Prelamination of Vascularized Tensor Fascia Lata for Complex Abdominal Wall Reconstruction.

ABSTRACT: There are 2 to 5 million laparotomies performed in the United States annually. Of these, 250,000 to 350,000 will undergo a ventral hernia repair. Repairs are often complicated by recurrence and infection. These risks are significantly increased in previously infected repairs, with reported recurrence rates varying from 17% to 28% after repair of infected ventral hernias, double the rates reported for first-time uninfected repairs. We describe here a novel treatment strategy involving the creation then use of bilateral prelaminated permanent mesh-reinforced tensor fascia latae flaps for abdominal wall reconstruction in patients who have recurrent ventral hernias and had undergone previous repairs complicated by infection. Previous repairs included anterior components separation, thereby making subsequent fascial release techniques and achievement of a reinforced repair extremely unlikely. Three patients were treated by a single surgeon using this 2-stage technique. There have been no incidences of recurrence and no infections after 2 to 10 years. In these patients, the only conventional option would have been a bridged repair with absorbable mesh. Combining the advantages of permanent mesh and well-vascularized autologous tissue optimizes the repair's tensile strength while mitigating the chance of recurrent infection associated with the use of permanent mesh. We propose that this strategy may be an appropriate treatment option for patients with recurrent ventral hernias that have not responded to other conventional modalities of treatment.

Acral Lentiginous Melanoma: Do Surgical Approach and Sentinel Lymph Node Biopsy Matter?

Management of acral lentiginous melanoma (ALM) remains controversial. Traditionally, ALM was managed with digit amputation (DA), resulting in significant morbidity, but recent evidence has advocated for digit sparing management. Furthermore, the significance of nodal metastasis for ALM is not well reported. The aims of this study were to determine if surgical approach for primary ALM impacts outcomes and to evaluate the predictive value of nodal status for ALM. METHODS: Patients with localized ALM diagnosed from 1982 to 2017 were retrospectively identified. Clinicopathologic characteristics were correlated with surgical approach, nodal metastasis, overall survival, and recurrence-free survival. RESULTS: There were 47 patients with ALM. Median age was 59 years, and median thickness was 3 mm. 51% of patients underwent wide local excision (WLE), 27.9% underwent DA, and 20.9% underwent partial digit amputation (PDA). ALM on the hand versus foot (OR: 12.7, 95%, confidence interval (CI), 2.0-80.1; P = 0.007) and subungual versus nonsubungual location (OR: 28.0, 95% confidence interval, 2.7-295.7; P = 0.006) were significantly associated with surgical approach (DA and PDA versus WLE). There were no significant differences in overall survival or recurrence-free survival between DA, PDA, or WLE cases (P = 0.481 and P = 0.778, respectively). There were no significant differences in overall survival or recurrence-free survival based on nodal status (P = 0.562 and P = 0.136, respectively). CONCLUSIONS: No significant differences in overall survival or recurrence-free survival were seen between ALM patients treated with DA, PDA, and WLE. Given these results, PDA or WLE may be options in select patients with digital ALM; however, careful consideration must be taken when deciding on the surgical approach.

A novel anti-melanoma SRC-family kinase inhibitor.

The major drawback of melanoma therapy with BRAF and MAPK inhibitors is the innate and acquired drug resistance. We therefore explored alternative targets and developed a new compound, SAB298, that is a SRC-family kinase (SFK) inhibitor. The drug is cytotoxic to patient-derived melanoma cells regardless of oncogene expression and inhibits tumor growth in vivo. As expected, it inhibited SRC and PI3K activity, and had the additional property of ERBB2 inhibition, that lead to inactivation of the two ERK phosphatases PP2A and SHP2. In 57% of the melanoma cell lines tested, the consequent increase in ERK activity lead to proteolytic degradation of its substrate, the lineage specific transcription factor MITF, likely contributing to growth arrest. Treatment with a combination of SAB298 and AZD6244 (selumetinib), induced a synergistic growth inhibition, suggesting that the new compound could be used in the clinic as a substitute for, or in combination with MAPK inhibitors.

