Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration.

Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die. Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn2+) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn2+ increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn2+ accumulation in amacrine cell processes involves the Zn2+ transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn2+ chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn2+ chelation extends for several days after nerve injury. These results show that retinal Zn2+ dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn2+ chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.

Precautions for breast cancer-related lymphoedema: risk from air travel, ipsilateral arm blood pressure measurements, skin puncture, extreme temperatures, and cellulitis.

Precautionary recommendations conveyed to survivors of cancer by health-care practitioners to reduce the risk of breast cancer-related lymphoedema are indispensable aspects of clinical care, yet remain unsubstantiated by high-level scientific evidence. By reviewing the literature, we identified 31 original research articles that examined whether lifestyle-associated risk factors (air travel, ipsilateral arm blood pressure measurements, skin puncture, extreme temperatures, and skin infections-eg, cellulitis) increase the risk of breast cancer-related lymphoedema. Among the few studies that lend support to precautionary guidelines, most provide low-level (levels 3-5) or inconclusive evidence of an association between lymphoedema and these risk factors, and only four level 2 studies show a significant association. Skin infections and previous infection or inflammation on the ipsilateral arm were among the most clearly defined and well established risk factors for lymphoedema. The paucity of high-level evidence and the conflicting nature of the existing literature make it difficult to establish definitive predictive factors for breast cancer-related lymphoedema, which could be a considerable source of patient distress and anxiety. Along with further research into these risk factors, continued discussion regarding modification of the guidelines and adoption of a risk-adjusted approach is needed.

A comprehensive review of bioimpedance spectroscopy as a diagnostic tool for the detection and measurement of breast cancer-related lymphedema.

As treatment for breast cancer improves and the threat of life-long chronic lymphedema becomes more prevalent, the need for effective screening tools emerges as crucial. This review was conducted using literature beginning in 1992 to analyze primary research testing the accuracy of bioimpedance spectroscopy as a diagnostic and early detection tool for breast cancer-related lymphedema. We concluded bioimpedance is an accurate diagnostic tool for pre-existent lymphedema, however, it has not been validated for early detection. J. Surg. Oncol. 2016;114:537-542. © 2016 Wiley Periodicals, Inc.

Neutrophilic Dermatosis and Management Strategies for the Inpatient Dermatologist.

Purpose of Review: Neutrophilic dermatoses are a heterogeneous group of disorders with significant overlap in associated conditions, clinical presentation, and histopathologic features. This review provides a structural overview of neutrophilic dermatoses that may present in the inpatient setting along with diagnostic work-up and management strategies. Recent Findings: Sweet's syndrome has been found in patients with coronavirus disease 2019 (COVID-19). Pyoderma gangrenosum (PG) has been shown to be equally associated with ulcerative colitis and Crohn's disease. A clinical trial shows that cyclosporine is equally effective as prednisone in treating PG. Neutrophilic eccrine hidradenitis has been found in the setting of newer antineoplastic medications, such as BRAF inhibitors, as well as in the setting of malignancy without chemotherapy exposure. Summary: Neutrophilic dermatoses are a rare and complex group of dermatoses with varying and overlapping clinical presentations. Physicians should be aware of the growing list of associated diseases in order to build a better differential diagnosis or to potentially investigate for co-existing disease.

Association of Bullous Pemphigoid With Immune Checkpoint Inhibitor Therapy in Patients With Cancer: A Systematic Review.

Importance: There is limited information on immune checkpoint inhibitor-induced bullous pemphigoid (ICI-BP) in patients with cancer, with most existing studies being case reports or small case series from a single institution. Prior review attempts have not approached the literature in a systematic manner and have focused only on ICI-BP secondary to anti-programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) therapy. The current knowledge base of all aspects of ICI-BP is limited. Objective: To characterize the risk factors, clinical presentation, diagnostic findings, treatments, and outcomes of ICI-BP in patients with cancer as reported in the current literature. Evidence Review: A systematic review was performed using PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Articles reporting data on individual patients who met preestablished inclusion criteria were selected, and a predefined set of data was abstracted. When possible, study results were quantitatively combined. Findings: In total, 70 studies reporting data on 127 individual patients undergoing ICI therapy for cancer (median [IQR] age, 71 [64-77] years; 27 women [21.3%]) were included. In pooled analyses, patients ranged in age from 35 to 90 years. Immune checkpoint inhibitor-induced bullous pemphigoid often occurred during the course of anti-PD-1, PD-L1, or cytotoxic T lymphocyte-associated antigen 4 therapy but was also found to develop up to several months after treatment cessation. Prodromal symptoms, such as pruritus or nonspecific skin eruptions, were found in approximately half of the patient population. Histopathologic or serologic testing, when undertaken, was a helpful adjunct in establishing diagnosis. Treatment with immunotherapy was discontinued after ICI-BP development in most patients. The most common treatments were systemic and topical corticosteroids. Steroid-sparing therapies, such as antibiotics and other systemic immunomodulators, were also used as adjuvant treatment modalities. Biologic and targeted agents, used predominantly in cases refractory to treatment with corticosteroids, were associated with marked symptomatic improvement in most patients. Conclusions and Relevance: The results of this systematic review suggest that ICI-BP often poses a therapeutic challenge for patients with cancer who are receiving immunotherapy. Further research on the early recognition, diagnosis, and use of targeted treatment modalities will be essential in developing more personalized treatment options for affected patients while minimizing morbidity and mortality.

