fertility preservation procedures of oocytes and embryo cryopreservation, ovarian tissue cryopreservation became a standard option in 2019 when ASRM removed its experimental designation.¹¹ Given the potential time constraints of urgent cancer treatment, ovarian tissue cryopreservation has the advantage of not requiring ovarian stimulation or sexual maturity and is able to be performed while patients are receiving chemotherapy. If successful, ovarian tissue cryopreservation followed by orthotopic transplantation has the potential to restore natural ovarian function and natural conceptions.¹² However, despite first successfully being described in 2004, ovarian tissue cryopreservation, which does require subsequent thawing and tissue transplantation, remains less available to patients due to low usage rates, which have resulted in few clinics having adequate proficiency.^13,14

Ovarian tissue cryopreservation involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. Live birth rates are modest.¹⁵ In all cancer survivors, particularly those with leukemia, autologous ovarian tissue transplantation may contain malignant cells that could lead to the reintroduction of cancer as the tissue is removed prior to treatment.¹⁶

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans is not known, but animal studies suggest that there may be higher rates of miscarriage and birth defects given the severe DNA damage to oocytes of developing follicles.¹⁷ Hence, ovarian stimulation should be initiated and completed before the start of chemotherapy.

Continue to: Planned oocyte cryopreservation...

Planned oocyte cryopreservation

With advances in ART, POC offers patients the opportunity to preserve fertility until desired. However, despite its potential benefits, POC compels the discussion of various considerations in addition to oncofertility, such as ethical concerns and insurance coverage.

CASE 2 Woman plans for elective egg freezing

A 32-year-old single, professional woman is advancing in her career and wishes to delay childbearing. She is concerned about the potential for age-related fertility decline and wants to explore the option of elective egg freezing. Emily has no medical conditions that would impair her fertility, but she wants to ensure that she has the option of having biological children in the future. She is unsure about the potential financial burden of the procedure and whether her employer’s insurance covers such elective procedures.

How do you counsel her about her options?

Medical considerations

Approximately 25% of reproductive-aged women have considered POC.¹⁸ An analysis revealed POC was more cost-effective than delaying procreation and undergoing IVF with preimplantation genetic testing for aneuploidies at an advanced reproductive age.¹⁹

The process of planned oocyte cryopreservation. POC involves ovarian stimulation, usually with parenteral gonadotropins, to produce multiple mature oocytes for same-day cryopreservation following transvaginal retrieval, typically in an office-based surgery center as an outpatient procedure while the patient is under IV sedation. While the procedure has been proven effective, there are inherent risks and limitations. The success rates of subsequent fertility treatments using the cryopreserved eggs are influenced by the woman’s age at the time of freezing, the number of mature oocytes retrieved and vitrified, and the quality of the oocytes following thaw. A recent study reported a 70% live-birth rate in women aged less than 38 years who cryopreserved ≥ 20 mature eggs.²⁰ To increase the number of cryopreserved oocytes, multiple egg retrievals or “batching” may be of benefit for women with diminished ovarian reserve.²¹

It is important for clinicians to thoroughly assess a patient’s medical history, ovarian reserve (by antral follicle count and levels of anti-müllerian hormone [AMH]), and reproductive goals before recommending proceeding with POC. Of note, AMH is a useful marker for ovarian reserve but has not been shown to predict natural fertility. Its value is in providing a guide to the dosage of ovarian stimulation and an estimation of the number of oocytes to be retrieved. Per ASRM, “Extremely low AMH values should not be used to refuse treatment in IVF.” AMH levels and antral follicle count have only a weak association with such qualitative outcomes as oocyte quality, clinical pregnancy rates, and live birth rates. Complications from egg retrieval, both short and long term, are rare. The inherent risk from POC is the lack of a guaranteed subsequent live birth.²²

Ethical and social considerations

POC raises several ethical considerations, including concerns of perpetuating societal pressure on women to defer procreation to prioritize their careers over family planning.²³ Despite controversies, POC appears as a chosen strategy against age-related infertility and may allow women to feel that they are more socially, psychologically, and financially stable before pursuing motherhood.²⁴ Open and honest discussions between clinicians and patients are crucial to ensure informed decision making and address these ethical concerns.

Per an ACOG statement from February 2023 (https://www.acog.org/womens-health/faqs/having-a-baby-after-age-35-how-aging-affects-fertility-and-pregnancy) “...egg freezing is recommended mainly for patients having cancer treatment that will affect their future fertility. There is not enough research to recommend routine egg freezing for the sole purpose of delaying childbearing.”

A recent survey of patients who had elected egg freezing at some point included more than 80% who were aged 35 or older, and revealed that 93% of the survey participants had not yet returned to use their frozen oocytes.²⁵ The most common reason cited in the survey for a delay in attempted procreation was lack of a partner. Another reason was undergoing oocyte cryopreservation after an optimal reproductive age, with participants concluding that they felt they had improved their reproductive future after undergoing oocyte cryopreservation and feeling empowered by the process. As part of counseling, women should be informed of the possibility of not utilizing their frozen eggs in the future, whether due to natural conception or other personal reasons.

Continue to: Employer insurance coverage...

Access to elective egg freezing is largely influenced by insurance coverage. Currently, employer-provided insurance coverage for this procedure varies widely. While some companies offer comprehensive coverage, others provide limited or no coverage at all. The cost of elective egg freezing can range from $10,000 to $15,000, excluding additional expenses such as medications and annual storage fees. The financial burden can create a gap between patients who desire POC and those with an ability to implement the process. The cost can be a significant barrier for many patients considering this option and perpetuates the lack of universal diversity, equity, and inclusion.

CASE 3 Gender dysphoria and fertility preservation

A 22-year-old transgender man is preparing to undergo gender-affirming hormone therapy and surgery. He is concerned about the potential impact of testosterone therapy on his oocytes and wishes to explore options for fertility preservation prior to oophorectomy.²⁶

What are the patient’s options for fertility preservation?

The patient has the fertility preservation options of OC following ovarian stimulation or ovarian tissue cryopreservation at the time of oophorectomy. Preliminary evidence does not demonstrate impairment of ovarian stimulation and oocyte retrieval number with concurrent testosterone exposure. Ethical considerations, in this case, involve respecting the patient’s autonomy, addressing potential conflicts between gender-affirming care and fertility preservation (eg, a risk of dysphoria in transgender patients preserving biological gametes from a prior assigned gender), and ensuring access to fertility preservation services without discrimination. It is essential to provide the patient in this case with comprehensive information regarding the impact of hormone therapy on fertility, the available options, and the potential financial costs involved. Supportive counseling should also be offered to address any psychological or emotional aspects related to fertility preservation for all patients considering this option.

A call for diversity, equity, and inclusion

To improve access to POC, advocating for employer-offered insurance coverage is paramount. Women’s health providers can encourage dialogue between employers, insurers, and policymakers, which can lead to policy changes that prioritize coverage for fertilitypreservation options. This could include mandating coverage for POC as part of comprehensive health care plans or providing tax incentives to employers who offer coverage for these procedures. Furthermore, public awareness campaigns and advocacy efforts can help educate employers about the importance of including fertility preservation coverage in their employee benefits packages.

Conclusion

Just as physicians must recognize their responsibility to patients to distinguish unproven yet promising science from evidence-based and clinically established science, so too must they advise their patients to consider fertility preservation services in a way that is both clinically justified and ethically appropriate. Informed decisions must be made by appropriate counseling of evidence-based medicine to protect the interest of patients. POC provides patients with an opportunity to preserve their fertility and exercise reproductive autonomy. However, access to this procedure is often hindered by limited or nonexistent employer insurance coverage. By recognizing the medical, ethical, and social implications of POC and implementing strategies to improve coverage, collaborative efforts may increase accessibility and defray costs to provide patients with the option of deferring childbearing and preserving their reproductive potential. ●

Throughout the 20th century, the management of ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing the conservative treatment of methotrexate and/or tubal surgery. I make this, seemingly obscure, reference to managing ectopic pregnancy to consider an analogous shift over time in the management of patients with cancer. Over the next decade, the number of people who have lived 5 or more years after their cancer diagnosis is projected to increase approximately 30%, to 16.3 million. Due to the improved survival rates following a cancer diagnosis,¹ revolutionary developments have been made in fertility preservation to obviate the impact of gonadotoxic therapy. We have evolved, however, from shielding and transposing ovaries to ovarian tissue cryopreservation,² with rapid implementation.

While advances in reproductive cryopreservation have allowed for the delay, or even potential “prevention” of infertility, assisted reproductive technology (ART) cannot yet claim a “cure” in ensuring procreation. Nevertheless, fertility preservation is a burgeoning field that has transitioned from an experimental label to a standard of care in 2012, as designated by the American Society for Reproductive Medicine (ASRM).³ From the original intention of offering oocyte cryopreservation to women at risk of ovarian failure from impending gonadotoxic cancer treatment, fertility preservation has accelerated to include freezing for nonmedical reasons—eg, planned oocyte cryopreservation (POC), or “social” egg freezing, to ovarian tissue cryopreservation to accommodate the expediency needed for the treatment of certain cancer treatments. Additionally, across the United States, the number of donor egg banks, which allow women an easily accessible option, is rivaling enduring sperm banks. Due to the advanced methodology of vitrification and growing demand for the technology due to increasing IVF cycles, cryopreservation has become a specialized area of reproductive medicine, and a target of venture capital and private equity commercialization. This article will review the latest techniques, appropriate counseling, and cost/benefit ratio of fertility preservation, with an emphasis on POC.

CASE 1 Fertility preservation options for patient with breast cancer

A 37-year-old woman with newly diagnosed hormone receptor−positive breast cancer is referred for a fertility preservation consultation prior to initiating treatment. Her oncologist plans chemotherapy, followed by radiation and a minimum of 5 years of tamoxifen therapy.

What is the best consultation approach for this patient?

Consultation involves understanding several factors

The consultation approach to this patient involves ascertaining her medical, social, and family history, along with her reproductive plans.

Medical history. For the medical component, we must focus on her diagnosis, anticipated treatment with timeline, risks of gonadal toxicity with planned treatments, her current medical stability, and prognosis for expected survival.

Social history. Her age, relationship status, and desired family size address her social history.

Family history. Given that her cancer affects the breast, there is the risk of genetic susceptibility and potential for embryo testing for the BRCA gene.

Reproductive plans. These include her and her partner’s, if applicable, number of desired children and their risk factors for infertility.

Regarding the reproductive timeline, the antihormonal therapy that may be required for her treatment may improve overall survival, but it would delay the time to pregnancy. Consequently, the pursuit of fertility preservation prior to cancer treatment is a multidisciplinary approach that can involve medical oncology, radiation oncology, REI, medical genetics, and often, psychology. Fortunately, evidence continues to support fertility preservation, with or without hormonal ovarian stimulation, for patients with breast cancer. Data, with up to 5 years of follow-up, has indicated that it is safe.⁴

Continue to: Oncofertility...

To address the need to maximize the reproductive potential of patients with newly diagnosed cancer, the field of oncofertility combines the specialties of oncology and reproductive medicine. The reproductive risk of cancer treatment is gonadotoxicity, with subsequent iatrogenic primary ovarian insufficiency (POI) and infertility. Alkylating agents (including cyclosphosphamide) have the highest risk for amenorrhea, while antimetabolites (including methotrexate, 5–fluorouracil) have the lowest risk.⁵ Treating bone marrow/stem cell transplantation using high-dose alkylating agents, with or without whole body irradiation, results in ≥80% amenorrhea. The minimum radiation dose to induce ovarian failure decreases with advancing age, from 18.4 Gy at age 10 years to 6 Gy at age 40 years, due to biologically diminishing ovarian reserve and an increase in the radiosensitivity of oocytes.⁶ An online tool—using varying factors including age, chemotherapy dose, prior treatment, smoking, and baseline diminished ovarian reserve—is available to help predict the chance of ovarian failure following chemotherapy.⁷

Cryopreservation to the rescue

Since 2012, when ASRM removed the experimental designation on oocyte cryopreservation (OC), the number of cycles offered for fertility preservation has increased dramatically (FIGURE),⁸ initially being used for patients with cancer and now also including women desiring POC.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a matter of routine when patients with infertility utilize frozen eggs from a donor. While there remains debate over better live birth rates with frozen eggs versus fresh eggs, clinic experience may be a critical factor.¹⁰

Ovarian tissue cryopreservation. In addition to the fertility preservation procedures of oocytes and embryo cryopreservation, ovarian tissue cryopreservation became a standard option in 2019 when ASRM removed its experimental designation.¹¹ Given the potential time constraints of urgent cancer treatment, ovarian tissue cryopreservation has the advantage of not requiring ovarian stimulation or sexual maturity and is able to be performed while patients are receiving chemotherapy. If successful, ovarian tissue cryopreservation followed by orthotopic transplantation has the potential to restore natural ovarian function and natural conceptions.¹² However, despite first successfully being described in 2004, ovarian tissue cryopreservation, which does require subsequent thawing and tissue transplantation, remains less available to patients due to low usage rates, which have resulted in few clinics having adequate proficiency.^13,14

Ovarian tissue cryopreservation involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. Live birth rates are modest.¹⁵ In all cancer survivors, particularly those with leukemia, autologous ovarian tissue transplantation may contain malignant cells that could lead to the reintroduction of cancer as the tissue is removed prior to treatment.¹⁶

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans is not known, but animal studies suggest that there may be higher rates of miscarriage and birth defects given the severe DNA damage to oocytes of developing follicles.¹⁷ Hence, ovarian stimulation should be initiated and completed before the start of chemotherapy.

Continue to: Planned oocyte cryopreservation...

Planned oocyte cryopreservation

With advances in ART, POC offers patients the opportunity to preserve fertility until desired. However, despite its potential benefits, POC compels the discussion of various considerations in addition to oncofertility, such as ethical concerns and insurance coverage.

CASE 2 Woman plans for elective egg freezing

A 32-year-old single, professional woman is advancing in her career and wishes to delay childbearing. She is concerned about the potential for age-related fertility decline and wants to explore the option of elective egg freezing. Emily has no medical conditions that would impair her fertility, but she wants to ensure that she has the option of having biological children in the future. She is unsure about the potential financial burden of the procedure and whether her employer’s insurance covers such elective procedures.

How do you counsel her about her options?

Medical considerations

Approximately 25% of reproductive-aged women have considered POC.¹⁸ An analysis revealed POC was more cost-effective than delaying procreation and undergoing IVF with preimplantation genetic testing for aneuploidies at an advanced reproductive age.¹⁹

The process of planned oocyte cryopreservation. POC involves ovarian stimulation, usually with parenteral gonadotropins, to produce multiple mature oocytes for same-day cryopreservation following transvaginal retrieval, typically in an office-based surgery center as an outpatient procedure while the patient is under IV sedation. While the procedure has been proven effective, there are inherent risks and limitations. The success rates of subsequent fertility treatments using the cryopreserved eggs are influenced by the woman’s age at the time of freezing, the number of mature oocytes retrieved and vitrified, and the quality of the oocytes following thaw. A recent study reported a 70% live-birth rate in women aged less than 38 years who cryopreserved ≥ 20 mature eggs.²⁰ To increase the number of cryopreserved oocytes, multiple egg retrievals or “batching” may be of benefit for women with diminished ovarian reserve.²¹

It is important for clinicians to thoroughly assess a patient’s medical history, ovarian reserve (by antral follicle count and levels of anti-müllerian hormone [AMH]), and reproductive goals before recommending proceeding with POC. Of note, AMH is a useful marker for ovarian reserve but has not been shown to predict natural fertility. Its value is in providing a guide to the dosage of ovarian stimulation and an estimation of the number of oocytes to be retrieved. Per ASRM, “Extremely low AMH values should not be used to refuse treatment in IVF.” AMH levels and antral follicle count have only a weak association with such qualitative outcomes as oocyte quality, clinical pregnancy rates, and live birth rates. Complications from egg retrieval, both short and long term, are rare. The inherent risk from POC is the lack of a guaranteed subsequent live birth.²²

Ethical and social considerations

POC raises several ethical considerations, including concerns of perpetuating societal pressure on women to defer procreation to prioritize their careers over family planning.²³ Despite controversies, POC appears as a chosen strategy against age-related infertility and may allow women to feel that they are more socially, psychologically, and financially stable before pursuing motherhood.²⁴ Open and honest discussions between clinicians and patients are crucial to ensure informed decision making and address these ethical concerns.