MicroRNA Microarray Profiling in Infantile Hemangiomas.

Objective: MicroRNAs are short, noncoding RNA molecules that negatively regulate the stability and translational efficiency of target mRNAs. They are critical regulators of growth and development. Our aim was to identify microRNAs involved in the growth and regulation of infantile hemangiomas. In addition, we searched for the presence of Piwi-interacting RNAs in hemangioma tissue as another regulator of infantile hemangiomas. Methods: RNA was extracted from hemangioma specimens from 3 clinical, age-based categories: proliferative (N = 16), quiescent (N = 8), and involuting (N = 9). RNAs from human dermal microvascular endothelial cells were used as controls. MicroRNA microarray was performed, and the expression profiles of the hemangiomas and endothelial cells were compared using the t test. 5' End-labeling of RNA of our hemangioma specimens was performed for Piwi-interacting RNA detection. Results: Analysis confirmed statistically significant downregulated (N = 18) and upregulated (N = 15) microRNAs. Piwi-interacting RNA analysis did not detect Piwi-interacting RNA transcripts in the hemangioma specimens. Conclusions: The differential expression of microRNAs found in our hemangioma specimens provides insight into the regulation of hemangioma formation and proliferation, quiescence, and fibrofatty involution. Piwi-interacting RNA transcripts were not detected in the hemangioma specimens. These novel findings will help in establishing new therapeutic and diagnostic initiatives for these tumors.

Altered In Vivo Lipid Fluxes and Cell Dynamics in Subcutaneous Adipose Tissues Are Associated With the Unfavorable Pattern of Fat Distribution in Obese Adolescent Girls.

Patterns of abdominal fat distribution (for example, a high vs. low visceral adipose tissue [VAT]/[VAT + subcutaneous adipose tissue (SAT)] ratio), independent of obesity, during adolescence carry a high risk for insulin resistance and type 2 diabetes. Longitudinal follow-up of a cohort of obese adolescents has recently revealed that a high ratio (high VAT/[VAT + SAT]) is a major determinant of fatty liver and metabolic impairment over time, with these effects being more pronounced in girls than in boys. To unravel the underlying metabolic alterations associated with the unfavorable VAT/(VAT + SAT) phenotype, we used the 2H2O labeling method to measure the turnover of adipose lipids and cells in the subcutaneous abdominal and gluteal/femoral adipose tissue (SAT) of weight-stable obese adolescent girls with a similar level of obesity but discordant VAT/(VAT + SAT) ratios. Girls with the unfavorable (high VAT/[VAT + SAT]) phenotype exhibited higher in vivo rates of triglyceride (TG) turnover (representing both lipolysis and synthesis at steady state), without significant differences in de novo lipogenesis in both abdominal and gluteal depots, compared with obese girls with the favorable phenotype. Moreover, mature adipocytes had higher turnover, with no difference in stromal vascular cell proliferation in both depots in the metabolically unfavorable phenotype. The higher TG turnover rates were significantly correlated with higher intrahepatic fat stores. These findings are contrary to the hypothesis that impaired capacity to deposit TGs or proliferation of new mature adipocytes are potential mechanisms for ectopic fat distribution in this setting. In summary, these results suggest that increased turnover of TGs (lipolysis) and of mature adipocytes in both abdominal and gluteal SAT may contribute to metabolic impairment and the development of fatty liver, even at this very early stage of disease.

Clinical Value of Single-photon Emission Computed Tomography Combined With Computed Tomography for Sentinel Lymph Node Identification in Melanoma.