Timing of Lymphedema After Treatment for Breast Cancer: When Are Patients Most At Risk?

PURPOSE: The purpose of the study was to determine when the risk of lymphedema is highest after treatment of breast cancer and which factors influence the time course of lymphedema development. METHODS AND MATERIALS: Between 2005 and 2017, 2171 women (with 2266 at-risk arms) who received surgery for unilateral or bilateral breast cancer at our institution were enrolled. Perometry was used to objectively assess limb volume preoperatively, and lymphedema was defined as a ≥10% relative arm-volume increase arising >3 months postoperatively. Multivariable regression was used to uncover risk factors associated with lymphedema, the Cox proportional hazards model was used to calculate lymphedema incidence, and the semiannual hazard rate of lymphedema was calculated. RESULTS: With a median follow-up of 4 years, the overall estimated 5-year cumulative incidence of lymphedema was 13.7%. Significant factors associated with lymphedema on multivariable analysis were high preoperative body mass index, axillary lymph node dissection (ALND), and regional lymph node radiation (RLNR). Patients receiving ALND with RLNR experienced the highest 5-year rate of lymphedema (31.2%), followed by those receiving ALND without RLNR (24.6%) and sentinel lymph node biopsy with RLNR (12.2%). Overall, the risk of lymphedema peaked between 12 and 30 months postoperatively; however, the time course varied as a function of therapy received. Early-onset lymphedema (<12 months postoperatively) was associated with ALND (HR [hazard ratio], 4.75; P < .0001) but not with RLNR (HR, 1.21; P = .55). In contrast, late-onset lymphedema (>12 months postoperatively) was associated with RLNR (HR, 3.86; P = .0001) and, to a lesser extent, ALND (HR, 1.86; P = .029). The lymphedema risk peaked between 6 and 12 months in the ALND-without-RLNR group, between 18 and 24 months in the ALND-with-RLNR group, and between 36 and 48 months in the group receiving sentinel lymph node biopsy with RLNR. CONCLUSIONS: The time course for lymphedema development depends on the breast cancer treatment received. ALND is associated with early-onset lymphedema, and RLNR is associated with late-onset lymphedema. These results can influence clinical practice to guide lymphedema surveillance strategies and patient education.

Hand Edema in Patients at Risk of Breast Cancer-Related Lymphedema: Health Professionals Should Take Notice.

Background: There is little research on hand edema in the population at risk for breast cancer-related lymphedema (BCRL). Objectives: Study aims included reporting potential importance of hand edema (HE) as a risk factor for progression of edema in patients treated for breast cancer at risk for BCRL, reporting risk factors for BCRL, and reporting treatment of HE. Design/Methods: This was a retrospective analysis of 9 patients treated for breast cancer in Massachusetts General Hospital's lymphedema screening program who presented with isolated HE. Limb volumes via perometry, BCRL risk factors, and HE treatment are reported. Results: Edema was mostly isolated to the hand. Three patients had arm edema >5% on perometry; and 2 of these had edema outside the hand on clinical examination. Patients were at high risk of BCRL with an average of 2.9/5 known risk factors. Arm edema progressed to >10% in 2 high-risk patients. Treatment resulted in an average hand volume reduction of 10.2% via perometry and improvement upon clinical examination. Limitations: The small sample size and lack of validated measures of subjective data were limitations. Conclusions: In this cohort, patients with HE carried significant risk factors for BCRL. Two out of 9 (22%), both carrying ≥4/5 risk factors, progressed to edema >10%. Isolated HE may be a prognostic factor for edema progression in patients treated for breast cancer at risk for BCRL. Further research is warranted.

Diagnostic Methods, Risk Factors, Prevention, and Management of Breast Cancer-Related Lymphedema: Past, Present, and Future Directions.

PURPOSE OF REVIEW: Breast cancer-related lymphedema (BCRL) is a chronic, adverse, and much feared complication of breast cancer treatment, which affects approximately 20% of patients following breast cancer treatment. BCRL has a tremendous impact on breast cancer survivors, including physical impairments and significant psychological consequences. The intent of this review is to discuss recent studies and analyses regarding the risk factors, diagnosis, prevention through early screening and intervention, and management of BCRL. RECENT FINDINGS: Highly-evidenced risk factors for BCRL include axillary lymph node dissection, lack of reconstruction, radiation to the lymph nodes, high BMI at diagnosis, weight fluctuations during and after treatment, subclinical edema within and beyond 3 months after surgery, and cellulitis in the at-risk arm. Avoidance of potential risk factors can serve as a method of prevention. Through establishing a screening program by which breast cancer patients are measured pre-operatively and at follow-ups, are objectively assessed through a weight-adjusted analysis, and are clinically assessed for signs and symptoms, BCRL can be tracked accurately and treated effectively. Management of BCRL is done by a trained professional, with research mounting towards the use of compression bandaging as a first line intervention against BCRL. Finally, exercise is safe for breast cancer patients with and without BCRL and does not incite or exacerbate symptoms of BCRL. SUMMARY: Recent research has shed light on BCRL risk factors, diagnosis, prevention, and management. We hope that education on these aspects of BCRL will promote an informed, consistent approach and encourage additional research in this field to improve patient outcomes and quality of life in breast cancer survivors.