Per an ACOG statement from February 2023 (https://www.acog.org/womens-health/faqs/having-a-baby-after-age-35-how-aging-affects-fertility-and-pregnancy) “...egg freezing is recommended mainly for patients having cancer treatment that will affect their future fertility. There is not enough research to recommend routine egg freezing for the sole purpose of delaying childbearing.”

A recent survey of patients who had elected egg freezing at some point included more than 80% who were aged 35 or older, and revealed that 93% of the survey participants had not yet returned to use their frozen oocytes.²⁵ The most common reason cited in the survey for a delay in attempted procreation was lack of a partner. Another reason was undergoing oocyte cryopreservation after an optimal reproductive age, with participants concluding that they felt they had improved their reproductive future after undergoing oocyte cryopreservation and feeling empowered by the process. As part of counseling, women should be informed of the possibility of not utilizing their frozen eggs in the future, whether due to natural conception or other personal reasons.

Continue to: Employer insurance coverage...

Access to elective egg freezing is largely influenced by insurance coverage. Currently, employer-provided insurance coverage for this procedure varies widely. While some companies offer comprehensive coverage, others provide limited or no coverage at all. The cost of elective egg freezing can range from $10,000 to $15,000, excluding additional expenses such as medications and annual storage fees. The financial burden can create a gap between patients who desire POC and those with an ability to implement the process. The cost can be a significant barrier for many patients considering this option and perpetuates the lack of universal diversity, equity, and inclusion.

CASE 3 Gender dysphoria and fertility preservation

A 22-year-old transgender man is preparing to undergo gender-affirming hormone therapy and surgery. He is concerned about the potential impact of testosterone therapy on his oocytes and wishes to explore options for fertility preservation prior to oophorectomy.²⁶

What are the patient’s options for fertility preservation?

The patient has the fertility preservation options of OC following ovarian stimulation or ovarian tissue cryopreservation at the time of oophorectomy. Preliminary evidence does not demonstrate impairment of ovarian stimulation and oocyte retrieval number with concurrent testosterone exposure. Ethical considerations, in this case, involve respecting the patient’s autonomy, addressing potential conflicts between gender-affirming care and fertility preservation (eg, a risk of dysphoria in transgender patients preserving biological gametes from a prior assigned gender), and ensuring access to fertility preservation services without discrimination. It is essential to provide the patient in this case with comprehensive information regarding the impact of hormone therapy on fertility, the available options, and the potential financial costs involved. Supportive counseling should also be offered to address any psychological or emotional aspects related to fertility preservation for all patients considering this option.

A call for diversity, equity, and inclusion

To improve access to POC, advocating for employer-offered insurance coverage is paramount. Women’s health providers can encourage dialogue between employers, insurers, and policymakers, which can lead to policy changes that prioritize coverage for fertilitypreservation options. This could include mandating coverage for POC as part of comprehensive health care plans or providing tax incentives to employers who offer coverage for these procedures. Furthermore, public awareness campaigns and advocacy efforts can help educate employers about the importance of including fertility preservation coverage in their employee benefits packages.

Conclusion

Just as physicians must recognize their responsibility to patients to distinguish unproven yet promising science from evidence-based and clinically established science, so too must they advise their patients to consider fertility preservation services in a way that is both clinically justified and ethically appropriate. Informed decisions must be made by appropriate counseling of evidence-based medicine to protect the interest of patients. POC provides patients with an opportunity to preserve their fertility and exercise reproductive autonomy. However, access to this procedure is often hindered by limited or nonexistent employer insurance coverage. By recognizing the medical, ethical, and social implications of POC and implementing strategies to improve coverage, collaborative efforts may increase accessibility and defray costs to provide patients with the option of deferring childbearing and preserving their reproductive potential. ●

Throughout the 20th century, the management of ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing the conservative treatment of methotrexate and/or tubal surgery. I make this, seemingly obscure, reference to managing ectopic pregnancy to consider an analogous shift over time in the management of patients with cancer. Over the next decade, the number of people who have lived 5 or more years after their cancer diagnosis is projected to increase approximately 30%, to 16.3 million. Due to the improved survival rates following a cancer diagnosis,¹ revolutionary developments have been made in fertility preservation to obviate the impact of gonadotoxic therapy. We have evolved, however, from shielding and transposing ovaries to ovarian tissue cryopreservation,² with rapid implementation.

While advances in reproductive cryopreservation have allowed for the delay, or even potential “prevention” of infertility, assisted reproductive technology (ART) cannot yet claim a “cure” in ensuring procreation. Nevertheless, fertility preservation is a burgeoning field that has transitioned from an experimental label to a standard of care in 2012, as designated by the American Society for Reproductive Medicine (ASRM).³ From the original intention of offering oocyte cryopreservation to women at risk of ovarian failure from impending gonadotoxic cancer treatment, fertility preservation has accelerated to include freezing for nonmedical reasons—eg, planned oocyte cryopreservation (POC), or “social” egg freezing, to ovarian tissue cryopreservation to accommodate the expediency needed for the treatment of certain cancer treatments. Additionally, across the United States, the number of donor egg banks, which allow women an easily accessible option, is rivaling enduring sperm banks. Due to the advanced methodology of vitrification and growing demand for the technology due to increasing IVF cycles, cryopreservation has become a specialized area of reproductive medicine, and a target of venture capital and private equity commercialization. This article will review the latest techniques, appropriate counseling, and cost/benefit ratio of fertility preservation, with an emphasis on POC.

CASE 1 Fertility preservation options for patient with breast cancer

A 37-year-old woman with newly diagnosed hormone receptor−positive breast cancer is referred for a fertility preservation consultation prior to initiating treatment. Her oncologist plans chemotherapy, followed by radiation and a minimum of 5 years of tamoxifen therapy.

What is the best consultation approach for this patient?

Consultation involves understanding several factors

The consultation approach to this patient involves ascertaining her medical, social, and family history, along with her reproductive plans.

Medical history. For the medical component, we must focus on her diagnosis, anticipated treatment with timeline, risks of gonadal toxicity with planned treatments, her current medical stability, and prognosis for expected survival.

Social history. Her age, relationship status, and desired family size address her social history.

Family history. Given that her cancer affects the breast, there is the risk of genetic susceptibility and potential for embryo testing for the BRCA gene.

Reproductive plans. These include her and her partner’s, if applicable, number of desired children and their risk factors for infertility.

Regarding the reproductive timeline, the antihormonal therapy that may be required for her treatment may improve overall survival, but it would delay the time to pregnancy. Consequently, the pursuit of fertility preservation prior to cancer treatment is a multidisciplinary approach that can involve medical oncology, radiation oncology, REI, medical genetics, and often, psychology. Fortunately, evidence continues to support fertility preservation, with or without hormonal ovarian stimulation, for patients with breast cancer. Data, with up to 5 years of follow-up, has indicated that it is safe.⁴

Continue to: Oncofertility...

To address the need to maximize the reproductive potential of patients with newly diagnosed cancer, the field of oncofertility combines the specialties of oncology and reproductive medicine. The reproductive risk of cancer treatment is gonadotoxicity, with subsequent iatrogenic primary ovarian insufficiency (POI) and infertility. Alkylating agents (including cyclosphosphamide) have the highest risk for amenorrhea, while antimetabolites (including methotrexate, 5–fluorouracil) have the lowest risk.⁵ Treating bone marrow/stem cell transplantation using high-dose alkylating agents, with or without whole body irradiation, results in ≥80% amenorrhea. The minimum radiation dose to induce ovarian failure decreases with advancing age, from 18.4 Gy at age 10 years to 6 Gy at age 40 years, due to biologically diminishing ovarian reserve and an increase in the radiosensitivity of oocytes.⁶ An online tool—using varying factors including age, chemotherapy dose, prior treatment, smoking, and baseline diminished ovarian reserve—is available to help predict the chance of ovarian failure following chemotherapy.⁷

Cryopreservation to the rescue

Since 2012, when ASRM removed the experimental designation on oocyte cryopreservation (OC), the number of cycles offered for fertility preservation has increased dramatically (FIGURE),⁸ initially being used for patients with cancer and now also including women desiring POC.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a matter of routine when patients with infertility utilize frozen eggs from a donor. While there remains debate over better live birth rates with frozen eggs versus fresh eggs, clinic experience may be a critical factor.¹⁰

Ovarian tissue cryopreservation. In addition to the fertility preservation procedures of oocytes and embryo cryopreservation, ovarian tissue cryopreservation became a standard option in 2019 when ASRM removed its experimental designation.¹¹ Given the potential time constraints of urgent cancer treatment, ovarian tissue cryopreservation has the advantage of not requiring ovarian stimulation or sexual maturity and is able to be performed while patients are receiving chemotherapy. If successful, ovarian tissue cryopreservation followed by orthotopic transplantation has the potential to restore natural ovarian function and natural conceptions.¹² However, despite first successfully being described in 2004, ovarian tissue cryopreservation, which does require subsequent thawing and tissue transplantation, remains less available to patients due to low usage rates, which have resulted in few clinics having adequate proficiency.^13,14

Ovarian tissue cryopreservation involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. Live birth rates are modest.¹⁵ In all cancer survivors, particularly those with leukemia, autologous ovarian tissue transplantation may contain malignant cells that could lead to the reintroduction of cancer as the tissue is removed prior to treatment.¹⁶

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans is not known, but animal studies suggest that there may be higher rates of miscarriage and birth defects given the severe DNA damage to oocytes of developing follicles.¹⁷ Hence, ovarian stimulation should be initiated and completed before the start of chemotherapy.

Continue to: Planned oocyte cryopreservation...

Planned oocyte cryopreservation

With advances in ART, POC offers patients the opportunity to preserve fertility until desired. However, despite its potential benefits, POC compels the discussion of various considerations in addition to oncofertility, such as ethical concerns and insurance coverage.

CASE 2 Woman plans for elective egg freezing

A 32-year-old single, professional woman is advancing in her career and wishes to delay childbearing. She is concerned about the potential for age-related fertility decline and wants to explore the option of elective egg freezing. Emily has no medical conditions that would impair her fertility, but she wants to ensure that she has the option of having biological children in the future. She is unsure about the potential financial burden of the procedure and whether her employer’s insurance covers such elective procedures.

How do you counsel her about her options?

Medical considerations

Approximately 25% of reproductive-aged women have considered POC.¹⁸ An analysis revealed POC was more cost-effective than delaying procreation and undergoing IVF with preimplantation genetic testing for aneuploidies at an advanced reproductive age.¹⁹

The process of planned oocyte cryopreservation. POC involves ovarian stimulation, usually with parenteral gonadotropins, to produce multiple mature oocytes for same-day cryopreservation following transvaginal retrieval, typically in an office-based surgery center as an outpatient procedure while the patient is under IV sedation. While the procedure has been proven effective, there are inherent risks and limitations. The success rates of subsequent fertility treatments using the cryopreserved eggs are influenced by the woman’s age at the time of freezing, the number of mature oocytes retrieved and vitrified, and the quality of the oocytes following thaw. A recent study reported a 70% live-birth rate in women aged less than 38 years who cryopreserved ≥ 20 mature eggs.²⁰ To increase the number of cryopreserved oocytes, multiple egg retrievals or “batching” may be of benefit for women with diminished ovarian reserve.²¹

It is important for clinicians to thoroughly assess a patient’s medical history, ovarian reserve (by antral follicle count and levels of anti-müllerian hormone [AMH]), and reproductive goals before recommending proceeding with POC. Of note, AMH is a useful marker for ovarian reserve but has not been shown to predict natural fertility. Its value is in providing a guide to the dosage of ovarian stimulation and an estimation of the number of oocytes to be retrieved. Per ASRM, “Extremely low AMH values should not be used to refuse treatment in IVF.” AMH levels and antral follicle count have only a weak association with such qualitative outcomes as oocyte quality, clinical pregnancy rates, and live birth rates. Complications from egg retrieval, both short and long term, are rare. The inherent risk from POC is the lack of a guaranteed subsequent live birth.²²

Ethical and social considerations

POC raises several ethical considerations, including concerns of perpetuating societal pressure on women to defer procreation to prioritize their careers over family planning.²³ Despite controversies, POC appears as a chosen strategy against age-related infertility and may allow women to feel that they are more socially, psychologically, and financially stable before pursuing motherhood.²⁴ Open and honest discussions between clinicians and patients are crucial to ensure informed decision making and address these ethical concerns.

Per an ACOG statement from February 2023 (https://www.acog.org/womens-health/faqs/having-a-baby-after-age-35-how-aging-affects-fertility-and-pregnancy) “...egg freezing is recommended mainly for patients having cancer treatment that will affect their future fertility. There is not enough research to recommend routine egg freezing for the sole purpose of delaying childbearing.”

A recent survey of patients who had elected egg freezing at some point included more than 80% who were aged 35 or older, and revealed that 93% of the survey participants had not yet returned to use their frozen oocytes.²⁵ The most common reason cited in the survey for a delay in attempted procreation was lack of a partner. Another reason was undergoing oocyte cryopreservation after an optimal reproductive age, with participants concluding that they felt they had improved their reproductive future after undergoing oocyte cryopreservation and feeling empowered by the process. As part of counseling, women should be informed of the possibility of not utilizing their frozen eggs in the future, whether due to natural conception or other personal reasons.

Continue to: Employer insurance coverage...

Access to elective egg freezing is largely influenced by insurance coverage. Currently, employer-provided insurance coverage for this procedure varies widely. While some companies offer comprehensive coverage, others provide limited or no coverage at all. The cost of elective egg freezing can range from $10,000 to $15,000, excluding additional expenses such as medications and annual storage fees. The financial burden can create a gap between patients who desire POC and those with an ability to implement the process. The cost can be a significant barrier for many patients considering this option and perpetuates the lack of universal diversity, equity, and inclusion.

CASE 3 Gender dysphoria and fertility preservation

A 22-year-old transgender man is preparing to undergo gender-affirming hormone therapy and surgery. He is concerned about the potential impact of testosterone therapy on his oocytes and wishes to explore options for fertility preservation prior to oophorectomy.²⁶

What are the patient’s options for fertility preservation?

The patient has the fertility preservation options of OC following ovarian stimulation or ovarian tissue cryopreservation at the time of oophorectomy. Preliminary evidence does not demonstrate impairment of ovarian stimulation and oocyte retrieval number with concurrent testosterone exposure. Ethical considerations, in this case, involve respecting the patient’s autonomy, addressing potential conflicts between gender-affirming care and fertility preservation (eg, a risk of dysphoria in transgender patients preserving biological gametes from a prior assigned gender), and ensuring access to fertility preservation services without discrimination. It is essential to provide the patient in this case with comprehensive information regarding the impact of hormone therapy on fertility, the available options, and the potential financial costs involved. Supportive counseling should also be offered to address any psychological or emotional aspects related to fertility preservation for all patients considering this option.

A call for diversity, equity, and inclusion

To improve access to POC, advocating for employer-offered insurance coverage is paramount. Women’s health providers can encourage dialogue between employers, insurers, and policymakers, which can lead to policy changes that prioritize coverage for fertilitypreservation options. This could include mandating coverage for POC as part of comprehensive health care plans or providing tax incentives to employers who offer coverage for these procedures. Furthermore, public awareness campaigns and advocacy efforts can help educate employers about the importance of including fertility preservation coverage in their employee benefits packages.

