Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.

While common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD.

Prophylactic use of pentoxifylline (Trental) and vitamin E to prevent capsular contracture after implant reconstruction in patients requiring adjuvant radiation.

BACKGROUND: The combination of pentoxifylline (Trental) and vitamin E has been reported to reverse significant consequences of radiation after mastectomy with immediate reconstruction, such as severe capsular contracture or loss of implants. We questioned whether prophylactic use could prevent these consequences. METHODS: Thirty women with implants or tissue expanders after mastectomy that underwent adjuvant radiation were treated with Trental and vitamin E for 180 days. All subjects then entered a 12-month observational phase. RESULTS: Of the 26 evaluable subjects, 3 subjects required implant revisions. One due to malposition of the nonradiated breast and 2 were due to contracture (7.7%). There were no implant losses. CONCLUSIONS: The combination of Trental and vitamin E can prevent severe contracture and implant losses allowing for immediate reconstruction with implant or tissue expander even if radiation is planned after mastectomy.

Effect of paravertebral nerve blocks on narcotic use after mastectomy with reconstruction.

INTRODUCTION: Pain control outcomes using local anesthetic delivery systems vs usual narcotics at our institution revealed that use of local anesthetic delivery systems decreased narcotic use greater than 40% in patients with no reconstruction but had very little effect in patients receiving reconstruction. As part of our quality improvement program, the anesthesiology department trained and began offering paravertebral blocks (PVBs) to patients having reconstruction. We reviewed pain control outcomes to understand how the use of paravertebral nerve blocks affected narcotic use in reconstructed patients. METHODS: Retrospective review of prospectively collected data on patients undergoing mastectomy with or without reconstruction in the 6-month period after introduction of PVB analgesia. Patients received preoperative single-shot paravertebral nerve blocks at T2 to T3 and T5 to T6 with bupivacaine .5% and epinephrine 1:200,000 (7.5 mL per injection). Patients who had a bilateral mastectomy with reconstruction received bilateral paravertebral nerve blocks at the same locations. Narcotic doses were converted to morphine equivalents (MSEs) to allow comparison. RESULTS: There were 102 patients with mastectomy during that period and 91 were evaluable. Fifty-one had no reconstruction with an average MSE use of 37.9. There were 40 with reconstruction, 33 had PVB with average MSE of 42.6, and 7 patients had reconstruction with no PVB with average MSE of 71.1. There were no major complications. CONCLUSIONS: Institution of the PVB for patients undergoing mastectomy with reconstruction lowered average MSE use. We will continue to offer paravertebral blocks in this cohort of patients.

Axillary reverse lymphatic mapping reduces patient perceived incidence of lymphedema after axillary dissection in breast cancer.

BACKGROUND: Lymphedema is a feared complication of many patients following axillary lymph node dissection for breast cancer. Axillary reverse lymphatic mapping (ARM) was adopted to decrease the incidence of lymphedema. METHODS: A retrospective review was conducted on 139 patients with breast cancer who had greater than 10 lymph nodes removed. A survey was sent to patients to identify those with lymphedema. RESULTS: One hundred nine women were contacted via mail survey to determine the presence of lymphedema. Of the 46 surveys returned, the incidence of lymphedema was 39%. Twenty-seven percent of the ARM group identified themselves as having lymphedema compared with 50% in non-ARM group. Eighteen percent of women in the ARM group needed an arm sleeve for treatment compared with 45.8% in the non-ARM group. CONCLUSIONS: The incidence of perceived lymphedema and the need for arm compression sleeve devices were lower in the ARM cohort. ARM should be adopted to decrease patient perception of lymphedema.

Increasing incidence of bilateral mastectomies: the patient perspective.

BACKGROUND: Numerous studies have reported increasing rates of contralateral prophylactic mastectomies (CPMs). Understanding patient rationale for the surgical choice may provide insight into this trend. METHODS: A questionnaire was mailed to 350 mastectomy patients identified from a community health system tumor registry. RESULTS: Two hundred fifty questionnaires were received; of these, 237 had undergone mastectomy. Fifty-two percent had unilateral mastectomy (UM), and 43% had bilateral mastectomies (BMs) (6% for bilateral disease). Women younger than 60 years of age were more likely to choose BM (P = .0046). Those who had CPM were significantly more likely to make the same surgical decision (P < .0001). Reconstruction was performed in 52%, with BM patients more likely to undergo reconstruction (P = .009). Twenty-three (19%) needed unanticipated reoperation for reconstruction complications. CPM had equivalent rates of unanticipated surgery versus UM (P = .64). CONCLUSIONS: Patients choosing BMs are younger, have equivalent rates of reoperation because of reconstruction complications, and are significantly more satisfied with their decision than those who chose UM.

Alternative therapy used as primary treatment for breast cancer negatively impacts outcomes.

BACKGROUND: The use of complementary and alternative medicine (CAM) has escalated over the past decade, despite the fact that clinical studies validating the efficacy of CAM remain sparse. Clinicians frequently encounter patients who reject standard treatment, but data on outcomes of patients choosing CAM as primary treatment for breast cancer are also lacking. MATERIALS AND METHODS: Breast cancer patients who refused/delayed standard treatments in favor of alternative therapies were identified in a community surgical practice over a 10-year period. A retrospective chart review was performed with telephone interviews when possible. Estimated 10-year survival given recommended treatment was calculated. RESULTS: A total of 61 patients was identified; median age was 53. Median follow-up was 54 months. Patients were stratified into 2 subgroups: those who omitted/delayed surgery (SSG, n = 26) and those who were nonadherent to adjuvant therapy recommendations (ASG, n = 35). In the SSG, 96.2% experienced disease progression; 50% died of disease. Mean stage at initial presentation was II; mean stage at re-presentation after primary treatment with alternative therapies was IV. Disease progression occurred in 86.2% of those in the ASG; 20% died of disease. The mean 10-year survival calculated for those omitting surgery was 69.5%; observed survival for this group was 36.4% at a median follow-up of 33 months. CONCLUSIONS: Alternative therapies used as primary treatment for breast cancer are associated with disease progression and increased risk of recurrence and death. Diminished outcomes are more profound in those delaying/omitting surgery. Reviewing these results with our patients may help bridge the gap between CAM and standard treatments.