INTRODUCTION: Melanoma is the deadliest form of skin cancer and has the ability to metastasize widely. Accurate diagnosis of sentinel lymph nodes (SLN) is crucial to its management. The gold standard for SLN identification is planar lymphoscintigraphy. Recently, single-photon emission computed tomography combined with computed tomography (SPECT/CT) has been used as a hybrid method to map lymphatic drainage networks. We aim to better characterize the utility of this tool in head and neck melanoma by evaluating its effectiveness in the preoperative setting for melanoma patients undergoing sentinel lymph node biopsy (SLNB). METHODS: We performed a retrospective chart review at the West Haven Veterans Affairs Hospital. Inclusion criteria were patients with melanoma with a thickness greater than 0.75 mm and SPECT/CT use before operative sentinel lymph node excision. Exclusion criteria included clinically palpable lymph nodes, evidence of distant metastatic disease, melanoma with a Breslow depth less than 0.75 mm, and melanoma in situ. Our primary endpoints were correlation with intraoperative findings and whether the test had any influence on the operative plan. RESULTS: Thirty-five patients between 2011 and 2017 met our criteria. SPECT/CT correlated with the sentinel node biopsy based on intraoperative lymphoscintigraphy in 30 (86%) of 35 cases, and there were no changes to the operative plan after SPECT/CT was performed. Sentinel lymph nodes were correctly identified in all 35 cases. CONCLUSIONS: The role of SPECT/CT in SLNB is uncertain. According to some studies, SPECT/CT can help decision making and change surgical approach in up to 35% of patients. However, other studies have reported questionable correlation with intraoperative findings and no added intraoperative value in over 50% of patients. We have demonstrated that preoperative SPECT/CT was consistent with intraoperative findings in 86.0% of cases but did not change the surgical approach for the SLNB. Surveillance over a period of 12 months did not reveal any signs of melanoma recurrence. A possible advantage of SPECT/CT is potentially decreasing costs by lowering operative time. However, financial cost in the literature suggests SPECT/CT is costlier than lymphoscintigraphy and therefore this must be weighed against any potential benefit. Overall, we did not find that SPECT/CT gives added value when compared with lymphoscintigraphy.

An Algorithm for the Management of Residual Head and Neck Melanoma In Situ Using Topical Imiquimod: A Pilot Study.

INTRODUCTION: Melanoma in situ (MIS) is an early variant of melanoma in which the disease is limited to the epidermis. Standard therapy is currently surgical excision with at least 5-mm margins. In some instances, there are large or anatomically difficult lesions where complete excision will result in significant esthetic or functional impairment. Our experience has shown a 6-week course to be sufficient in certain patients compared with the suggested 12-week course. In this context, we propose a shortened duration of treatment of positive margins with topical imiquimod and propose an algorithm that results in the least amount of dysfunction for the patient. METHODS: Our inclusion criteria were patients undergoing excision of a lesion found to have postsurgical margins, which were positive for MIS. Patients applied 5% imiquimod 3 to 5 times per week for at least 6 weeks at the site of the positive margin(s). Duration and frequency of treatment were titrated based on response. A reexcision skin biopsy using 1-mm margins was performed after residual inflammation subsided. Our endpoints were recurrence and effectiveness with length of treatment. RESULTS: Sixteen patients met our criteria. All patients were found to have MIS in the margins after surgical excision. Twelve of those lesions were classified as MIS in the initial biopsy; the remaining 4 were either melanoma stage T1A or T1B. Mean follow-up time was 14.3 months, and 1 patient was lost to follow-up. We had 3 patients without response, and of these, 1 was found to have atypical squamous cell carcinoma and the other had a recurrence of MIS. Cure rate after use of topical imiquimod was 93.3% (14/15). DISCUSSION: The proposed algorithm for the treatment of residual disease in head and neck melanoma and MIS using topical imiquimod offers various advantages. This anatomical region is cosmetically sensitive, and the option of using 1 mm versus 5 mm reexcision margins after imiquimod treatment yields comparable cure rates with less tissue excised overall. Our algorithm demonstrates that 6 weeks of active inflammation provides comparable results with the traditional 12-week course. This decreased treatment time reduces patient discomfort and improves patient adherence.

Management of intussusception in patients with melanoma.