Conclusion

Just as physicians must recognize their responsibility to patients to distinguish unproven yet promising science from evidence-based and clinically established science, so too must they advise their patients to consider fertility preservation services in a way that is both clinically justified and ethically appropriate. Informed decisions must be made by appropriate counseling of evidence-based medicine to protect the interest of patients. POC provides patients with an opportunity to preserve their fertility and exercise reproductive autonomy. However, access to this procedure is often hindered by limited or nonexistent employer insurance coverage. By recognizing the medical, ethical, and social implications of POC and implementing strategies to improve coverage, collaborative efforts may increase accessibility and defray costs to provide patients with the option of deferring childbearing and preserving their reproductive potential. ●

FROM SOHO 2023

It may be possible for patients with Hodgkin lymphoma to safely skip their interim PET-CT scan (PET2) following two cycles of frontline brentuximab vedotin (Adcetris), according to research presented at the annual meeting of the Society of Hematologic Oncology in Houston.

Data from four recent studies indicate that adding frontline brentuximab vedotin to AVD chemotherapy (doxorubicin, vinblastine, dacarbazine) improves outcomes for patients, regardless of PET2 scan results, according to lead investigator Ravand Samaeekia, MD, MSc, from Loma Linda (Calif.) University Medical Center.

These studies, including one conducted by Dr. Samaeekia’s team, provide “evidence for the safe omission of PET2 in treatment regimens that contain brentuximab vedotin,” Dr. Samaeekia, who presented the data, concluded.

Performing an interim PET-CT scan after two cycles of chemotherapy can help oncologists adapt treatment protocols for patients with Hodgkin lymphoma and has become the standard of care for these patients.

However, “there are obviously challenges associated with implementing a PET-guided approach,” said Dr. Samaeekia. Additional PET-CT scans can be costly, time consuming, and increase patients’ risk for toxicities when treatment is escalated based on the scan results.

Given these caveats, Dr. Samaeekia reviewed data exploring whether PET2 has predictive value for patients who receive the anti-CD30 antibody-drug conjugate, brentuximab vedotin, as part of first-line treatment alongside AVD chemotherapy.

Dr. Samaeekia’s team analyzed findings from three trials – ECHELON-1, AHOD1331, and BREACH – which assessed frontline standard of care chemotherapy with or without brentuximab. The team found that incorporating brentuximab into frontline treatment resulted in superior efficacy, and PET2 scans results generally did not change how patients were managed.

In ECHELON-1, 6-year overall survival favored patients with advanced Hodgkin lymphoma who received brentuximab and were PET2 negative (94.9% vs. 90.6%; hazard ratio for death, 0.54) as well as those who were PET2 positive (95% vs. 77%; HR, 0.16). Overall, just over 2% of patients who received the brentuximab regimen switched to an alternative chemotherapy and even fewer did so based on PET2 results.

In AHOD1331, 3-year event-free survival was significantly higher among adolescents and children with Hodgkin lymphoma who received brentuximab – 90.7% for those who had slow-responding lesions and 92.3% for those with rapid-responding lesions. Based on these results, the authors concluded that adding brentuximab “eliminated the predictive value of the interim PET assessment.” The BREACH trial echoed the findings from ECHELON-1 and AHOD1331.

Finally, in a retrospective study of 40 patients treated at Loma Linda with brentuximab vedotin plus AVD, Dr. Samaeekia and colleagues found that 24 were PET2 negative and 12 were PET2 positive. All patients who were PET2 negative remained negative on the end-of-treatment PET, indicating no cancer progression. Of the 12 PET2-positive patients, four (33%) remained PET positive at the end of treatment. Only one patient overall changed regimens following PET2.

Dr. Samaeekia’s team concluded that PET2 scan results “did not have any meaningful impact” on patient management or outcomes.

During the Q&A, Martin Hutchings, MD, PhD, challenged the idea that PET2 can be omitted. Dr. Hutchings, from the Rigshospitalet in Copenhagen, pointed out that 4 of the 12 PET2-positive patients treated at Loma Linda were still PET positive at the end of treatment.

Even so, Dr. Samaeekia explained, PET2 findings did not alter treatment for most patients, noting that doing a PET2 scan may make “us feel better,” but it ultimately doesn’t “make any difference in our management.”

In the AHOD1331 study, “the findings on the interim PET scan were not helpful in the ultimate outcome, whether it was either positive or negative,” added session comoderator Jonathan W. Friedberg, MD, MMSc, director of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.) Medical Center.

The study by Dr. Samaeekia and colleagues was internally funded. Dr. Samaeekia reports no relevant financial relationships. Dr. Hutchings has previously reported consultancy and research funding from numerous companies. Dr. Friedberg reports no relevant financial relationships.

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

FROM SOHO 2023

It may be possible for patients with Hodgkin lymphoma to safely skip their interim PET-CT scan (PET2) following two cycles of frontline brentuximab vedotin (Adcetris), according to research presented at the annual meeting of the Society of Hematologic Oncology in Houston.

Data from four recent studies indicate that adding frontline brentuximab vedotin to AVD chemotherapy (doxorubicin, vinblastine, dacarbazine) improves outcomes for patients, regardless of PET2 scan results, according to lead investigator Ravand Samaeekia, MD, MSc, from Loma Linda (Calif.) University Medical Center.

These studies, including one conducted by Dr. Samaeekia’s team, provide “evidence for the safe omission of PET2 in treatment regimens that contain brentuximab vedotin,” Dr. Samaeekia, who presented the data, concluded.

Performing an interim PET-CT scan after two cycles of chemotherapy can help oncologists adapt treatment protocols for patients with Hodgkin lymphoma and has become the standard of care for these patients.

However, “there are obviously challenges associated with implementing a PET-guided approach,” said Dr. Samaeekia. Additional PET-CT scans can be costly, time consuming, and increase patients’ risk for toxicities when treatment is escalated based on the scan results.

Given these caveats, Dr. Samaeekia reviewed data exploring whether PET2 has predictive value for patients who receive the anti-CD30 antibody-drug conjugate, brentuximab vedotin, as part of first-line treatment alongside AVD chemotherapy.

Dr. Samaeekia’s team analyzed findings from three trials – ECHELON-1, AHOD1331, and BREACH – which assessed frontline standard of care chemotherapy with or without brentuximab. The team found that incorporating brentuximab into frontline treatment resulted in superior efficacy, and PET2 scans results generally did not change how patients were managed.

In ECHELON-1, 6-year overall survival favored patients with advanced Hodgkin lymphoma who received brentuximab and were PET2 negative (94.9% vs. 90.6%; hazard ratio for death, 0.54) as well as those who were PET2 positive (95% vs. 77%; HR, 0.16). Overall, just over 2% of patients who received the brentuximab regimen switched to an alternative chemotherapy and even fewer did so based on PET2 results.

In AHOD1331, 3-year event-free survival was significantly higher among adolescents and children with Hodgkin lymphoma who received brentuximab – 90.7% for those who had slow-responding lesions and 92.3% for those with rapid-responding lesions. Based on these results, the authors concluded that adding brentuximab “eliminated the predictive value of the interim PET assessment.” The BREACH trial echoed the findings from ECHELON-1 and AHOD1331.

Finally, in a retrospective study of 40 patients treated at Loma Linda with brentuximab vedotin plus AVD, Dr. Samaeekia and colleagues found that 24 were PET2 negative and 12 were PET2 positive. All patients who were PET2 negative remained negative on the end-of-treatment PET, indicating no cancer progression. Of the 12 PET2-positive patients, four (33%) remained PET positive at the end of treatment. Only one patient overall changed regimens following PET2.

Dr. Samaeekia’s team concluded that PET2 scan results “did not have any meaningful impact” on patient management or outcomes.

During the Q&A, Martin Hutchings, MD, PhD, challenged the idea that PET2 can be omitted. Dr. Hutchings, from the Rigshospitalet in Copenhagen, pointed out that 4 of the 12 PET2-positive patients treated at Loma Linda were still PET positive at the end of treatment.

Even so, Dr. Samaeekia explained, PET2 findings did not alter treatment for most patients, noting that doing a PET2 scan may make “us feel better,” but it ultimately doesn’t “make any difference in our management.”

In the AHOD1331 study, “the findings on the interim PET scan were not helpful in the ultimate outcome, whether it was either positive or negative,” added session comoderator Jonathan W. Friedberg, MD, MMSc, director of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.) Medical Center.

The study by Dr. Samaeekia and colleagues was internally funded. Dr. Samaeekia reports no relevant financial relationships. Dr. Hutchings has previously reported consultancy and research funding from numerous companies. Dr. Friedberg reports no relevant financial relationships.

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

FROM SOHO 2023

It may be possible for patients with Hodgkin lymphoma to safely skip their interim PET-CT scan (PET2) following two cycles of frontline brentuximab vedotin (Adcetris), according to research presented at the annual meeting of the Society of Hematologic Oncology in Houston.

Data from four recent studies indicate that adding frontline brentuximab vedotin to AVD chemotherapy (doxorubicin, vinblastine, dacarbazine) improves outcomes for patients, regardless of PET2 scan results, according to lead investigator Ravand Samaeekia, MD, MSc, from Loma Linda (Calif.) University Medical Center.

These studies, including one conducted by Dr. Samaeekia’s team, provide “evidence for the safe omission of PET2 in treatment regimens that contain brentuximab vedotin,” Dr. Samaeekia, who presented the data, concluded.

Performing an interim PET-CT scan after two cycles of chemotherapy can help oncologists adapt treatment protocols for patients with Hodgkin lymphoma and has become the standard of care for these patients.

However, “there are obviously challenges associated with implementing a PET-guided approach,” said Dr. Samaeekia. Additional PET-CT scans can be costly, time consuming, and increase patients’ risk for toxicities when treatment is escalated based on the scan results.

Given these caveats, Dr. Samaeekia reviewed data exploring whether PET2 has predictive value for patients who receive the anti-CD30 antibody-drug conjugate, brentuximab vedotin, as part of first-line treatment alongside AVD chemotherapy.

Dr. Samaeekia’s team analyzed findings from three trials – ECHELON-1, AHOD1331, and BREACH – which assessed frontline standard of care chemotherapy with or without brentuximab. The team found that incorporating brentuximab into frontline treatment resulted in superior efficacy, and PET2 scans results generally did not change how patients were managed.

In ECHELON-1, 6-year overall survival favored patients with advanced Hodgkin lymphoma who received brentuximab and were PET2 negative (94.9% vs. 90.6%; hazard ratio for death, 0.54) as well as those who were PET2 positive (95% vs. 77%; HR, 0.16). Overall, just over 2% of patients who received the brentuximab regimen switched to an alternative chemotherapy and even fewer did so based on PET2 results.

In AHOD1331, 3-year event-free survival was significantly higher among adolescents and children with Hodgkin lymphoma who received brentuximab – 90.7% for those who had slow-responding lesions and 92.3% for those with rapid-responding lesions. Based on these results, the authors concluded that adding brentuximab “eliminated the predictive value of the interim PET assessment.” The BREACH trial echoed the findings from ECHELON-1 and AHOD1331.

Finally, in a retrospective study of 40 patients treated at Loma Linda with brentuximab vedotin plus AVD, Dr. Samaeekia and colleagues found that 24 were PET2 negative and 12 were PET2 positive. All patients who were PET2 negative remained negative on the end-of-treatment PET, indicating no cancer progression. Of the 12 PET2-positive patients, four (33%) remained PET positive at the end of treatment. Only one patient overall changed regimens following PET2.

Dr. Samaeekia’s team concluded that PET2 scan results “did not have any meaningful impact” on patient management or outcomes.

During the Q&A, Martin Hutchings, MD, PhD, challenged the idea that PET2 can be omitted. Dr. Hutchings, from the Rigshospitalet in Copenhagen, pointed out that 4 of the 12 PET2-positive patients treated at Loma Linda were still PET positive at the end of treatment.

Even so, Dr. Samaeekia explained, PET2 findings did not alter treatment for most patients, noting that doing a PET2 scan may make “us feel better,” but it ultimately doesn’t “make any difference in our management.”

In the AHOD1331 study, “the findings on the interim PET scan were not helpful in the ultimate outcome, whether it was either positive or negative,” added session comoderator Jonathan W. Friedberg, MD, MMSc, director of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.) Medical Center.

The study by Dr. Samaeekia and colleagues was internally funded. Dr. Samaeekia reports no relevant financial relationships. Dr. Hutchings has previously reported consultancy and research funding from numerous companies. Dr. Friedberg reports no relevant financial relationships.

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

Patients with cutaneous Merkel cell carcinoma (MCC) have a higher risk of subsequently developing solid and hematologic cancers, according to a new analysis.

In a cohort of 6,146 patients with a first primary MCC, a total of 725 (11.8%) developed subsequent primary cancers. For solid tumors, the risk was highest for cutaneous melanoma and papillary thyroid carcinoma, while for hematologic cancers, the risk was increased for non-Hodgkin lymphoma.

“Our study does confirm that patients with MCC are at higher risk for developing other cancers,” study author Lisa C. Zaba, MD, PhD, associate professor of dermatology and director of the Merkel cell carcinoma multidisciplinary clinic, Stanford (Calif.) Cancer Center, said in an interview. “MCC is a highly malignant cancer with a 40% recurrence risk.”

Because of this high risk, Dr. Zaba noted that patients with MCC get frequent surveillance with both imaging studies (PET-CT and CT) as well as frequent visits in clinic with MCC experts. “Specifically, a patient with MCC is imaged and seen in clinic every 3-6 months for the first 3 years after diagnosis, and every 6-12 months thereafter for up to 5 years,” she said. “Interestingly, this high level of surveillance may be one reason that we find so many cancers in patients who have been diagnosed with MCC, compared to the general population.”

The study was published online in JAMA Dermatology.

With the death of “Margaritaville” singer Jimmy Buffett, who recently died of MCC 4 years after his diagnosis, this rare, aggressive skin cancer has been put in the spotlight. Survival has been increasing, primarily because of the advent of immunotherapy, and the authors note that it is therefore imperative to better understand the risk of subsequent primary tumors to inform screening and treatment recommendations.

In this cohort study, Dr. Zaba and colleagues identified 6,146 patients from 17 registries of the Surveillance, Epidemiology, and End Results (SEER) Program who had been diagnosed with a first primary cutaneous MCC between 2000 and 2018.

Endpoints were the ratio of observed to expected number of cases of subsequent cancer (Standardized incidence ratio, or SIR) and the excess risk.

Overall, there was an elevated risk of developing a subsequent primary cancer after being diagnosed with MCC (SIR, 1.28; excess risk, 57.25 per 10,000 person-years). This included the risk for all solid tumors including liver (SIR, 1.92; excess risk, 2.77 per 10,000 person-years), pancreas (SIR, 1.65; excess risk, 4.55 per 10,000 person-years), cutaneous melanoma (SIR, 2.36; excess risk, 15.27 per 10,000 person-years), and kidney (SIR, 1.64; excess risk, 3.83 per 10,000 person-years).

There was also a higher risk of developing papillary thyroid carcinoma (PTC) (SIR, 5.26; excess risk, 6.16 per 10,000 person-years).

The risk of developing hematological cancers after MCC was also increased, especially for non-Hodgkin lymphoma (SIR, 2.62; excess risk, 15.48 per 10,000 person-years) and myelodysplastic syndrome (SIR, 2.17; excess risk, 2.73 per 10,000 person-years).

The risk for developing subsequent tumors, including melanoma and non-Hodgkin lymphoma, remained significant for up to 10 years, while the risk for developing PTC and kidney cancers remained for up to 5 years.

“After 3-5 years, when a MCC patient’s risk of MCC recurrence drops below 2%, we do not currently have guidelines in place for additional cancer screening,” Dr. Zaba said. “Regarding patient education, patients with MCC are educated to let us know if they experience any symptoms of cancer between visits, including unintentional weight loss, night sweats, headaches that increasingly worsen, or growing lumps or bumps. These symptoms may occur in a multitude of cancers and not just MCC.”

Weighing in on the study, Jeffrey M. Farma, MD, interim chair, department of surgical oncology at Fox Chase Cancer Center, Philadelphia, noted that MCC is considered to be high risk because of its chances of recurring after surgical resection or spreading to lymph nodes or other areas of the body. “There are approximately 3,000 new cases of melanoma a year in the U.S., and it is 40 times rarer than melanoma,” he said. “Patients are usually diagnosed with Merkel cell carcinoma later in life, and the tumors have been associated with sun exposure and immunosuppression and have also been associated with the polyomavirus.”

