Dual self-regulated delivery of insulin and glucagon by a hybrid patch.

Reduced ß-cell function and insulin deficiency are hallmarks of diabetes mellitus, which is often accompanied by the malfunction of glucagon-secreting α-cells. While insulin therapy has been developed to treat insulin deficiency, the on-demand supplementation of glucagon for acute hypoglycemia treatment remains inadequate. Here, we describe a transdermal patch that mimics the inherent counterregulatory effects of ß-cells and α-cells for blood glucose management by dynamically releasing insulin or glucagon. The two modules share a copolymerized matrix but comprise different ratios of the key monomers to be "dually responsive" to both hyper- and hypoglycemic conditions. In a type 1 diabetic mouse model, the hybrid patch effectively controls hyperglycemia while minimizing the occurrence of hypoglycemia in the setting of insulin therapy with simulated delayed meal or insulin overdose.

Preferentially Expressed Antigen in Melanoma Immunostaining in a Series of Melanocytic Neoplasms.

ABSTRACT: In their 2018 article, Lezcano et al [AJSP 2018(11):1456] show that diffuse tumor cell nuclear reactivity for Preferentially expressed Antigen in Melanoma (PRAME) is a feature of melanoma and that benign and atypical melanocytic tumors are PRAME negative or show only focal positivity for PRAME. We report our observations of PRAME staining in 253 melanocytic tumors. Tumors were classified by hematoxylin and eosin sections. The nuclear PRAME staining of neoplastic melanocytes in each case was categorized as absent, focally present, or diffusely present. The results were compared with those of Lezcano et al 105 of 134 (78%) melanocytic nevi were completely PRAME negative. Of the 29 PRAME-positive benign lesions, 28 exhibited focal but not diffuse positivity, including atypical (n = 11) and dysplastic nevi (n = 11). One of 11 Spitz nevi showed diffuse positivity (9%). Thirty-nine of 51 (76%) invasive melanomas, 41 of 50 (82%) melanoma in situ, and 15 of 18 (83%) metastatic melanomas were diffusely PRAME positive. Excluding desmoplastic melanomas, 39 of 49 (80%) primary melanomas were diffusely PRAME positive. Our findings of PRAME staining in melanocytic neoplasia are in general agreement with those of Lezcano et al. Diffuse PRAME reactivity in neoplastic melanocytes is a feature of malignancy and was only otherwise seen in 1 Spitz nevus. Caution is advised in interpretation of PRAME reactivity in melanocytic tumors of uncertain classification because melanoma arising in association with nevus and some atypical melanocytic tumors may show focal or incomplete PRAME staining. Routine histopathological findings, clinical information, PRAME staining, and judicious application of molecular studies are steps leading to accurate classification of melanocytic neoplasia.

DNA copy number changes correlate with clinical behavior in melanocytic neoplasms: proposal of an algorithmic approach.

Increasingly, molecular methods are being utilized in the workup of melanocytic neoplasms. To this end, we sought to correlate data from a single nucleotide polymorphism (SNP) array platform based on molecular inversion probes with clinical data. Copy number variation (CNV) data were obtained on 95 melanocytic tumors (6 ordinary nevi, 15 atypical nevi, 34 ambiguous neoplasms, and 40 melanomas) from 92 patients. The average number of significant CNVs was 0 for nevi, 0.6 for atypical nevi (range 0-3), 2.8 for ambiguous neoplasms (range 0-17), and 18.1 for melanomas (range 0-69). Clinical follow-up data were available in 57 of 95 lesions (56 of 92 patients). Tumors from patients with adverse events demonstrated an average number of CNVs of 24.5 (range 6-69) as compared with 7.9 (range 0-35) among tumors without an associated adverse event (p ≤ 0.001). No adverse events were observed in nevi including atypical nevi. Adverse events were found in 2 of 19 ambiguous neoplasms and 10 of 32 melanomas with follow up. In these two latter groups of neoplasms, the correlation between adverse events and the average number of CNVs remained statistically significant even when controlled for Breslow depth (21.5 versus 8.7, p value = 0.036). No neoplasm with adverse events had ≤3 CNVs. These results provide further evidence that SNP array testing for CNVs may be helpful in the classification and prognostication of ambiguous neoplasms. Based on these results, an algorithmic approach to challenging melanocytic neoplasms using CNV data is suggested, using as cutoff of >3 CNVs with some caveats, as the threshold for a positive result. Future clinical validation, using a larger cohort of relevant tumors, will be necessary.

Metastatic spiradenocarcinoma occurring in an 8-year-old boy.

We recently saw the case of an 8-year-old boy with histologic findings of spiradenocarcinoma. Malignant adnexal tumors in children are exceedingly rare, and cases of spiradenocarcinoma in children are absent in the literature. We report the case of an 8-year-old boy with metastatic spiradenocarcinoma. A biopsy 2 years before his presentation at our institution was interpreted as a benign lesion, but when the lesion regrew, a repeat biopsy was performed that demonstrated ominous findings, prompting a reexcision. This reexcision demonstrated an area with significant necrosis, many mitoses, and cellular pleomorphism apparently arising out of a sharply demarcated, adjacent, lower-grade area. The histologic features of this patient's biopsies were those of spiradenocarcinoma, potentially arising out of a preexisting spiradenoma, a finding that has not been documented previously in this age group. Staging studies demonstrated multiple bilateral pulmonary nodules, which were confirmed using thoracoscopic biopsy to be metastatic disease. His chemotherapy regimen has included several cycles of cisplatin and 5-flourouracil, with ongoing disease progression of pulmonary disease. It has been 16 months since he presented to our institution (>3 years since the appearance of his initial lesion). Imaging studies demonstrate a slowly increasing size and number of pulmonary lesions. The long-term prognosis is guarded.