BACKGROUND: Increased cross-sectional imaging for surveillance of metastatic melanoma has led to more diagnoses of asymptomatic intussusception. METHODS: We performed a multi-institutional retrospective review of patient records with a history of metastatic melanoma and a diagnosis of intussusception. Patients were divided into three groups: 1) asymptomatic patients without current evidence of melanoma (no evidence of disease [NED]); 2) asymptomatic intussusception and known active metastatic melanoma; 3) symptomatic intussusception and known active metastatic melanoma; the number of patients requiring surgery and intraoperative findings were recorded. RESULTS: We reviewed 73 patients diagnosed with intussusception from 2004 to 2017. Among asymptomatic patients with NED (n = 16), 14 spontaneously resolved and 2 underwent pre-emptive surgery without abnormal intraoperative findings. Of asymptomatic patients with active metastatic disease (n = 32), 25 were initially observed and 7 underwent pre-emptive surgery and 9 of the 25 initially observed patients required surgery for development of symptoms. In this group, all 16 patients undergoing surgery (50% of the group) had intraoperative findings of intussusception and/or metastatic intestinal melanoma.. All symptomatic patients with metastatic melanoma (n = 25) underwent surgery; all had intraoperative findings of intussusception and/or metastatic melanoma except 1 (Meckel's diverticulum). CONCLUSION: Asymptomatic patients with NED do not require surgery and intussusception will likely resolve spontaneously. Asymptomatic patients with known metastatic melanoma may be initially observed, but a low threshold for surgery should be maintained. Symptomatic patients with known metastases should undergo surgery.

Pain Management and Body Contouring.

Body contouring procedure is a catchall that includes mastopexy, abdominoplasty, liposuction, and lower body lift. It is well known that optimal postoperative pain control decreases hospitalization length of stay and promotes early ambulation, which in turn decreases the incidence of complications. There have been many innovations in pain control beyond opiate medications, including prolonged administration of local anesthesia, regional blocks, and the use of a multimodal regimen which utilizes nonopiates. All approaches aim to decrease oral or intravenous opiate use and, therefore, encourage faster return to normal bowel function and decreased risk of addiction. In this article, the authors focus on opiate alternatives.

Telehealth in Plastic Surgery: A Veterans Affairs Hospital Perspective.

BACKGROUND: Telemedicine is a rapidly growing tool since its invention in the 1950s. Recently, it has expanded to the field of plastic surgery. In the Connecticut VA System, there is 1 plastic surgeon at a central location for the state of Connecticut and southern Massachusetts. Our aim was to pilot a telehealth program for plastic surgery consultation within the VA to improve access to subspecialty care. We intend to discuss the value of telehealth as part of consultation services, and assess patient attitudes toward telemedicine. METHODS: Patients in the Connecticut VA System referred for plastic surgery consultation for evaluation of nonurgent diagnoses, such as skin lesions, carpal tunnel syndrome, and chronic wounds, were invited to participate. After being appropriately consented according to Connecticut state law, patients completed a postvisit questionnaire rating their overall satisfaction, quality of interaction, and ability to communicate using a modified 10-point Likert scale. Means were calculated for numerical responses. Preference for future telehealth visits was reported as a percentage. RESULTS: Forty-one of 44 eligible patients elected to participate. Of those patients, 83% (n = 34) stated they prefer telemedicine services for future visits. Patients rated overall satisfaction 9.2/10, overall quality of interaction 9.2/10, ability to communicate 9.3/10, and sound and video quality 8.6/10 and 9.0/10, respectively. CONCLUSION: Remote video telemedicine is a feasible method of plastic surgery consultation and results in high patient satisfaction. Further studies should focus on cost-effectiveness and ways to broaden the use of telehealth services in plastic surgery.

Nonvisualization of Sentinel Lymph Nodes by Lymphoscintigraphy in Primary Cutaneous Melanoma: Incidence, Risk Factors, and a Review of Management Options.