That said, however, he emphasized that great strides have been made in treatment. “These tumors are very sensitive to radiation, and we generally treat earlier-stage MCC with a combination of surgery and radiation therapy,” said Dr. Farma. “More recently we have had a lot of success with the use of immunotherapy to treat more advanced MCC.”

Dr. Zaba reported receiving grants from the Kuni Foundation outside the submitted work. No other disclosures were reported. Author Eleni Linos, MD, DrPH, MPH, is supported by grant K24AR075060 from the National Institutes of Health. No other outside funding was reported. Dr. Farma had no disclosures.

Patients with cutaneous Merkel cell carcinoma (MCC) have a higher risk of subsequently developing solid and hematologic cancers, according to a new analysis.

In a cohort of 6,146 patients with a first primary MCC, a total of 725 (11.8%) developed subsequent primary cancers. For solid tumors, the risk was highest for cutaneous melanoma and papillary thyroid carcinoma, while for hematologic cancers, the risk was increased for non-Hodgkin lymphoma.

“Our study does confirm that patients with MCC are at higher risk for developing other cancers,” study author Lisa C. Zaba, MD, PhD, associate professor of dermatology and director of the Merkel cell carcinoma multidisciplinary clinic, Stanford (Calif.) Cancer Center, said in an interview. “MCC is a highly malignant cancer with a 40% recurrence risk.”

Because of this high risk, Dr. Zaba noted that patients with MCC get frequent surveillance with both imaging studies (PET-CT and CT) as well as frequent visits in clinic with MCC experts. “Specifically, a patient with MCC is imaged and seen in clinic every 3-6 months for the first 3 years after diagnosis, and every 6-12 months thereafter for up to 5 years,” she said. “Interestingly, this high level of surveillance may be one reason that we find so many cancers in patients who have been diagnosed with MCC, compared to the general population.”

The study was published online in JAMA Dermatology.

With the death of “Margaritaville” singer Jimmy Buffett, who recently died of MCC 4 years after his diagnosis, this rare, aggressive skin cancer has been put in the spotlight. Survival has been increasing, primarily because of the advent of immunotherapy, and the authors note that it is therefore imperative to better understand the risk of subsequent primary tumors to inform screening and treatment recommendations.

In this cohort study, Dr. Zaba and colleagues identified 6,146 patients from 17 registries of the Surveillance, Epidemiology, and End Results (SEER) Program who had been diagnosed with a first primary cutaneous MCC between 2000 and 2018.

Endpoints were the ratio of observed to expected number of cases of subsequent cancer (Standardized incidence ratio, or SIR) and the excess risk.

Overall, there was an elevated risk of developing a subsequent primary cancer after being diagnosed with MCC (SIR, 1.28; excess risk, 57.25 per 10,000 person-years). This included the risk for all solid tumors including liver (SIR, 1.92; excess risk, 2.77 per 10,000 person-years), pancreas (SIR, 1.65; excess risk, 4.55 per 10,000 person-years), cutaneous melanoma (SIR, 2.36; excess risk, 15.27 per 10,000 person-years), and kidney (SIR, 1.64; excess risk, 3.83 per 10,000 person-years).

There was also a higher risk of developing papillary thyroid carcinoma (PTC) (SIR, 5.26; excess risk, 6.16 per 10,000 person-years).

The risk of developing hematological cancers after MCC was also increased, especially for non-Hodgkin lymphoma (SIR, 2.62; excess risk, 15.48 per 10,000 person-years) and myelodysplastic syndrome (SIR, 2.17; excess risk, 2.73 per 10,000 person-years).

The risk for developing subsequent tumors, including melanoma and non-Hodgkin lymphoma, remained significant for up to 10 years, while the risk for developing PTC and kidney cancers remained for up to 5 years.

“After 3-5 years, when a MCC patient’s risk of MCC recurrence drops below 2%, we do not currently have guidelines in place for additional cancer screening,” Dr. Zaba said. “Regarding patient education, patients with MCC are educated to let us know if they experience any symptoms of cancer between visits, including unintentional weight loss, night sweats, headaches that increasingly worsen, or growing lumps or bumps. These symptoms may occur in a multitude of cancers and not just MCC.”

Weighing in on the study, Jeffrey M. Farma, MD, interim chair, department of surgical oncology at Fox Chase Cancer Center, Philadelphia, noted that MCC is considered to be high risk because of its chances of recurring after surgical resection or spreading to lymph nodes or other areas of the body. “There are approximately 3,000 new cases of melanoma a year in the U.S., and it is 40 times rarer than melanoma,” he said. “Patients are usually diagnosed with Merkel cell carcinoma later in life, and the tumors have been associated with sun exposure and immunosuppression and have also been associated with the polyomavirus.”

That said, however, he emphasized that great strides have been made in treatment. “These tumors are very sensitive to radiation, and we generally treat earlier-stage MCC with a combination of surgery and radiation therapy,” said Dr. Farma. “More recently we have had a lot of success with the use of immunotherapy to treat more advanced MCC.”

Dr. Zaba reported receiving grants from the Kuni Foundation outside the submitted work. No other disclosures were reported. Author Eleni Linos, MD, DrPH, MPH, is supported by grant K24AR075060 from the National Institutes of Health. No other outside funding was reported. Dr. Farma had no disclosures.

Patients with cutaneous Merkel cell carcinoma (MCC) have a higher risk of subsequently developing solid and hematologic cancers, according to a new analysis.

In a cohort of 6,146 patients with a first primary MCC, a total of 725 (11.8%) developed subsequent primary cancers. For solid tumors, the risk was highest for cutaneous melanoma and papillary thyroid carcinoma, while for hematologic cancers, the risk was increased for non-Hodgkin lymphoma.

“Our study does confirm that patients with MCC are at higher risk for developing other cancers,” study author Lisa C. Zaba, MD, PhD, associate professor of dermatology and director of the Merkel cell carcinoma multidisciplinary clinic, Stanford (Calif.) Cancer Center, said in an interview. “MCC is a highly malignant cancer with a 40% recurrence risk.”

Because of this high risk, Dr. Zaba noted that patients with MCC get frequent surveillance with both imaging studies (PET-CT and CT) as well as frequent visits in clinic with MCC experts. “Specifically, a patient with MCC is imaged and seen in clinic every 3-6 months for the first 3 years after diagnosis, and every 6-12 months thereafter for up to 5 years,” she said. “Interestingly, this high level of surveillance may be one reason that we find so many cancers in patients who have been diagnosed with MCC, compared to the general population.”

The study was published online in JAMA Dermatology.

With the death of “Margaritaville” singer Jimmy Buffett, who recently died of MCC 4 years after his diagnosis, this rare, aggressive skin cancer has been put in the spotlight. Survival has been increasing, primarily because of the advent of immunotherapy, and the authors note that it is therefore imperative to better understand the risk of subsequent primary tumors to inform screening and treatment recommendations.

In this cohort study, Dr. Zaba and colleagues identified 6,146 patients from 17 registries of the Surveillance, Epidemiology, and End Results (SEER) Program who had been diagnosed with a first primary cutaneous MCC between 2000 and 2018.

Endpoints were the ratio of observed to expected number of cases of subsequent cancer (Standardized incidence ratio, or SIR) and the excess risk.

Overall, there was an elevated risk of developing a subsequent primary cancer after being diagnosed with MCC (SIR, 1.28; excess risk, 57.25 per 10,000 person-years). This included the risk for all solid tumors including liver (SIR, 1.92; excess risk, 2.77 per 10,000 person-years), pancreas (SIR, 1.65; excess risk, 4.55 per 10,000 person-years), cutaneous melanoma (SIR, 2.36; excess risk, 15.27 per 10,000 person-years), and kidney (SIR, 1.64; excess risk, 3.83 per 10,000 person-years).

There was also a higher risk of developing papillary thyroid carcinoma (PTC) (SIR, 5.26; excess risk, 6.16 per 10,000 person-years).

The risk of developing hematological cancers after MCC was also increased, especially for non-Hodgkin lymphoma (SIR, 2.62; excess risk, 15.48 per 10,000 person-years) and myelodysplastic syndrome (SIR, 2.17; excess risk, 2.73 per 10,000 person-years).

The risk for developing subsequent tumors, including melanoma and non-Hodgkin lymphoma, remained significant for up to 10 years, while the risk for developing PTC and kidney cancers remained for up to 5 years.

“After 3-5 years, when a MCC patient’s risk of MCC recurrence drops below 2%, we do not currently have guidelines in place for additional cancer screening,” Dr. Zaba said. “Regarding patient education, patients with MCC are educated to let us know if they experience any symptoms of cancer between visits, including unintentional weight loss, night sweats, headaches that increasingly worsen, or growing lumps or bumps. These symptoms may occur in a multitude of cancers and not just MCC.”

Weighing in on the study, Jeffrey M. Farma, MD, interim chair, department of surgical oncology at Fox Chase Cancer Center, Philadelphia, noted that MCC is considered to be high risk because of its chances of recurring after surgical resection or spreading to lymph nodes or other areas of the body. “There are approximately 3,000 new cases of melanoma a year in the U.S., and it is 40 times rarer than melanoma,” he said. “Patients are usually diagnosed with Merkel cell carcinoma later in life, and the tumors have been associated with sun exposure and immunosuppression and have also been associated with the polyomavirus.”

That said, however, he emphasized that great strides have been made in treatment. “These tumors are very sensitive to radiation, and we generally treat earlier-stage MCC with a combination of surgery and radiation therapy,” said Dr. Farma. “More recently we have had a lot of success with the use of immunotherapy to treat more advanced MCC.”

Dr. Zaba reported receiving grants from the Kuni Foundation outside the submitted work. No other disclosures were reported. Author Eleni Linos, MD, DrPH, MPH, is supported by grant K24AR075060 from the National Institutes of Health. No other outside funding was reported. Dr. Farma had no disclosures.

TOPLINE:

Globally, lead exposure is linked to more than 5.5 million adult cardiovascular deaths in 2019, as well as loss of 765 million intelligence quotient (IQ) points in children younger than 5 years, which cost U.S. $6 trillion in lost productivity, new research suggests.

METHODOLOGY:

• Global lead exposure has declined substantially since leaded gasoline was phased out, but several sources of lead remain, resulting in adverse health and economic effects, particularly in low- and middle-income countries (LMICs).
• Estimates of cardiovascular disease (CVD) deaths from lead exposure have been limited to effects of increased blood pressure, but studies show that lead exposure has cardiovascular impacts through mechanisms other than hypertension.
• Drawing from various sources and studies, researchers estimated global blood lead levels and the impact of lead exposure on CVD mortality in 2019 among adults aged 25 years or older, IQ loss in children younger than 5 years, and the related economic costs.

TAKEAWAY:

• Researchers estimated that there were 5,545,000 (95% confidence interval, 2,305,000-8,271,000) cardiovascular deaths in adults from lead exposure in 2019, with as many as 90.2% of these deaths in LMICs; however, this estimate may be incomplete because it does not include the effect of lead exposure on CVD mortality mediated through hypertension.
• The estimated global IQ loss in children younger than 5 years due to lead exposure was 765 million (95% CI, 443 million-1,098 million) IQ points in 2019, 95.3% of which occurred in LMICs.
• These estimates place lead exposure on a par with ambient particulate matter and household air pollution combined, and ahead of unsafe household drinking water, sanitation, and handwashing, as an environmental risk factor.
• The estimated global cost of lead exposure from CVD mortality and IQ loss combined is U.S. $6.0 trillion (range, $2.6 trillion-9.0 trillion) in 2019, equivalent to 6.9% of the 2019 global gross domestic product.

IN PRACTICE:

Given the magnitude of the estimated health effects of lead exposure, particularly in LMICs, “it is imperative that nationally representative periodic blood lead level measurements be institutionalized,” write the authors, adding that these measurements could be incorporated into existing household surveys.

STUDY DETAILS:

The study was conducted by Bjorn Larsen, PhD, environmental economist and consultant to the World Bank, and Ernesto Sánchez-Triana. It was published online in The Lancet Planetary Health.

LIMITATIONS:

• Global blood lead level estimates may be inaccurate, given that measurements are absent for many countries.
• Certain income projections and income losses are uncertain.
• Because the study does not capture the detrimental effects of lead exposure other than IQ loss and CVD mortality, the estimates of global costs are conservative.

DISCLOSURES:

The study received support from the Korea Green Growth Trust Fund and the World Bank’s Pollution Management and Environmental Health Program. The authors have no relevant conflicts of interest.

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

TOPLINE:

Globally, lead exposure is linked to more than 5.5 million adult cardiovascular deaths in 2019, as well as loss of 765 million intelligence quotient (IQ) points in children younger than 5 years, which cost U.S. $6 trillion in lost productivity, new research suggests.

METHODOLOGY:

• Global lead exposure has declined substantially since leaded gasoline was phased out, but several sources of lead remain, resulting in adverse health and economic effects, particularly in low- and middle-income countries (LMICs).
• Estimates of cardiovascular disease (CVD) deaths from lead exposure have been limited to effects of increased blood pressure, but studies show that lead exposure has cardiovascular impacts through mechanisms other than hypertension.
• Drawing from various sources and studies, researchers estimated global blood lead levels and the impact of lead exposure on CVD mortality in 2019 among adults aged 25 years or older, IQ loss in children younger than 5 years, and the related economic costs.

TAKEAWAY:

• Researchers estimated that there were 5,545,000 (95% confidence interval, 2,305,000-8,271,000) cardiovascular deaths in adults from lead exposure in 2019, with as many as 90.2% of these deaths in LMICs; however, this estimate may be incomplete because it does not include the effect of lead exposure on CVD mortality mediated through hypertension.
• The estimated global IQ loss in children younger than 5 years due to lead exposure was 765 million (95% CI, 443 million-1,098 million) IQ points in 2019, 95.3% of which occurred in LMICs.
• These estimates place lead exposure on a par with ambient particulate matter and household air pollution combined, and ahead of unsafe household drinking water, sanitation, and handwashing, as an environmental risk factor.
• The estimated global cost of lead exposure from CVD mortality and IQ loss combined is U.S. $6.0 trillion (range, $2.6 trillion-9.0 trillion) in 2019, equivalent to 6.9% of the 2019 global gross domestic product.

IN PRACTICE:

Given the magnitude of the estimated health effects of lead exposure, particularly in LMICs, “it is imperative that nationally representative periodic blood lead level measurements be institutionalized,” write the authors, adding that these measurements could be incorporated into existing household surveys.

STUDY DETAILS:

The study was conducted by Bjorn Larsen, PhD, environmental economist and consultant to the World Bank, and Ernesto Sánchez-Triana. It was published online in The Lancet Planetary Health.

LIMITATIONS:

• Global blood lead level estimates may be inaccurate, given that measurements are absent for many countries.
• Certain income projections and income losses are uncertain.
• Because the study does not capture the detrimental effects of lead exposure other than IQ loss and CVD mortality, the estimates of global costs are conservative.

DISCLOSURES:

The study received support from the Korea Green Growth Trust Fund and the World Bank’s Pollution Management and Environmental Health Program. The authors have no relevant conflicts of interest.

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

TOPLINE:

Globally, lead exposure is linked to more than 5.5 million adult cardiovascular deaths in 2019, as well as loss of 765 million intelligence quotient (IQ) points in children younger than 5 years, which cost U.S. $6 trillion in lost productivity, new research suggests.

METHODOLOGY:

• Global lead exposure has declined substantially since leaded gasoline was phased out, but several sources of lead remain, resulting in adverse health and economic effects, particularly in low- and middle-income countries (LMICs).
• Estimates of cardiovascular disease (CVD) deaths from lead exposure have been limited to effects of increased blood pressure, but studies show that lead exposure has cardiovascular impacts through mechanisms other than hypertension.
• Drawing from various sources and studies, researchers estimated global blood lead levels and the impact of lead exposure on CVD mortality in 2019 among adults aged 25 years or older, IQ loss in children younger than 5 years, and the related economic costs.