Region of Interest Detection in Melanocytic Skin Tumor Whole Slide Images - Nevus & Melanoma.

Automated region of interest detection in histopathological image analysis is a challenging and important topic with tremendous potential impact on clinical practice. The deep-learning methods used in computational pathology may help us to reduce costs and increase the speed and accuracy of cancer diagnosis. We started with the UNC Melanocytic Tumor Dataset cohort that contains 160 hematoxylin and eosin whole-slide images of primary melanomas (86) and nevi (74). We randomly assigned 80% (134) as a training set and built an in-house deep-learning method to allow for classification, at the slide level, of nevi and melanomas. The proposed method performed well on the other 20% (26) test dataset; the accuracy of the slide classification task was 92.3% and our model also performed well in terms of predicting the region of interest annotated by the pathologists, showing excellent performance of our model on melanocytic skin tumors. Even though we tested the experiments on the skin tumor dataset, our work could also be extended to other medical image detection problems to benefit the clinical evaluation and diagnosis of different tumors.

Standardized Protocols for Clinical and Histopathological Characterization of Hidradenitis Suppurativa Tissue Specimens.

Methods for describing and reporting the clinical and histological characteristics of cutaneous tissue samples from patients with hidradenitis suppurativa (HS) are not currently standardized, limiting clinicians' and scientists' ability to uniformly record, report, and communicate about the characteristics of tissue used in translational experiments. A recently published consensus statement outlined morphological definitions of typical HS lesions, but no consensus has been reached regarding clinical characterization and examination of HS tissue samples. Here we aimed to establish a protocol for reporting histopathologic and clinical characteristics of HS tissue specimens. This study was conducted from May 2023 to August 2023. Experts in clinical care, dermatopathology, and translational research were recruited, and a modified Delphi technique was used to develop a protocol for histologic reporting and clinical characterization of submitted tissue specimens from HS patients. A total of 27 experts participated (14 dermatologists, 3 fellowship-trained dermatopathologists, 3 plastic surgeons, 3 general surgeons, and 4 research scientists) in creating and reviewing protocols for the clinical and histopathological examination of HS tissue specimens. The protocols were formatted as a synoptic report and will help consistently classify specimens in biobanks based on histological features and more accurately report and select samples used in translational research projects.

Molecular testing of borderline cutaneous melanocytic lesions: SNP array is more sensitive and specific than FISH.

Melanocytic lesions with borderline features are diagnostically challenging. Single-nucleotide polymorphism (SNP) arrays, which detect genomic copy number alterations (CNAs), can be helpful in distinguishing between nevi and melanoma. Fluorescence in situ hybridization (FISH) has been used as a more rapid, less expensive alternative to SNP array, using a panel of probes that are often gained or lost in melanoma. We used SNP array data from 63 borderline cutaneous melanocytic lesions and 44 definitive melanomas to predict the performance of FISH testing. Lesions were considered positive by "virtual FISH" if 1 or more of the 5 FISH-probed loci demonstrated appropriate CNAs by SNP array. Cases were classified as positive by SNP array if ≥3 CNAs were present, based on internal validation studies, or if FISH criteria were met. Conventional FISH was performed in 33 cases (17 borderline lesions, 16 melanomas). Of the 63 borderline cases, 44 (70%) were positive by SNP array and 30 (48%) were positive by virtual FISH. A higher proportion of melanomas were positive by SNP array (41/44, 93% sensitivity) and virtual FISH (36/44, 82% sensitivity). Virtual FISH had 61% sensitivity in the borderline group using SNP array as the gold standard, whereas specificity was 84%. There was good correlation between conventional and virtual FISH, with agreement in 30 of 33 (91%) cases. Although FISH is highly effective in distinguishing between nevi and melanoma in cases where the histological diagnosis is straightforward, it is not nearly as sensitive or specific as SNP array when applied to borderline lesions.

Cutaneous meningioma.

Cutaneous meningioma is a rare tumor that most commonly occurs on the scalp and occurs in both congenital and acquired forms. It invokes a wide clinical differential diagnosis, but diagnosis is based on characteristic histologic and cytologic findings. Congenital lesions can often present years after birth and even in adult patients. Acquired lesions occur in adulthood. We review histologic, cytologic, and electron microscopic findings and explore how these are used to separate this entity from other entities in the differential diagnosis. While ultrastructural and cytologic findings are similar to those of more common intracranial meningiomas, these tumors exhibit a range of histologic differences. A lack of awareness of this entity precludes correct diagnosis.

Practical issues for frozen section diagnosis in gastrointestinal and liver diseases.

Surgeons frequently utilize frozen sections as a tool to gain information intraoperatively. The use of frozen sections has certain benefits as well as limitations which vary according to the situation. After reviewing the available literature we provide the reader with an idea of when and how to use frozen sections in common situations involving the gastrointestinal tract and liver as well as address the benefits and limitations in each setting.