BACKGROUND: Lymphoscintigraphy is often performed before sentinel lymph node biopsy, especially in areas likely to have multiple or aberrant drainage patterns. This study aims to determine the incidence and characteristics of melanoma patients with negative lymphoscintigraphic findings and to review the management options and surgical recommendations. METHODS: This is a retrospective study of patients with primary cutaneous melanoma who underwent sentinel lymph node biopsy between 2005 and 2016. Patients with nonvisualized lymph nodes on preoperative lymphoscintigraphy were compared in a 1:4 ratio with a randomly selected unmatched cohort drawn from all melanoma patients who underwent preoperative lymphoscintigraphy within the period of the study. Demographic, clinical, and outcome data were compared between these groups. RESULTS: A negative lymphoscintigraphic scan was seen in 2.3 percent of all cases (25 of 1073). In both univariate and multivariate analyses, predictive patient- and tumor-specific factors for negative lymphoscintigraphy included older age and head and neck location. Patients with a nonvisualized sentinel lymph node had significantly worse overall survival compared with patients who had a visualized sentinel lymph node, but there was no difference in melanoma-specific survival. In 16 of the 25 cases (64 percent), at least one sentinel lymph node was found intraoperatively despite the negative lymphoscintigraphic findings. CONCLUSIONS: Older patients with head and neck melanomas are more likely to experience nodal nonvisualization on lymphoscintigraphy. In patients who have nodal nonvisualization, the surgeon should attempt sentinel lymph node biopsy at the time of excision of the primary lesion because a sentinel lymph node can still be found in a majority of cases, and it offers prognostic information. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Eliminating Preoperative Lymphoscintigraphy in Extremity Melanomas.

BACKGROUND: Preoperative lymphoscintigraphy (LSG) is an imaging procedure routinely used to identify the draining nodal basin in melanomas. At our institute, we have traditionally performed preoperative LSG followed by intraoperative LSG for logistical and evaluative reasons. We sought to determine if preoperative LSG could be safely eliminated in the treatment of extremity melanomas, which exhibit consistent and predictable lymphatic drainage patterns. METHODS: We reviewed the Yale Melanoma Registry 1308012545 for cutaneous extremity melanomas treated at our institution. From this registry, we calculated the incidence of atypical lymph node drainage patterns outside the axillary and inguinal regions. Based on these data, we eliminated preoperative LSG in 21 cases (8 upper extremities and 13 lower extremities). Additionally, we calculated the potential hospital charge reduction of forgoing preoperative LSG. RESULTS: Upper and lower extremity melanomas treated at our institution exhibited atypical lymph node drainage at a rate of 3.4% and 2.0%, respectively. The sites of atypical drainage were to the epitrochlear and popliteal regions. In all 21 cases where preoperative LSG was eliminated, we were able to correctly identify the sentinel lymph node. The potential hospital charge reduction of forgoing preoperative LSG totaled $2,393. CONCLUSIONS: Preoperative LSG can be safely eliminated in the management of upper and lower extremity melanomas. Exceptions may be considered for primary lesions of the posterior calf, ankle, and heel as well as for patients with history of prior surgery or radiation. Forgoing preoperative LSG results in a hospital charge reduction of $2,393 and provides additional benefits to the patient. Ultimately, there is potential for significant charge reduction if applied across health care systems.

Phage treatment of an aortic graft infected with Pseudomonas aeruginosa.

Management of prosthetic vascular graft infections caused by Pseudomonas aeruginosa can be a significant challenge to clinicians. These infections often do not resolve with antibiotic therapy alone due to antibiotic resistance/tolerance by bacteria, poor ability of antibiotics to permeate/reduce biofilms and/or other factors. Bacteriophage OMKO1 binding to efflux pump proteins in P. aeruginosa was consistent with an evolutionary trade-off: wildtype bacteria were killed by phage whereas evolution of phage-resistance led to increased antibiotic sensitivity. However, phage clinical-use has not been demonstrated. Here, we present a case report detailing therapeutic application of phage OMKO1 to treat a chronic P. aeruginosa infection of an aortic Dacron graft with associated aorto-cutaneous fistula. Following a single application of phage OMKO1 and ceftazidime, the infection appeared to resolve with no signs of recurrence.