TAKEAWAY:

• Researchers estimated that there were 5,545,000 (95% confidence interval, 2,305,000-8,271,000) cardiovascular deaths in adults from lead exposure in 2019, with as many as 90.2% of these deaths in LMICs; however, this estimate may be incomplete because it does not include the effect of lead exposure on CVD mortality mediated through hypertension.
• The estimated global IQ loss in children younger than 5 years due to lead exposure was 765 million (95% CI, 443 million-1,098 million) IQ points in 2019, 95.3% of which occurred in LMICs.
• These estimates place lead exposure on a par with ambient particulate matter and household air pollution combined, and ahead of unsafe household drinking water, sanitation, and handwashing, as an environmental risk factor.
• The estimated global cost of lead exposure from CVD mortality and IQ loss combined is U.S. $6.0 trillion (range, $2.6 trillion-9.0 trillion) in 2019, equivalent to 6.9% of the 2019 global gross domestic product.

IN PRACTICE:

Given the magnitude of the estimated health effects of lead exposure, particularly in LMICs, “it is imperative that nationally representative periodic blood lead level measurements be institutionalized,” write the authors, adding that these measurements could be incorporated into existing household surveys.

STUDY DETAILS:

The study was conducted by Bjorn Larsen, PhD, environmental economist and consultant to the World Bank, and Ernesto Sánchez-Triana. It was published online in The Lancet Planetary Health.

LIMITATIONS:

• Global blood lead level estimates may be inaccurate, given that measurements are absent for many countries.
• Certain income projections and income losses are uncertain.
• Because the study does not capture the detrimental effects of lead exposure other than IQ loss and CVD mortality, the estimates of global costs are conservative.

DISCLOSURES:

The study received support from the Korea Green Growth Trust Fund and the World Bank’s Pollution Management and Environmental Health Program. The authors have no relevant conflicts of interest.

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

A physician in your office is hot-tempered, critical, and upsets both the physicians and staff. Two of your partners are arguing over a software vendor and refuse to compromise. One doctor’s spouse is the office manager and snipes at everyone; the lead partner micromanages and second-guesses other doctors’ treatment plans, and no one will stand up to her.

If your practice has similar scenarios, you’re likely dealing with your own anger, irritation, and dread at work. You’re struggling with a toxic practice atmosphere, and you must make changes – fast.

However, this isn’t easy, given that what goes on in a doctor’s office is “high consequence,” says Leonard J. Marcus, PhD, founding director of the program for health care negotiation and conflict resolution at the Harvard School of Public Health in Boston.

The two things that tend to plague medical practices most: A culture of fear and someone who is letting ego run the day-to-day, he says.

“Fear overwhelms any chance for good morale among colleagues,” says Dr. Marcus, who is also the coauthor of “Renegotiating Health Care: Resolving Conflict to Build Collaboration.” “In a work environment where the fear is overwhelming, the ego can take over, and someone at the practice becomes overly concerned about getting credit, taking control, ordering other people around, and deciding who is on top and who is on the bottom.”

Tension, stress, back-biting, and rudeness are also symptoms of a more significant problem, says Jes Montgomery, MD, a psychiatrist and medical director of APN Dallas, a mental health–focused practice.

“If you don’t get toxicity under control, it will blow the office apart,” Dr. Montgomery says.

Here are five tips to turn around a toxic practice culture.
 

1. Recognize the signs

Part of the problem with a toxic medical practice is that, culturally, we don’t treat mental health and burnout as real illnesses. “A physician who is depressed is not going to be melancholy or bursting into tears with patients,” Dr. Montgomery says. “They’ll get behind on paperwork, skip meals, or find that it’s difficult to sleep at night. Next, they’ll yell at the partners and staff, always be in a foul mood, and gripe about inconsequential things. Their behavior affects everyone.”

Dr. Montgomery says that physicians aren’t taught to ask for help, making it difficult to see what’s really going on when someone displays toxic behavior in the practice. If it’s a partner, take time to ask what’s going on. If it’s yourself, step back and see if you can ask someone for the help you need.
 

2. Have difficult conversations

This is tough for most of us, says Jeremy Pollack, PhD, CEO and founder of Pollack Peacebuilding Systems, a conflict resolution consulting firm. If a team member is hot-tempered, disrespectful, or talking to patients in an unproductive manner, see if you can have an effective conversation with that person. The tricky part is critiquing in a way that doesn’t make them feel defensive – and wanting to push back.

For a micromanaging office manager, for example, you could say something like,”You’re doing a great job with the inventory, but I need you to let the staff have some autonomy and not hover over every supply they use in the break room, so that people won’t feel resentful toward us.” Make it clear you’re a team, and this is a team challenge. “However, if a doctor feels like they’ve tried to communicate to that colleague and are still walking on eggshells, it’s time to try to get help from someone – perhaps a practice management organization,” says Dr. Pollack.
 

3. Open lines of communication

It’s critical to create a comfortable space to speak with your colleagues, says Marisa Garshick, MD, a dermatologist in private practice in New York. “Creating an environment where there is an open line of communication, whether it’s directly to somebody in charge or having a system where you can give feedback more privately or anonymously, is important so that tension doesn’t build.”

“Being a doctor is a social enterprise,” Dr. Marcus says. “The science of medicine is critically important, but patients and the other health care workers on your team are also critically important. In the long run, the most successful physicians pay attention to both. It’s a full package.”
 

4. Emphasize the positive

Instead of discussing things only when they go wrong, try optimism, Dr. Garshick said. When positive things happen, whether it’s an excellent patient encounter or the office did something really well together, highlight it so everyone has a sense of accomplishment. If a patient compliments a medical assistant or raves about a nurse, share those compliments with the employees so that not every encounter you have calls out problems and staff missteps.

Suppose partners have a conflict with one another or are arguing over something. In that case, you may need to mediate or invest in a meaningful intervention so people can reflect on the narrative they’re contributing to the culture.
 

5. Practice self-care

Finally, the work of a physician is exhausting, so it’s crucial to practice personal TLC. That may mean taking micro breaks, getting adequate sleep, maintaining a healthy diet, and exercising well and managing stress to maintain energy levels and patience.

“Sometimes, when I’m fed up with the office, I need to get away,” Dr. Montgomery says. “I’ll take a day to go fishing, golfing, and not think about the office.” Just a small break can shift the lens that you see through when you return to the office and put problems in perspective.

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

A physician in your office is hot-tempered, critical, and upsets both the physicians and staff. Two of your partners are arguing over a software vendor and refuse to compromise. One doctor’s spouse is the office manager and snipes at everyone; the lead partner micromanages and second-guesses other doctors’ treatment plans, and no one will stand up to her.

If your practice has similar scenarios, you’re likely dealing with your own anger, irritation, and dread at work. You’re struggling with a toxic practice atmosphere, and you must make changes – fast.

However, this isn’t easy, given that what goes on in a doctor’s office is “high consequence,” says Leonard J. Marcus, PhD, founding director of the program for health care negotiation and conflict resolution at the Harvard School of Public Health in Boston.

The two things that tend to plague medical practices most: A culture of fear and someone who is letting ego run the day-to-day, he says.

“Fear overwhelms any chance for good morale among colleagues,” says Dr. Marcus, who is also the coauthor of “Renegotiating Health Care: Resolving Conflict to Build Collaboration.” “In a work environment where the fear is overwhelming, the ego can take over, and someone at the practice becomes overly concerned about getting credit, taking control, ordering other people around, and deciding who is on top and who is on the bottom.”

Tension, stress, back-biting, and rudeness are also symptoms of a more significant problem, says Jes Montgomery, MD, a psychiatrist and medical director of APN Dallas, a mental health–focused practice.

“If you don’t get toxicity under control, it will blow the office apart,” Dr. Montgomery says.

Here are five tips to turn around a toxic practice culture.
 

1. Recognize the signs

Part of the problem with a toxic medical practice is that, culturally, we don’t treat mental health and burnout as real illnesses. “A physician who is depressed is not going to be melancholy or bursting into tears with patients,” Dr. Montgomery says. “They’ll get behind on paperwork, skip meals, or find that it’s difficult to sleep at night. Next, they’ll yell at the partners and staff, always be in a foul mood, and gripe about inconsequential things. Their behavior affects everyone.”

Dr. Montgomery says that physicians aren’t taught to ask for help, making it difficult to see what’s really going on when someone displays toxic behavior in the practice. If it’s a partner, take time to ask what’s going on. If it’s yourself, step back and see if you can ask someone for the help you need.
 

2. Have difficult conversations

This is tough for most of us, says Jeremy Pollack, PhD, CEO and founder of Pollack Peacebuilding Systems, a conflict resolution consulting firm. If a team member is hot-tempered, disrespectful, or talking to patients in an unproductive manner, see if you can have an effective conversation with that person. The tricky part is critiquing in a way that doesn’t make them feel defensive – and wanting to push back.

For a micromanaging office manager, for example, you could say something like,”You’re doing a great job with the inventory, but I need you to let the staff have some autonomy and not hover over every supply they use in the break room, so that people won’t feel resentful toward us.” Make it clear you’re a team, and this is a team challenge. “However, if a doctor feels like they’ve tried to communicate to that colleague and are still walking on eggshells, it’s time to try to get help from someone – perhaps a practice management organization,” says Dr. Pollack.
 

3. Open lines of communication

It’s critical to create a comfortable space to speak with your colleagues, says Marisa Garshick, MD, a dermatologist in private practice in New York. “Creating an environment where there is an open line of communication, whether it’s directly to somebody in charge or having a system where you can give feedback more privately or anonymously, is important so that tension doesn’t build.”

“Being a doctor is a social enterprise,” Dr. Marcus says. “The science of medicine is critically important, but patients and the other health care workers on your team are also critically important. In the long run, the most successful physicians pay attention to both. It’s a full package.”
 

4. Emphasize the positive

Instead of discussing things only when they go wrong, try optimism, Dr. Garshick said. When positive things happen, whether it’s an excellent patient encounter or the office did something really well together, highlight it so everyone has a sense of accomplishment. If a patient compliments a medical assistant or raves about a nurse, share those compliments with the employees so that not every encounter you have calls out problems and staff missteps.

Suppose partners have a conflict with one another or are arguing over something. In that case, you may need to mediate or invest in a meaningful intervention so people can reflect on the narrative they’re contributing to the culture.
 

5. Practice self-care

Finally, the work of a physician is exhausting, so it’s crucial to practice personal TLC. That may mean taking micro breaks, getting adequate sleep, maintaining a healthy diet, and exercising well and managing stress to maintain energy levels and patience.

“Sometimes, when I’m fed up with the office, I need to get away,” Dr. Montgomery says. “I’ll take a day to go fishing, golfing, and not think about the office.” Just a small break can shift the lens that you see through when you return to the office and put problems in perspective.

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

A physician in your office is hot-tempered, critical, and upsets both the physicians and staff. Two of your partners are arguing over a software vendor and refuse to compromise. One doctor’s spouse is the office manager and snipes at everyone; the lead partner micromanages and second-guesses other doctors’ treatment plans, and no one will stand up to her.

If your practice has similar scenarios, you’re likely dealing with your own anger, irritation, and dread at work. You’re struggling with a toxic practice atmosphere, and you must make changes – fast.

However, this isn’t easy, given that what goes on in a doctor’s office is “high consequence,” says Leonard J. Marcus, PhD, founding director of the program for health care negotiation and conflict resolution at the Harvard School of Public Health in Boston.

The two things that tend to plague medical practices most: A culture of fear and someone who is letting ego run the day-to-day, he says.

“Fear overwhelms any chance for good morale among colleagues,” says Dr. Marcus, who is also the coauthor of “Renegotiating Health Care: Resolving Conflict to Build Collaboration.” “In a work environment where the fear is overwhelming, the ego can take over, and someone at the practice becomes overly concerned about getting credit, taking control, ordering other people around, and deciding who is on top and who is on the bottom.”

Tension, stress, back-biting, and rudeness are also symptoms of a more significant problem, says Jes Montgomery, MD, a psychiatrist and medical director of APN Dallas, a mental health–focused practice.

“If you don’t get toxicity under control, it will blow the office apart,” Dr. Montgomery says.

Here are five tips to turn around a toxic practice culture.
 

1. Recognize the signs

Part of the problem with a toxic medical practice is that, culturally, we don’t treat mental health and burnout as real illnesses. “A physician who is depressed is not going to be melancholy or bursting into tears with patients,” Dr. Montgomery says. “They’ll get behind on paperwork, skip meals, or find that it’s difficult to sleep at night. Next, they’ll yell at the partners and staff, always be in a foul mood, and gripe about inconsequential things. Their behavior affects everyone.”

Dr. Montgomery says that physicians aren’t taught to ask for help, making it difficult to see what’s really going on when someone displays toxic behavior in the practice. If it’s a partner, take time to ask what’s going on. If it’s yourself, step back and see if you can ask someone for the help you need.
 

2. Have difficult conversations

This is tough for most of us, says Jeremy Pollack, PhD, CEO and founder of Pollack Peacebuilding Systems, a conflict resolution consulting firm. If a team member is hot-tempered, disrespectful, or talking to patients in an unproductive manner, see if you can have an effective conversation with that person. The tricky part is critiquing in a way that doesn’t make them feel defensive – and wanting to push back.

For a micromanaging office manager, for example, you could say something like,”You’re doing a great job with the inventory, but I need you to let the staff have some autonomy and not hover over every supply they use in the break room, so that people won’t feel resentful toward us.” Make it clear you’re a team, and this is a team challenge. “However, if a doctor feels like they’ve tried to communicate to that colleague and are still walking on eggshells, it’s time to try to get help from someone – perhaps a practice management organization,” says Dr. Pollack.
 

3. Open lines of communication

It’s critical to create a comfortable space to speak with your colleagues, says Marisa Garshick, MD, a dermatologist in private practice in New York. “Creating an environment where there is an open line of communication, whether it’s directly to somebody in charge or having a system where you can give feedback more privately or anonymously, is important so that tension doesn’t build.”

“Being a doctor is a social enterprise,” Dr. Marcus says. “The science of medicine is critically important, but patients and the other health care workers on your team are also critically important. In the long run, the most successful physicians pay attention to both. It’s a full package.”
 

4. Emphasize the positive

Instead of discussing things only when they go wrong, try optimism, Dr. Garshick said. When positive things happen, whether it’s an excellent patient encounter or the office did something really well together, highlight it so everyone has a sense of accomplishment. If a patient compliments a medical assistant or raves about a nurse, share those compliments with the employees so that not every encounter you have calls out problems and staff missteps.

Suppose partners have a conflict with one another or are arguing over something. In that case, you may need to mediate or invest in a meaningful intervention so people can reflect on the narrative they’re contributing to the culture.
 

5. Practice self-care

Finally, the work of a physician is exhausting, so it’s crucial to practice personal TLC. That may mean taking micro breaks, getting adequate sleep, maintaining a healthy diet, and exercising well and managing stress to maintain energy levels and patience.

“Sometimes, when I’m fed up with the office, I need to get away,” Dr. Montgomery says. “I’ll take a day to go fishing, golfing, and not think about the office.” Just a small break can shift the lens that you see through when you return to the office and put problems in perspective.

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

SINGAPORE – Can the prolonged use of skin-lightening products, such as hydroquinone, lead to skin cancer?

This question was posed by Ousmane Faye, MD, PhD, director general of Mali’s Bamako Dermatology Hospital, at the World Congress of Dermatology. 

Dr. Faye explored the issue during a hot topics session at the meeting, prefacing that it was an important question to ask because “in West Africa, skin bleaching is very common.”

“There are many local names” for skin bleaching, he said. “For example, in Senegal, it’s called xessal; in Mali and Ivory Coast, its name is caco; in South Africa, there are many names, like ukutsheyisa.”

Skin bleaching refers to the cosmetic misuse of topical agents to change one’s natural skin color. It’s a centuries-old practice that people, mainly women, adopt “to increase attractiveness and self-esteem,” explained Dr. Faye.

To demonstrate how pervasive skin bleaching is on the continent, he presented a slide that summarized figures from six studies spanning the past 2 decades. Prevalence ranged from 25% in Mali (based on a 1993 survey of 210 women) to a high of 79.25% in Benin (from a sample size of 511 women in 2019). In other studies of women in Burkina Faso and Togo, the figures were 44.3% and 58.9%, respectively. The most recently conducted study, which involved 2,689 Senegalese women and was published in 2022, found that nearly 6 in 10 (59.2%) respondents used skin-lightening products.

But skin bleaching isn’t just limited to Africa, said session moderator Omar Lupi, MD, PhD, associate professor of dermatology at the Federal University of the State of Rio de Janeiro, when approached for an independent comment. “It’s a traditional practice around the world. Maybe not in the developed countries, but it’s quite common in Africa, in South America, and in Asia.”

His sentiments are echoed in a meta-analysis that was published in the International Journal of Dermatology in 2019. The work examined 68 studies involving more than 67,000 people across Africa, Asia, Europe, the Middle East, and North America. It found that the pooled lifetime prevalence of skin bleaching was 27.7% (95% confidence interval, 19.6-37.5; P < .01).

“This is an important and interesting topic because our world is shrinking,” Dr. Lupi told this news organization. “Even in countries that don’t have bleaching as a common situation, we now have patients who are migrating from one part [of the world] to another, so bleaching is something that can knock on your door and you need to be prepared.”

Misuse leads to complications

The issue is pertinent to dermatologists because skin bleaching is associated with a wide range of complications. Take, for example, topical steroids, which are the most common products used for bleaching, said Dr. Faye in his talk. 

“Clobetasol can suppress the hypothalamic-pituitary-adrenal (HPA) function,” he said, referring to the body’s main stress response system. “It can also foster skin infection, including bacterial, fungal, viral, and parasitic infection.”

In addition, topical steroids that are misused as skin lighteners have been reported to cause stretch marks, skin atrophy, inflammatory acne, and even metabolic disorders such as diabetes and hypertension, said Dr. Faye.

To further his point, he cited a 2021 prospective case-control study conducted across five sub-Saharan countries, which found that the use of “voluntary cosmetic depigmentation” significantly increased a person’s risk for necrotizing fasciitis of the lower limbs (odds ratio, 2.29; 95% CI, 1.19-3.73; P = .0226).

Similarly, mercury, another substance found in products commonly used to bleach skin, has been associated with problems ranging from rashes to renal toxicity. And because it’s so incredibly harmful, mercury is also known to cause neurologic abnormalities. 

Apart from causing certain conditions, prolonged use of skin-lightening products can change the way existing diseases present themselves as well as their severity, added Dr. Faye. 
 

An increased risk

But what about skin bleaching’s link with cancer? “Skin cancer on Black skin is uncommon, yet it occurs in skin-bleaching women,” said Dr. Faye.

“Since 2000, we have had some cases of skin cancer associated with skin bleaching,” he continued, adding that squamous cell carcinoma (SCC) is the most frequent type of cancer observed. 

If you look at what’s been published on the topic so far, you’ll see that “all the cases of skin cancer are located over the neck or some exposed area when skin bleaching products are used for more than 10 years,” said Dr. Faye. “And most of the time, the age of the patient ranges from 30 to 60 years.”

The first known case in Africa was reported in a 58-year-old woman from Ghana, who had been using skin bleaching products for close to 30 years. The patient presented with tumors on her face, neck, and arms.

Dr. Faye then proceeded to share more than 10 such carcinoma cases. “These previous reports strongly suggest a relationship between skin bleaching and skin cancers,” said Dr. Faye.

Indeed, there have been reports and publications in the literature that support his observation, including one last year, which found that use of the tyrosinase inhibitor hydroquinone was associated with approximately a threefold increased risk for skin cancer.

For some, including Brazil’s Dr. Lupi, Dr. Faye’s talk was enlightening: “I didn’t know about this relationship [of bleaching] with skin cancer, it was something new for me.”

But the prevalence of SCC is very low, compared with that of skin bleaching, Dr. Faye acknowledged. Moreover, the cancer observed in the cases reported could have resulted from a number of reasons, including exposure to harmful ultraviolet rays from the sun and genetic predisposition in addition to the use of bleaching products such as hydroquinone. “Other causes of skin cancer are not excluded,” he said.

To further explore the link between skin bleaching and cancer, “we need case-control studies to provide more evidence,” he added. Until then, dermatologists “should keep on promoting messages” to prevent SCC from occurring. This includes encouraging the use of proper sun protection in addition to discouraging the practice of skin bleaching, which still persists despite more than 10 African nations banning the use of toxic skin-lightening products.

Dr. Faye and Dr. Lupi report no relevant financial relationships.

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

SINGAPORE – Can the prolonged use of skin-lightening products, such as hydroquinone, lead to skin cancer?

This question was posed by Ousmane Faye, MD, PhD, director general of Mali’s Bamako Dermatology Hospital, at the World Congress of Dermatology. 

Dr. Faye explored the issue during a hot topics session at the meeting, prefacing that it was an important question to ask because “in West Africa, skin bleaching is very common.”

“There are many local names” for skin bleaching, he said. “For example, in Senegal, it’s called xessal; in Mali and Ivory Coast, its name is caco; in South Africa, there are many names, like ukutsheyisa.”

Skin bleaching refers to the cosmetic misuse of topical agents to change one’s natural skin color. It’s a centuries-old practice that people, mainly women, adopt “to increase attractiveness and self-esteem,” explained Dr. Faye.

To demonstrate how pervasive skin bleaching is on the continent, he presented a slide that summarized figures from six studies spanning the past 2 decades. Prevalence ranged from 25% in Mali (based on a 1993 survey of 210 women) to a high of 79.25% in Benin (from a sample size of 511 women in 2019). In other studies of women in Burkina Faso and Togo, the figures were 44.3% and 58.9%, respectively. The most recently conducted study, which involved 2,689 Senegalese women and was published in 2022, found that nearly 6 in 10 (59.2%) respondents used skin-lightening products.

But skin bleaching isn’t just limited to Africa, said session moderator Omar Lupi, MD, PhD, associate professor of dermatology at the Federal University of the State of Rio de Janeiro, when approached for an independent comment. “It’s a traditional practice around the world. Maybe not in the developed countries, but it’s quite common in Africa, in South America, and in Asia.”

His sentiments are echoed in a meta-analysis that was published in the International Journal of Dermatology in 2019. The work examined 68 studies involving more than 67,000 people across Africa, Asia, Europe, the Middle East, and North America. It found that the pooled lifetime prevalence of skin bleaching was 27.7% (95% confidence interval, 19.6-37.5; P < .01).

“This is an important and interesting topic because our world is shrinking,” Dr. Lupi told this news organization. “Even in countries that don’t have bleaching as a common situation, we now have patients who are migrating from one part [of the world] to another, so bleaching is something that can knock on your door and you need to be prepared.”

Misuse leads to complications

The issue is pertinent to dermatologists because skin bleaching is associated with a wide range of complications. Take, for example, topical steroids, which are the most common products used for bleaching, said Dr. Faye in his talk. 

“Clobetasol can suppress the hypothalamic-pituitary-adrenal (HPA) function,” he said, referring to the body’s main stress response system. “It can also foster skin infection, including bacterial, fungal, viral, and parasitic infection.”

In addition, topical steroids that are misused as skin lighteners have been reported to cause stretch marks, skin atrophy, inflammatory acne, and even metabolic disorders such as diabetes and hypertension, said Dr. Faye.

To further his point, he cited a 2021 prospective case-control study conducted across five sub-Saharan countries, which found that the use of “voluntary cosmetic depigmentation” significantly increased a person’s risk for necrotizing fasciitis of the lower limbs (odds ratio, 2.29; 95% CI, 1.19-3.73; P = .0226).

Similarly, mercury, another substance found in products commonly used to bleach skin, has been associated with problems ranging from rashes to renal toxicity. And because it’s so incredibly harmful, mercury is also known to cause neurologic abnormalities. 

Apart from causing certain conditions, prolonged use of skin-lightening products can change the way existing diseases present themselves as well as their severity, added Dr. Faye. 
 

An increased risk

But what about skin bleaching’s link with cancer? “Skin cancer on Black skin is uncommon, yet it occurs in skin-bleaching women,” said Dr. Faye.

“Since 2000, we have had some cases of skin cancer associated with skin bleaching,” he continued, adding that squamous cell carcinoma (SCC) is the most frequent type of cancer observed. 

If you look at what’s been published on the topic so far, you’ll see that “all the cases of skin cancer are located over the neck or some exposed area when skin bleaching products are used for more than 10 years,” said Dr. Faye. “And most of the time, the age of the patient ranges from 30 to 60 years.”

The first known case in Africa was reported in a 58-year-old woman from Ghana, who had been using skin bleaching products for close to 30 years. The patient presented with tumors on her face, neck, and arms.

Dr. Faye then proceeded to share more than 10 such carcinoma cases. “These previous reports strongly suggest a relationship between skin bleaching and skin cancers,” said Dr. Faye.

Indeed, there have been reports and publications in the literature that support his observation, including one last year, which found that use of the tyrosinase inhibitor hydroquinone was associated with approximately a threefold increased risk for skin cancer.

For some, including Brazil’s Dr. Lupi, Dr. Faye’s talk was enlightening: “I didn’t know about this relationship [of bleaching] with skin cancer, it was something new for me.”

But the prevalence of SCC is very low, compared with that of skin bleaching, Dr. Faye acknowledged. Moreover, the cancer observed in the cases reported could have resulted from a number of reasons, including exposure to harmful ultraviolet rays from the sun and genetic predisposition in addition to the use of bleaching products such as hydroquinone. “Other causes of skin cancer are not excluded,” he said.

To further explore the link between skin bleaching and cancer, “we need case-control studies to provide more evidence,” he added. Until then, dermatologists “should keep on promoting messages” to prevent SCC from occurring. This includes encouraging the use of proper sun protection in addition to discouraging the practice of skin bleaching, which still persists despite more than 10 African nations banning the use of toxic skin-lightening products.

Dr. Faye and Dr. Lupi report no relevant financial relationships.

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

SINGAPORE – Can the prolonged use of skin-lightening products, such as hydroquinone, lead to skin cancer?

This question was posed by Ousmane Faye, MD, PhD, director general of Mali’s Bamako Dermatology Hospital, at the World Congress of Dermatology. 

Dr. Faye explored the issue during a hot topics session at the meeting, prefacing that it was an important question to ask because “in West Africa, skin bleaching is very common.”

“There are many local names” for skin bleaching, he said. “For example, in Senegal, it’s called xessal; in Mali and Ivory Coast, its name is caco; in South Africa, there are many names, like ukutsheyisa.”

Skin bleaching refers to the cosmetic misuse of topical agents to change one’s natural skin color. It’s a centuries-old practice that people, mainly women, adopt “to increase attractiveness and self-esteem,” explained Dr. Faye.

To demonstrate how pervasive skin bleaching is on the continent, he presented a slide that summarized figures from six studies spanning the past 2 decades. Prevalence ranged from 25% in Mali (based on a 1993 survey of 210 women) to a high of 79.25% in Benin (from a sample size of 511 women in 2019). In other studies of women in Burkina Faso and Togo, the figures were 44.3% and 58.9%, respectively. The most recently conducted study, which involved 2,689 Senegalese women and was published in 2022, found that nearly 6 in 10 (59.2%) respondents used skin-lightening products.

But skin bleaching isn’t just limited to Africa, said session moderator Omar Lupi, MD, PhD, associate professor of dermatology at the Federal University of the State of Rio de Janeiro, when approached for an independent comment. “It’s a traditional practice around the world. Maybe not in the developed countries, but it’s quite common in Africa, in South America, and in Asia.”

His sentiments are echoed in a meta-analysis that was published in the International Journal of Dermatology in 2019. The work examined 68 studies involving more than 67,000 people across Africa, Asia, Europe, the Middle East, and North America. It found that the pooled lifetime prevalence of skin bleaching was 27.7% (95% confidence interval, 19.6-37.5; P < .01).

“This is an important and interesting topic because our world is shrinking,” Dr. Lupi told this news organization. “Even in countries that don’t have bleaching as a common situation, we now have patients who are migrating from one part [of the world] to another, so bleaching is something that can knock on your door and you need to be prepared.”

Misuse leads to complications

The issue is pertinent to dermatologists because skin bleaching is associated with a wide range of complications. Take, for example, topical steroids, which are the most common products used for bleaching, said Dr. Faye in his talk. 

“Clobetasol can suppress the hypothalamic-pituitary-adrenal (HPA) function,” he said, referring to the body’s main stress response system. “It can also foster skin infection, including bacterial, fungal, viral, and parasitic infection.”

In addition, topical steroids that are misused as skin lighteners have been reported to cause stretch marks, skin atrophy, inflammatory acne, and even metabolic disorders such as diabetes and hypertension, said Dr. Faye.

To further his point, he cited a 2021 prospective case-control study conducted across five sub-Saharan countries, which found that the use of “voluntary cosmetic depigmentation” significantly increased a person’s risk for necrotizing fasciitis of the lower limbs (odds ratio, 2.29; 95% CI, 1.19-3.73; P = .0226).

Similarly, mercury, another substance found in products commonly used to bleach skin, has been associated with problems ranging from rashes to renal toxicity. And because it’s so incredibly harmful, mercury is also known to cause neurologic abnormalities. 

Apart from causing certain conditions, prolonged use of skin-lightening products can change the way existing diseases present themselves as well as their severity, added Dr. Faye. 
 

An increased risk

But what about skin bleaching’s link with cancer? “Skin cancer on Black skin is uncommon, yet it occurs in skin-bleaching women,” said Dr. Faye.

“Since 2000, we have had some cases of skin cancer associated with skin bleaching,” he continued, adding that squamous cell carcinoma (SCC) is the most frequent type of cancer observed. 

If you look at what’s been published on the topic so far, you’ll see that “all the cases of skin cancer are located over the neck or some exposed area when skin bleaching products are used for more than 10 years,” said Dr. Faye. “And most of the time, the age of the patient ranges from 30 to 60 years.”

The first known case in Africa was reported in a 58-year-old woman from Ghana, who had been using skin bleaching products for close to 30 years. The patient presented with tumors on her face, neck, and arms.

Dr. Faye then proceeded to share more than 10 such carcinoma cases. “These previous reports strongly suggest a relationship between skin bleaching and skin cancers,” said Dr. Faye.

Indeed, there have been reports and publications in the literature that support his observation, including one last year, which found that use of the tyrosinase inhibitor hydroquinone was associated with approximately a threefold increased risk for skin cancer.

For some, including Brazil’s Dr. Lupi, Dr. Faye’s talk was enlightening: “I didn’t know about this relationship [of bleaching] with skin cancer, it was something new for me.”

But the prevalence of SCC is very low, compared with that of skin bleaching, Dr. Faye acknowledged. Moreover, the cancer observed in the cases reported could have resulted from a number of reasons, including exposure to harmful ultraviolet rays from the sun and genetic predisposition in addition to the use of bleaching products such as hydroquinone. “Other causes of skin cancer are not excluded,” he said.

To further explore the link between skin bleaching and cancer, “we need case-control studies to provide more evidence,” he added. Until then, dermatologists “should keep on promoting messages” to prevent SCC from occurring. This includes encouraging the use of proper sun protection in addition to discouraging the practice of skin bleaching, which still persists despite more than 10 African nations banning the use of toxic skin-lightening products.

Dr. Faye and Dr. Lupi report no relevant financial relationships.

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

In the wake of the COVID-19 pandemic, the American Academy of Child and Adolescent Psychiatry, American Academy of Pediatrics, and Children’s Hospital Association declared a national emergency in child and adolescent mental health. Additionally, the U.S. Surgeon General issued an advisory highlighting increased prevalence of mental health challenges in youth, impacts of the COVID-19 pandemic, and recommendations to address this crisis.

The pandemic required youth to isolate from peers and community supports, navigate remote learning environments, and cope with grief and loss; some 140,000 children in the United States experienced the death of a caregiver due to COVID-19.¹ Virtually every system that supports children was affected. Whereas schools have historically been a main provider of child and adolescent mental health services, delivery of many school-based mental health programs was disrupted by school closures and staffing challenges. Subgroups of children (for example, those with intellectual and developmental disabilities) were particularly affected by these disruptions to daily life, and their use of emergency services increased.² Surges in psychiatric emergency department visits among children led to increased boarding, reflecting unleveraged opportunities for early intervention. Families faced changes in child care, economic uncertainty, educational responsibilities, and increased rates of domestic violence.³ Communities of color were disproportionately affected in every way, from disease mortality to learning loss and increased school dropout rates.