Epidemiology of malignant cutaneous granular cell tumors: A US population-based cohort analysis using the Surveillance, Epidemiology, and End Results (SEER) database.

BACKGROUND: Malignant cutaneous granular cell tumors (mcGCTs) are rare and associated with substantial morbidity and mortality. The literature includes single-institution studies. OBJECTIVE: To examine the incidence, secondary malignancies, treatment, overall survival, and disease-specific survival (DSS) of patients with mcGCT. METHODS: A population-based cohort analysis was conducted in the Surveillance, Epidemiology, and End Results database from 1973 to 2013 for patients with a diagnosis of mcGCT. Risk-adjusted associations between overall survival/DSS and patient characteristics and treatment modalities were assessed by Cox proportional hazard regression. Quantile regression was used to determine median survival times. RESULTS: The 5-year DSS rate was 62.8%. Patients demonstrated an increased risk for renal and pancreatic cancers. In risk-adjusted models, male sex (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.06-0.82; P = .02), advanced cancer stage (HR, 2.29; 95% CI, 1.40-3.72; P < .01), and surgical resection (HR, 0.06; 95% CI, 0.01-0.59; P = .02) predicted DSS. Median survival time in years increased for males (1.39), earlier stage (0.60), and surgical intervention (5.34). LIMITATIONS: Absent or incorrect reporting in retrospective Surveillance, Epidemiology, and End Results data is possible. The database is more likely to include academic centers. Some subanalyses may be underpowered because of the limited sample size for a rare cancer. CONCLUSIONS: Our study presents an in-depth assessment of factors that identify high-risk patients. Residency in a nonmetro area, black race, female sex, and no surgical resection were each associated with poorer DSS.

Use of Indocyanine Green for Sentinel Lymph Node Biopsy: Case Series and Methods Comparison.

INTRODUCTION: Sentinel lymph node biopsy is indicated for patients with biopsy-proven thickness melanoma greater than 1.0 mm. Use of lymphoscintigraphy along with vital blue dyes is the gold standard for identifying sentinel lymph nodes intraoperatively. Indocyanine green (ICG) has recently been used as a method of identifying sentinel lymph nodes. We herein describe a case series of patients who have successfully undergone ICG-assisted sentinel lymph node biopsy for melanoma. We compare 2 imaging systems that are used for ICG-assisted sentinel lymph node biopsy. METHODS: Fourteen patients underwent ICG-assisted sentinel lymph node biopsy for melanoma using the SPY Elite system (Novadaq, Mississigua, Canada) and the Hamamatsu PDE-Neo probe system (Mitaka USA, Park City, Utah). We analyzed costs for 2 systems that utilize ICG for sentinel lymph node biopsies. RESULTS: Intraoperative use of ICG for sentinel lymph node biopsies was successful in correctly identifying sentinel lymph nodes. There was no difference between the Hamamatsu PDE-Neo probe and SPY Elite systems in the ability to detect sentinel lymph nodes; however, the former was associated with a lower operating cost and ease of use compared with the latter. CONCLUSION: ICG-assisted sentinel lymph biopsy using the SPY Elite or the Hamamatsu PDE-Neo probe systems for melanoma are comparable in terms of sentinel node detection. The Neo probe system delivers pertinent clinical data with the advantages of lower cost and ease of operation.

Divisive influence of interleukin-1 receptor antagonist polymorphisms in melanoma patients.