Meaningful improvement in children’s mental health will require remodeling broken systems to ensure that children are supported early, effectively, and equitably. To address gaps in the system, we must leverage school-based mental health programs, bolster access to and support of primary care providers, and embrace new, innovative models.
 

School-based mental health programs

Schools may be an ideal setting for universal mental health screening and opportunities for training, leadership, and whole school interventions. There is promising evidence that school-based interventions can decrease the incidence of suicide attempts and increase help-seeking behavior in students.⁴ There has long been interest in mental health screening in schools, though it has not been widely implemented given the significant resources required to both facilitate screening and effectively serve students who need additional support. Mobile apps may be one solution to scalability of both screening and interventions, but these initiatives should only be implemented within a stakeholder-engaged, family-centered multi-tiered model of behavioral support.

Other school-based initiatives include providing advice and training to teachers and school counselors and increasing access to specialized mental health professionals, including school psychologists, social workers, nurses, and behavior support workers, as well as community-based mental health providers. The 2021 American Rescue Plan Act included $170 billion for school funding, which many schools used to hire mental health workers. The Student Mental Health Helpline Act, if passed, will create helplines to support teachers as they help students address mental health issues.⁵ Educators can be trained to identify mental health needs, addressing mild symptoms themselves and referring students requiring more specialized services. Specific training programs for educators include Classroom Well-Being Information and Strategies for Educators (WISE), Youth Mental Health First Aid, and other resources funded by the U.S. Department of Health and Human Services. In addition to educators, other non–mental health professions interfacing with youth, including other youth, parents, clergy, coaches, and other community members, can be empowered with additional behavioral health knowledge and skills.
 

Increasing capacity in primary care

A number of programs are designed to improve knowledge and skills in children’s mental health among primary care providers, such as pediatricians. In Project ECHO, a “hub” of specialists, typically at an academic medical center, provides didactic lectures and case presentations for primary care “spokes” using teleconferencing.⁶ The REACH Institute uses interactive group learning followed by ongoing coaching and case-based training.

Collaborative care models known as Child Psychiatry Access Programs (CPAPs) engage child and adolescent psychiatrists to support primary care management of psychiatric disorders. Consultations may be direct or indirect, and involve technology or in-person care. Available in most states, these models increase access to mental health care, expand the capacity of the existing workforce, and decrease stigma and inconvenience for patients. Collaborative care models have been shown to lead to improved patient and family satisfaction, reduced utilization of emergency room and inpatient hospitalizations, and improved clinical outcomes. Off-site integrated care models may additionally serve larger and more geographically dispersed populations, minimize changes to existing infrastructure, reduce travel costs for clinicians, and decrease isolation of specialists. These programs are feasible, desirable, and sustainable. There is currently no cost to patients for their primary care providers’ participation in these models, as they are supported by the state, local, or insurance payer sources in addition to federal funding. Financially sustainable models are essential to ensure equitable access to these services in the future.
 

New service models

For adolescents and young adults, integrated youth service hubs such as those that have emerged in Australia, the United Kingdom, Canada, and more recently in the United States may be particularly appealing. These hubs emphasize rapid access to care and early intervention, youth and family engagement, youth-friendly settings and services, evidence-informed approaches, and partnerships and collaboration.⁷ In addition to mental health, these “one-stop shops” offer physical health, vocational supports, and case management to support basic needs. They address a particular system gap by providing services for transition-age youth rather than cutting off at age 18, as many children’s mental health services do.

Emerging solutions to the high utilization of emergency departments for pediatric mental health needs include utilization of pediatric Crisis Stabilization Units (CSUs). CSUs are community-based, short-term outpatient units that provide immediate care to children and families experiencing a mental health crisis. The goal of CSUs is to quickly stabilize the individual – often within 72 hours – and refer that individual to available community resources. This model may also reduce police involvement in mental health crises, which may be particularly important for racialized populations.
 

Conclusion

The thoughtful implementation and stable funding of evidence-based models can help schools, the health care system, and communities more effectively support children’s mental health in the post–COVID-19 pandemic era. Only with sufficient investments in the mental health system and other systems designed to support children and families, as well as careful consideration of unintended consequences on equity-deserving populations, will we see an end to this crisis.

Dr. Richards is assistant clinical professor in the department of psychiatry and biobehavioral sciences; program director of the child and adolescent psychiatry fellowship; and associate medical director of the perinatal program at the University of California, Los Angeles, Semel Institute for Neuroscience and Human Behavior.

References

1. Hillis SD et al. COVID-19–Associated orphanhood and caregiver death in the United States. Pediatrics. 2021;148:e2021053760.

2. Edgcomb JB et al. Mental health‐related emergency department visits among children during the early COVID‐19 pandemic. Psychiatr Res Clin Pract. 2022;4:4-11.

3. Pereda N, Díaz-Faes DA. Family violence against children in the wake of COVID-19 pandemic: A review of current perspectives and risk factors. Child and Adolescent Psychiatry and Mental Health. 2020;4:40.

4. Gijzen MWM et al. Effectiveness of school-based preventive programs in suicidal thoughts and behaviors: A meta-analysis. Journal of Affective Disorders. 2022;298:408-420.

5. Newman M: H.R.5235 – 117th Congress (2021-2022): Student Mental Health Helpline Act of 2021 [Internet] 2021; [cited 2023 Jan 11] Available from: http://www.congress.gov.

6. Raney L et al. Digitally driven integrated primary care and behavioral health: How technology can expand access to effective treatment. Curr Psychiatry Rep. 2017;19:86.

7. Settipani CA et al. Key attributes of integrated community-based youth service hubs for mental health: A scoping review. Int J Ment Health Syst. 2019;13:52.

In the wake of the COVID-19 pandemic, the American Academy of Child and Adolescent Psychiatry, American Academy of Pediatrics, and Children’s Hospital Association declared a national emergency in child and adolescent mental health. Additionally, the U.S. Surgeon General issued an advisory highlighting increased prevalence of mental health challenges in youth, impacts of the COVID-19 pandemic, and recommendations to address this crisis.

The pandemic required youth to isolate from peers and community supports, navigate remote learning environments, and cope with grief and loss; some 140,000 children in the United States experienced the death of a caregiver due to COVID-19.¹ Virtually every system that supports children was affected. Whereas schools have historically been a main provider of child and adolescent mental health services, delivery of many school-based mental health programs was disrupted by school closures and staffing challenges. Subgroups of children (for example, those with intellectual and developmental disabilities) were particularly affected by these disruptions to daily life, and their use of emergency services increased.² Surges in psychiatric emergency department visits among children led to increased boarding, reflecting unleveraged opportunities for early intervention. Families faced changes in child care, economic uncertainty, educational responsibilities, and increased rates of domestic violence.³ Communities of color were disproportionately affected in every way, from disease mortality to learning loss and increased school dropout rates.

Meaningful improvement in children’s mental health will require remodeling broken systems to ensure that children are supported early, effectively, and equitably. To address gaps in the system, we must leverage school-based mental health programs, bolster access to and support of primary care providers, and embrace new, innovative models.
 

School-based mental health programs

Schools may be an ideal setting for universal mental health screening and opportunities for training, leadership, and whole school interventions. There is promising evidence that school-based interventions can decrease the incidence of suicide attempts and increase help-seeking behavior in students.⁴ There has long been interest in mental health screening in schools, though it has not been widely implemented given the significant resources required to both facilitate screening and effectively serve students who need additional support. Mobile apps may be one solution to scalability of both screening and interventions, but these initiatives should only be implemented within a stakeholder-engaged, family-centered multi-tiered model of behavioral support.

Other school-based initiatives include providing advice and training to teachers and school counselors and increasing access to specialized mental health professionals, including school psychologists, social workers, nurses, and behavior support workers, as well as community-based mental health providers. The 2021 American Rescue Plan Act included $170 billion for school funding, which many schools used to hire mental health workers. The Student Mental Health Helpline Act, if passed, will create helplines to support teachers as they help students address mental health issues.⁵ Educators can be trained to identify mental health needs, addressing mild symptoms themselves and referring students requiring more specialized services. Specific training programs for educators include Classroom Well-Being Information and Strategies for Educators (WISE), Youth Mental Health First Aid, and other resources funded by the U.S. Department of Health and Human Services. In addition to educators, other non–mental health professions interfacing with youth, including other youth, parents, clergy, coaches, and other community members, can be empowered with additional behavioral health knowledge and skills.
 

Increasing capacity in primary care

A number of programs are designed to improve knowledge and skills in children’s mental health among primary care providers, such as pediatricians. In Project ECHO, a “hub” of specialists, typically at an academic medical center, provides didactic lectures and case presentations for primary care “spokes” using teleconferencing.⁶ The REACH Institute uses interactive group learning followed by ongoing coaching and case-based training.

Collaborative care models known as Child Psychiatry Access Programs (CPAPs) engage child and adolescent psychiatrists to support primary care management of psychiatric disorders. Consultations may be direct or indirect, and involve technology or in-person care. Available in most states, these models increase access to mental health care, expand the capacity of the existing workforce, and decrease stigma and inconvenience for patients. Collaborative care models have been shown to lead to improved patient and family satisfaction, reduced utilization of emergency room and inpatient hospitalizations, and improved clinical outcomes. Off-site integrated care models may additionally serve larger and more geographically dispersed populations, minimize changes to existing infrastructure, reduce travel costs for clinicians, and decrease isolation of specialists. These programs are feasible, desirable, and sustainable. There is currently no cost to patients for their primary care providers’ participation in these models, as they are supported by the state, local, or insurance payer sources in addition to federal funding. Financially sustainable models are essential to ensure equitable access to these services in the future.
 

New service models

For adolescents and young adults, integrated youth service hubs such as those that have emerged in Australia, the United Kingdom, Canada, and more recently in the United States may be particularly appealing. These hubs emphasize rapid access to care and early intervention, youth and family engagement, youth-friendly settings and services, evidence-informed approaches, and partnerships and collaboration.⁷ In addition to mental health, these “one-stop shops” offer physical health, vocational supports, and case management to support basic needs. They address a particular system gap by providing services for transition-age youth rather than cutting off at age 18, as many children’s mental health services do.

Emerging solutions to the high utilization of emergency departments for pediatric mental health needs include utilization of pediatric Crisis Stabilization Units (CSUs). CSUs are community-based, short-term outpatient units that provide immediate care to children and families experiencing a mental health crisis. The goal of CSUs is to quickly stabilize the individual – often within 72 hours – and refer that individual to available community resources. This model may also reduce police involvement in mental health crises, which may be particularly important for racialized populations.
 

Conclusion

The thoughtful implementation and stable funding of evidence-based models can help schools, the health care system, and communities more effectively support children’s mental health in the post–COVID-19 pandemic era. Only with sufficient investments in the mental health system and other systems designed to support children and families, as well as careful consideration of unintended consequences on equity-deserving populations, will we see an end to this crisis.

Dr. Richards is assistant clinical professor in the department of psychiatry and biobehavioral sciences; program director of the child and adolescent psychiatry fellowship; and associate medical director of the perinatal program at the University of California, Los Angeles, Semel Institute for Neuroscience and Human Behavior.

References

1. Hillis SD et al. COVID-19–Associated orphanhood and caregiver death in the United States. Pediatrics. 2021;148:e2021053760.

2. Edgcomb JB et al. Mental health‐related emergency department visits among children during the early COVID‐19 pandemic. Psychiatr Res Clin Pract. 2022;4:4-11.

3. Pereda N, Díaz-Faes DA. Family violence against children in the wake of COVID-19 pandemic: A review of current perspectives and risk factors. Child and Adolescent Psychiatry and Mental Health. 2020;4:40.

4. Gijzen MWM et al. Effectiveness of school-based preventive programs in suicidal thoughts and behaviors: A meta-analysis. Journal of Affective Disorders. 2022;298:408-420.

5. Newman M: H.R.5235 – 117th Congress (2021-2022): Student Mental Health Helpline Act of 2021 [Internet] 2021; [cited 2023 Jan 11] Available from: http://www.congress.gov.

6. Raney L et al. Digitally driven integrated primary care and behavioral health: How technology can expand access to effective treatment. Curr Psychiatry Rep. 2017;19:86.

7. Settipani CA et al. Key attributes of integrated community-based youth service hubs for mental health: A scoping review. Int J Ment Health Syst. 2019;13:52.

In the wake of the COVID-19 pandemic, the American Academy of Child and Adolescent Psychiatry, American Academy of Pediatrics, and Children’s Hospital Association declared a national emergency in child and adolescent mental health. Additionally, the U.S. Surgeon General issued an advisory highlighting increased prevalence of mental health challenges in youth, impacts of the COVID-19 pandemic, and recommendations to address this crisis.

The pandemic required youth to isolate from peers and community supports, navigate remote learning environments, and cope with grief and loss; some 140,000 children in the United States experienced the death of a caregiver due to COVID-19.¹ Virtually every system that supports children was affected. Whereas schools have historically been a main provider of child and adolescent mental health services, delivery of many school-based mental health programs was disrupted by school closures and staffing challenges. Subgroups of children (for example, those with intellectual and developmental disabilities) were particularly affected by these disruptions to daily life, and their use of emergency services increased.² Surges in psychiatric emergency department visits among children led to increased boarding, reflecting unleveraged opportunities for early intervention. Families faced changes in child care, economic uncertainty, educational responsibilities, and increased rates of domestic violence.³ Communities of color were disproportionately affected in every way, from disease mortality to learning loss and increased school dropout rates.

Meaningful improvement in children’s mental health will require remodeling broken systems to ensure that children are supported early, effectively, and equitably. To address gaps in the system, we must leverage school-based mental health programs, bolster access to and support of primary care providers, and embrace new, innovative models.
 

School-based mental health programs

Schools may be an ideal setting for universal mental health screening and opportunities for training, leadership, and whole school interventions. There is promising evidence that school-based interventions can decrease the incidence of suicide attempts and increase help-seeking behavior in students.⁴ There has long been interest in mental health screening in schools, though it has not been widely implemented given the significant resources required to both facilitate screening and effectively serve students who need additional support. Mobile apps may be one solution to scalability of both screening and interventions, but these initiatives should only be implemented within a stakeholder-engaged, family-centered multi-tiered model of behavioral support.

Other school-based initiatives include providing advice and training to teachers and school counselors and increasing access to specialized mental health professionals, including school psychologists, social workers, nurses, and behavior support workers, as well as community-based mental health providers. The 2021 American Rescue Plan Act included $170 billion for school funding, which many schools used to hire mental health workers. The Student Mental Health Helpline Act, if passed, will create helplines to support teachers as they help students address mental health issues.⁵ Educators can be trained to identify mental health needs, addressing mild symptoms themselves and referring students requiring more specialized services. Specific training programs for educators include Classroom Well-Being Information and Strategies for Educators (WISE), Youth Mental Health First Aid, and other resources funded by the U.S. Department of Health and Human Services. In addition to educators, other non–mental health professions interfacing with youth, including other youth, parents, clergy, coaches, and other community members, can be empowered with additional behavioral health knowledge and skills.
 

Increasing capacity in primary care

A number of programs are designed to improve knowledge and skills in children’s mental health among primary care providers, such as pediatricians. In Project ECHO, a “hub” of specialists, typically at an academic medical center, provides didactic lectures and case presentations for primary care “spokes” using teleconferencing.⁶ The REACH Institute uses interactive group learning followed by ongoing coaching and case-based training.

Collaborative care models known as Child Psychiatry Access Programs (CPAPs) engage child and adolescent psychiatrists to support primary care management of psychiatric disorders. Consultations may be direct or indirect, and involve technology or in-person care. Available in most states, these models increase access to mental health care, expand the capacity of the existing workforce, and decrease stigma and inconvenience for patients. Collaborative care models have been shown to lead to improved patient and family satisfaction, reduced utilization of emergency room and inpatient hospitalizations, and improved clinical outcomes. Off-site integrated care models may additionally serve larger and more geographically dispersed populations, minimize changes to existing infrastructure, reduce travel costs for clinicians, and decrease isolation of specialists. These programs are feasible, desirable, and sustainable. There is currently no cost to patients for their primary care providers’ participation in these models, as they are supported by the state, local, or insurance payer sources in addition to federal funding. Financially sustainable models are essential to ensure equitable access to these services in the future.
 

New service models

For adolescents and young adults, integrated youth service hubs such as those that have emerged in Australia, the United Kingdom, Canada, and more recently in the United States may be particularly appealing. These hubs emphasize rapid access to care and early intervention, youth and family engagement, youth-friendly settings and services, evidence-informed approaches, and partnerships and collaboration.⁷ In addition to mental health, these “one-stop shops” offer physical health, vocational supports, and case management to support basic needs. They address a particular system gap by providing services for transition-age youth rather than cutting off at age 18, as many children’s mental health services do.

Emerging solutions to the high utilization of emergency departments for pediatric mental health needs include utilization of pediatric Crisis Stabilization Units (CSUs). CSUs are community-based, short-term outpatient units that provide immediate care to children and families experiencing a mental health crisis. The goal of CSUs is to quickly stabilize the individual – often within 72 hours – and refer that individual to available community resources. This model may also reduce police involvement in mental health crises, which may be particularly important for racialized populations.
 

Conclusion

The thoughtful implementation and stable funding of evidence-based models can help schools, the health care system, and communities more effectively support children’s mental health in the post–COVID-19 pandemic era. Only with sufficient investments in the mental health system and other systems designed to support children and families, as well as careful consideration of unintended consequences on equity-deserving populations, will we see an end to this crisis.

Dr. Richards is assistant clinical professor in the department of psychiatry and biobehavioral sciences; program director of the child and adolescent psychiatry fellowship; and associate medical director of the perinatal program at the University of California, Los Angeles, Semel Institute for Neuroscience and Human Behavior.

References

1. Hillis SD et al. COVID-19–Associated orphanhood and caregiver death in the United States. Pediatrics. 2021;148:e2021053760.

2. Edgcomb JB et al. Mental health‐related emergency department visits among children during the early COVID‐19 pandemic. Psychiatr Res Clin Pract. 2022;4:4-11.

3. Pereda N, Díaz-Faes DA. Family violence against children in the wake of COVID-19 pandemic: A review of current perspectives and risk factors. Child and Adolescent Psychiatry and Mental Health. 2020;4:40.

4. Gijzen MWM et al. Effectiveness of school-based preventive programs in suicidal thoughts and behaviors: A meta-analysis. Journal of Affective Disorders. 2022;298:408-420.

5. Newman M: H.R.5235 – 117th Congress (2021-2022): Student Mental Health Helpline Act of 2021 [Internet] 2021; [cited 2023 Jan 11] Available from: http://www.congress.gov.

6. Raney L et al. Digitally driven integrated primary care and behavioral health: How technology can expand access to effective treatment. Curr Psychiatry Rep. 2017;19:86.

7. Settipani CA et al. Key attributes of integrated community-based youth service hubs for mental health: A scoping review. Int J Ment Health Syst. 2019;13:52.

Pleural mesothelioma is generally treated by extended pleurectomy decortication, and there has been little improvement in systemic treatment of early-stage, resectable mesothelioma, which has led to the recommendations of maximum cytoreduction. U.S. and European guidelines, as well as an international consensus statement, support this approach, but it has never been tested in a randomized, controlled trial.

Now it has, and the result is surprising: Surgery led to reduced survival and more serious adverse events, compared with chemotherapy alone. The conclusion was uncomfortable for Eric Lim, MD, who presented the results of the MARS2 trial at the annual World Conference on Lung Cancer. “Ladies and gentlemen, as a surgeon standing here, you have no idea how much it pains me to conclude that extended pleurectomy decortication, an operation that we have been offering for over 70 years, has been associated with a higher risk of death, more serious complications, poorer quality of life, and higher costs, compared to mesothelioma patients who were randomized to chemotherapy alone,” said Dr. Lim of the Royal Brompton Hospital, London, during his presentation.

Although the line drew laughter and applause from the audience, Paula Ugalde Figueroa, MD, who served as a discussant, raised some concerns about the study. Disease presence in one hemithorax was assessed only by chest CT scan, which is notorious for underestimating the volume of disease during surgery. There was also no information on pleural effusion or how many patients received it prior to intervention. Existing guidelines suggest staging of mesothelioma should also use PET scans, and invasive mediastinal staging should be assessed with endobronchial ultrasound. “None of these were performed during the trial,” said Dr. Figueroa, who is an associate thoracic surgeon at Brigham and Women’s Hospital, Boston. “At this point, my question is, are the arms of this study well balanced in regard to tumor volume? We don’t know,” she added.

Dr. Figueroa noted that the 90-day mortality seemed higher than that seen in other studies. “So, does the surgeon’s experience and center volume affect the outcome of this study?” she asked. Dr. Figueroa personally made phone calls to the participating centers and found that 45% of the patients in the trial were treated at low-volume centers, defined by her as two to three patients per year. “Should we assume that their surgical outcomes are similar between those centers? In this trial, with approximately half of patients from low-volume centers, extended pleurectomy decortication for mesothelioma had no significant difference when compared to those patients that underwent chemotherapy alone. Would the outcome be different in exclusively high-volume centers?” she concluded.

The study randomized 335 patients to receive surgery and chemotherapy, or chemotherapy alone. They received two cycles of platinum-based chemotherapy and pemetrexed prior to surgery and up to four cycles after surgery. The average age was 69 years; 86.9% were male, and 85.7% of tumors were epithelioid only. Among those in the surgery group, 88.5% underwent extended pleurectomy/decortication, 8.3% underwent pleurectomy decortication, 1.9% underwent partial pleurectomy, 0.6% exploration with no pleurodesis, and 0.6% were classified as “other” surgery. Completeness of resection was R0 in 3.2% of surgeries, R1 in 80.9%, and R2 in 15.9%. In-hospital mortality occurred in 3.8% of patients, and postsurgical 90-day mortality was 8.9%.

Over the first 42 months of follow-up, the hazard ratio for overall survival was 1.28 in the no-surgery group (P = .03). “The survival was so good in this early-stage cohort that we had to extend the trial by 6 months to get the prerequisite number of deaths, underscoring the phenomenal importance of having a randomized comparative cohort for all future studies on surgery for mesothelioma,” said Dr. Lim.

After 42 months, there was no survival difference between the two groups (hazard ratio, 0.48; P = .15). Dr. Lim attributed the change at 42 months to the fact that only 15 patients remained in each arm at that stage. There was no significant difference between the two groups with respect to progression-free survival.

The survival benefit of the no-surgery group was sustained after additional analyses, including adjustment of the number of first-line chemotherapy cycles and immunotherapy received after completion of the trial protocol.

Adverse events were more common in the surgery group (incidence rate ratio, 3.6; P < .001), including any cardiac disorder (IRR, 2.73; 95% confidence interval, 1.11-6.67); any infection or infestation (IRR, 1.99; 95% CI, 1.33-2.99); any respiratory, thoracic, or mediastinal disorder (IRR, 2.40; 95% CI, 1.52-3.80); and any surgical or medical procedure (IRR, 2.23; 95% CI, 1.04-4.78). The EORTC quality of life score favored the nonsurgery group at 6 weeks, but there was no significant difference at other time points.

Dr. Lim and Dr. Figueroa have no relevant financial disclosures.

Pleural mesothelioma is generally treated by extended pleurectomy decortication, and there has been little improvement in systemic treatment of early-stage, resectable mesothelioma, which has led to the recommendations of maximum cytoreduction. U.S. and European guidelines, as well as an international consensus statement, support this approach, but it has never been tested in a randomized, controlled trial.

Now it has, and the result is surprising: Surgery led to reduced survival and more serious adverse events, compared with chemotherapy alone. The conclusion was uncomfortable for Eric Lim, MD, who presented the results of the MARS2 trial at the annual World Conference on Lung Cancer. “Ladies and gentlemen, as a surgeon standing here, you have no idea how much it pains me to conclude that extended pleurectomy decortication, an operation that we have been offering for over 70 years, has been associated with a higher risk of death, more serious complications, poorer quality of life, and higher costs, compared to mesothelioma patients who were randomized to chemotherapy alone,” said Dr. Lim of the Royal Brompton Hospital, London, during his presentation.

Although the line drew laughter and applause from the audience, Paula Ugalde Figueroa, MD, who served as a discussant, raised some concerns about the study. Disease presence in one hemithorax was assessed only by chest CT scan, which is notorious for underestimating the volume of disease during surgery. There was also no information on pleural effusion or how many patients received it prior to intervention. Existing guidelines suggest staging of mesothelioma should also use PET scans, and invasive mediastinal staging should be assessed with endobronchial ultrasound. “None of these were performed during the trial,” said Dr. Figueroa, who is an associate thoracic surgeon at Brigham and Women’s Hospital, Boston. “At this point, my question is, are the arms of this study well balanced in regard to tumor volume? We don’t know,” she added.

Dr. Figueroa noted that the 90-day mortality seemed higher than that seen in other studies. “So, does the surgeon’s experience and center volume affect the outcome of this study?” she asked. Dr. Figueroa personally made phone calls to the participating centers and found that 45% of the patients in the trial were treated at low-volume centers, defined by her as two to three patients per year. “Should we assume that their surgical outcomes are similar between those centers? In this trial, with approximately half of patients from low-volume centers, extended pleurectomy decortication for mesothelioma had no significant difference when compared to those patients that underwent chemotherapy alone. Would the outcome be different in exclusively high-volume centers?” she concluded.

The study randomized 335 patients to receive surgery and chemotherapy, or chemotherapy alone. They received two cycles of platinum-based chemotherapy and pemetrexed prior to surgery and up to four cycles after surgery. The average age was 69 years; 86.9% were male, and 85.7% of tumors were epithelioid only. Among those in the surgery group, 88.5% underwent extended pleurectomy/decortication, 8.3% underwent pleurectomy decortication, 1.9% underwent partial pleurectomy, 0.6% exploration with no pleurodesis, and 0.6% were classified as “other” surgery. Completeness of resection was R0 in 3.2% of surgeries, R1 in 80.9%, and R2 in 15.9%. In-hospital mortality occurred in 3.8% of patients, and postsurgical 90-day mortality was 8.9%.

Over the first 42 months of follow-up, the hazard ratio for overall survival was 1.28 in the no-surgery group (P = .03). “The survival was so good in this early-stage cohort that we had to extend the trial by 6 months to get the prerequisite number of deaths, underscoring the phenomenal importance of having a randomized comparative cohort for all future studies on surgery for mesothelioma,” said Dr. Lim.

After 42 months, there was no survival difference between the two groups (hazard ratio, 0.48; P = .15). Dr. Lim attributed the change at 42 months to the fact that only 15 patients remained in each arm at that stage. There was no significant difference between the two groups with respect to progression-free survival.

The survival benefit of the no-surgery group was sustained after additional analyses, including adjustment of the number of first-line chemotherapy cycles and immunotherapy received after completion of the trial protocol.

Adverse events were more common in the surgery group (incidence rate ratio, 3.6; P < .001), including any cardiac disorder (IRR, 2.73; 95% confidence interval, 1.11-6.67); any infection or infestation (IRR, 1.99; 95% CI, 1.33-2.99); any respiratory, thoracic, or mediastinal disorder (IRR, 2.40; 95% CI, 1.52-3.80); and any surgical or medical procedure (IRR, 2.23; 95% CI, 1.04-4.78). The EORTC quality of life score favored the nonsurgery group at 6 weeks, but there was no significant difference at other time points.

Dr. Lim and Dr. Figueroa have no relevant financial disclosures.

Pleural mesothelioma is generally treated by extended pleurectomy decortication, and there has been little improvement in systemic treatment of early-stage, resectable mesothelioma, which has led to the recommendations of maximum cytoreduction. U.S. and European guidelines, as well as an international consensus statement, support this approach, but it has never been tested in a randomized, controlled trial.

Now it has, and the result is surprising: Surgery led to reduced survival and more serious adverse events, compared with chemotherapy alone. The conclusion was uncomfortable for Eric Lim, MD, who presented the results of the MARS2 trial at the annual World Conference on Lung Cancer. “Ladies and gentlemen, as a surgeon standing here, you have no idea how much it pains me to conclude that extended pleurectomy decortication, an operation that we have been offering for over 70 years, has been associated with a higher risk of death, more serious complications, poorer quality of life, and higher costs, compared to mesothelioma patients who were randomized to chemotherapy alone,” said Dr. Lim of the Royal Brompton Hospital, London, during his presentation.

Although the line drew laughter and applause from the audience, Paula Ugalde Figueroa, MD, who served as a discussant, raised some concerns about the study. Disease presence in one hemithorax was assessed only by chest CT scan, which is notorious for underestimating the volume of disease during surgery. There was also no information on pleural effusion or how many patients received it prior to intervention. Existing guidelines suggest staging of mesothelioma should also use PET scans, and invasive mediastinal staging should be assessed with endobronchial ultrasound. “None of these were performed during the trial,” said Dr. Figueroa, who is an associate thoracic surgeon at Brigham and Women’s Hospital, Boston. “At this point, my question is, are the arms of this study well balanced in regard to tumor volume? We don’t know,” she added.

Dr. Figueroa noted that the 90-day mortality seemed higher than that seen in other studies. “So, does the surgeon’s experience and center volume affect the outcome of this study?” she asked. Dr. Figueroa personally made phone calls to the participating centers and found that 45% of the patients in the trial were treated at low-volume centers, defined by her as two to three patients per year. “Should we assume that their surgical outcomes are similar between those centers? In this trial, with approximately half of patients from low-volume centers, extended pleurectomy decortication for mesothelioma had no significant difference when compared to those patients that underwent chemotherapy alone. Would the outcome be different in exclusively high-volume centers?” she concluded.

The study randomized 335 patients to receive surgery and chemotherapy, or chemotherapy alone. They received two cycles of platinum-based chemotherapy and pemetrexed prior to surgery and up to four cycles after surgery. The average age was 69 years; 86.9% were male, and 85.7% of tumors were epithelioid only. Among those in the surgery group, 88.5% underwent extended pleurectomy/decortication, 8.3% underwent pleurectomy decortication, 1.9% underwent partial pleurectomy, 0.6% exploration with no pleurodesis, and 0.6% were classified as “other” surgery. Completeness of resection was R0 in 3.2% of surgeries, R1 in 80.9%, and R2 in 15.9%. In-hospital mortality occurred in 3.8% of patients, and postsurgical 90-day mortality was 8.9%.

Over the first 42 months of follow-up, the hazard ratio for overall survival was 1.28 in the no-surgery group (P = .03). “The survival was so good in this early-stage cohort that we had to extend the trial by 6 months to get the prerequisite number of deaths, underscoring the phenomenal importance of having a randomized comparative cohort for all future studies on surgery for mesothelioma,” said Dr. Lim.

After 42 months, there was no survival difference between the two groups (hazard ratio, 0.48; P = .15). Dr. Lim attributed the change at 42 months to the fact that only 15 patients remained in each arm at that stage. There was no significant difference between the two groups with respect to progression-free survival.

The survival benefit of the no-surgery group was sustained after additional analyses, including adjustment of the number of first-line chemotherapy cycles and immunotherapy received after completion of the trial protocol.

Adverse events were more common in the surgery group (incidence rate ratio, 3.6; P < .001), including any cardiac disorder (IRR, 2.73; 95% confidence interval, 1.11-6.67); any infection or infestation (IRR, 1.99; 95% CI, 1.33-2.99); any respiratory, thoracic, or mediastinal disorder (IRR, 2.40; 95% CI, 1.52-3.80); and any surgical or medical procedure (IRR, 2.23; 95% CI, 1.04-4.78). The EORTC quality of life score favored the nonsurgery group at 6 weeks, but there was no significant difference at other time points.

Dr. Lim and Dr. Figueroa have no relevant financial disclosures.