OBJECTIVE: The interleukin-1 receptor antagonist (IL-1RA) contributes to tumor survival and progression in multiple cancer entities. IL-1RA polymorphisms influence IL-1RA expression patterns and function. A known polymorphism was correlated with clinical outcomes in melanoma patients with particularly aggressive disease. METHODS: DNA of 343 controls and 97 melanoma patients with poor prognostic indicators (time from diagnosis to death, nodal status, metastasis) was analyzed for a variable number of tandem repeat polymorphisms (VNTR) of the IL-1RA gene. Five alleles containing two (allele 2), three (allele 4), four (allele 1), five (allele 3) or six (allele 5) 86-bp repeats were targeted via PCR amplification. RESULTS: Genotype 1/2 is less common in the melanoma patient group vs. the control (28.8% vs. 39.6%; p = 0.06). Significant was the stage of the melanoma in order to predict the survivability (p = 0.008). The 1/1 and 1/2 genotype appeared to have lower hazards ratios than the 2/2 genotype (p > 0.05). CONCLUSIONS: Compared to the general population, the distribution of alleles coding for IL-1RA is different in melanoma patients. This alteration and the potential impact on tumor protein function and systemic inflammatory response may warrant further investigation.

Leptin Is Produced by Parathyroid Glands and Stimulates Parathyroid Hormone Secretion.

OBJECTIVE: We asked if leptin and its cognate receptor were present in normal and diseased parathyroid glands, and if so, whether they had any functional effects on parathyroid hormone (PTH) secretion in parathyroid neoplasms. BACKGROUND: The parathyroid glands acting through PTH play a critical role in the regulation of serum calcium. Based on leptin's recently discovered role in bone metabolism, we hypothesized these glands were the sites of a functional interaction between these 2 hormones. METHODS: From July 2010 to July 2011, 96 patients were enrolled in a prospective study of leptin and hyperparathyroidism, all of whom were enrolled based on their diagnosis of hyperparathyroidism, and their candidacy for surgical intervention provided informed consent. Immediately after parathyroidectomy, 100 to 300 mg of adenomatous or hyperplastic diseased parathyroid tissue was prepared and processed according to requirements of the following: in situ hybridization, immunohistochemistry, immunofluorescence by conventional and spinning disc confocal microscopy, electron microscopy, parathyroid culture, whole organ explant, and animal model assays. RESULTS: Leptin, leptin receptor (long isoform), and PTH mRNA transcripts and protein were detected in an overlapping fashion in parathyroid chief cells in adenoma and hyperplastic glands, and also in normal parathyroid by in situ hybridization, qRT-PCR, and immunohistochemistry. Confocal microscopy confirmed active exogenous leptin uptake in cultured parathyroid cells. PTH secretion in explants increased in response to leptin and decreased with leptin receptor signaling inhibition by AG490, a JAK2/STAT3 inhibitor. Ob/ob mice injected with mouse leptin exhibited increased PTH levels from baseline. CONCLUSIONS: Taken together, these data suggest that leptin is a functionally active product of the parathyroid glands and stimulates PTH release.

Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cells.

Heterogeneity of tumor cells and their microenvironment can affect outcome in cancer. Blockade of immune checkpoints (ICPs) expressed only on a subset of immune cells leads to durable responses in advanced melanoma. Tissue-resident memory T (TRM) cells have recently emerged as a distinct subset of memory T cells in nonlymphoid tissues. Here, we show that functional properties and expression of ICPs within tumor-infiltrating lymphocytes (TILs) differ from those of blood T cells. TILs secrete less IL-2, IFN-γ, and TNF-α compared with circulating counterparts, and expression of VEGF correlated with reduced TIL infiltration. Within tumors, ICPs are particularly enriched within T cells with phenotype and genomic features of TRM cells and the CD16+ subset of myeloid cells. Concurrent T cell receptor (TCR) and tumor exome sequencing of individual metastases in the same patient revealed that interlesional diversity of TCRs exceeded differences in mutation/neoantigen load in tumor cells. These findings suggest that the TRM subset of TILs may be the major target of ICP blockade and illustrate interlesional diversity of tissue-resident TCRs within individual metastases, which did not equilibrate between metastases and may differentially affect the outcome of immune therapy at each site.