Apocrine Hidrocystoma of the Nail: A Unique Case.

ABSTRACT: Apocrine hidrocystomas are benign, cystic neoplastic lesions resulting from the apocrine secretory component of the sweat gland. They most commonly occur on the head and neck, with predilection to the periorbital area. Less frequent sites include the axilla, nipple, external auditory canal, foreskin, conjunctiva, lower lip, and fingers, among others. The authors report a unique case of a nail bed hidrocystoma in a 55-year-old woman, a site not previously described.

Detection of Antiviral Tissue Responses and Increased Cell Stress in the Pancreatic Islets of Newly Diagnosed Type 1 Diabetes Patients: Results From the DiViD Study.

Aims/hypothesis: The Diabetes Virus Detection (DiViD) study has suggested the presence of low-grade enteroviral infection in pancreatic tissue collected from six of six live adult patients newly diagnosed with type 1 diabetes. The present study aimed to compare the gene and protein expression of selected virally induced pathogen recognition receptors and interferon stimulated genes in islets from these newly diagnosed type 1 diabetes (DiViD) subjects vs age-matched non-diabetic (ND) controls. Methods: RNA was extracted from laser-captured islets and Affymetrix Human Gene 2.0 ST arrays used to obtain gene expression profiles. Lists of differentially expressed genes were subjected to a data-mining pipeline searching for enrichment of canonical pathways, KEGG pathways, Gene Ontologies, transcription factor binding sites and other upstream regulators. In addition, the presence and localisation of specific viral response proteins (PKR, MxA and MDA5) were examined by combined immunofluorescent labelling in sections of pancreatic tissue. Results: The data analysis and data mining process revealed a significant enrichment of gene ontologies covering viral reproduction and infectious cycles; peptide translation, elongation and initiation, as well as oxidoreductase activity. Enrichment was identified in the KEGG pathways for oxidative phosphorylation; ribosomal and metabolic activity; antigen processing and presentation and in canonical pathways for mitochondrial dysfunction, oxidative phosphorylation and EIF2 signaling. Protein Kinase R (PKR) expression did not differ between newly diagnosed type 1 diabetes and ND islets at the level of total RNA, but a small subset of ß-cells displayed markedly increased PKR protein levels. These PKR+ ß-cells correspond to those previously shown to contain the viral protein, VP1. RNA encoding MDA5 was increased significantly in newly diagnosed type 1 diabetes islets, and immunostaining of MDA5 protein was seen in α- and certain ß-cells in both newly diagnosed type 1 diabetes and ND islets, but the expression was increased in ß-cells in type 1 diabetes. In addition, an uncharacterised subset of synaptophysin positive, but islet hormone negative, cells expressed intense MDA5 staining and these were more prevalent in DiViD cases. MxA RNA was upregulated in newly diagnosed type 1 diabetes vs ND islets and MxA protein was detected exclusively in newly diagnosed type 1 diabetes ß-cells. Conclusion/interpretation: The gene expression signatures reveal that pathways associated with cellular stress and increased immunological activity are enhanced in islets from newly diagnosed type 1 diabetes patients compared to controls. The increases in viral response proteins seen in ß-cells in newly diagnosed type 1 diabetes provide clear evidence for the activation of IFN signalling pathways. As such, these data strengthen the hypothesis that an enteroviral infection of islet ß-cells contributes to the pathogenesis of type 1 diabetes.

Single-fraction high-dose palliative radiotherapy for facial cutaneous squamous cell carcinoma: a case report.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is a common malignancy affecting the skin, and its incidence increases with age; as such, it disproportionately affects the elderly. It is especially difficult to treat advanced skin cancers in elderly patients with dementia, who may not tolerate radiotherapy. CASE DESCRIPTION: A 100-year-old woman with advanced dementia was referred to dermatology for a large cSCC involving the nasal bridge and abutting the bilateral orbits. She was initially deemed a poor candidate for surgical resection, but over time the tumor grew and became increasingly destructive. Due to tumor growth causing symptoms and threatening vision, her family requested treatment. The patient was therefore referred to radiation oncology, and she received palliative radiation, using a single fraction of 16 gray (Gy) via a single electron field. Within 3 months, she had a clinical complete response, with no residual tumor and no persistent side effects from radiotherapy (RT). Ongoing follow-up revealed durable treatment response with no bothersome late toxicity. CONCLUSIONS: Single-fraction palliative radiotherapy is a suitable treatment option for durable palliation in elderly patients unable to undergo surgery and unable to tolerate conventional, fractionated RT in cases of symptomatic or rapidly-progressing non-melanoma skin cancers (NMSC). It is well-tolerated in frail patients or those with dementia.

Surgical delays of less than 1 year in Mohs surgery associated with tumor growth in moderately- and poorly-differentiated squamous cell carcinomas but not lower-grade squamous cell carcinomas or basal cell carcinomas: A retrospective analysis.

BACKGROUND: Evidence is controversial and limited concerning whether surgical delays are associated with tumor growth for cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas. OBJECTIVE: Identify tumor subpopulations that may demonstrate an association between tumor growth and surgical delay. METHODS: We retrospectively analyzed 299 SCCs and 802 basal cell carcinomas treated with Mohs surgery at a single institution. Time interval from biopsy to surgery represented surgical delay. Change in major diameter (ΔMD) from size at biopsy to postoperative defect represented tumor growth. Independent predictors of ΔMD were identified by multivariate analysis. Linear regression was then utilized to assess for whether the ΔMD from these independent predictors trended with surgical delay. RESULTS: Surgical delays ranged from 0 to 331 days. Among SCCs, histologic subtype and prior treatment were identified as independent predictors of ΔMD. Significant associations between ΔMD and surgical delay were found for poorly- and moderately-differentiated SCCs, demonstrating growth rates of 0.28 cm and 0.24 cm per month of delay, respectively. The ΔMD for SCCs with prior treatment and basal cell carcinoma subgroups did not vary with surgical delay. LIMITATIONS: Retrospective design, single center. CONCLUSION: Surgical delays of less than a year were associated with tumor growth for higher-grade SCCs, with effect sizes bearing potential for clinical significance.

Investigation of the utility of the 1.1B4 cell as a model human beta cell line for study of persistent enteroviral infection.

The generation of a human pancreatic beta cell line which reproduces the responses seen in primary beta cells, but is amenable to propagation in culture, has long been an important goal in diabetes research. This is particularly true for studies focussing on the role of enteroviral infection as a potential cause of beta-cell autoimmunity in type 1 diabetes. In the present work we made use of a clonal beta cell line (1.1B4) available from the European Collection of Authenticated Cell Cultures, which had been generated by the fusion of primary human beta-cells with a pancreatic ductal carcinoma cell, PANC-1. Our goal was to study the factors allowing the development and persistence of a chronic enteroviral infection in human beta-cells. Since PANC-1 cells have been reported to support persistent enteroviral infection, the hybrid 1.1B4 cells appeared to offer an ideal vehicle for our studies. In support of this, infection of the cells with a Coxsackie virus isolated originally from the pancreas of a child with type 1 diabetes, CVB4.E2, at a low multiplicity of infection, resulted in the development of a state of persistent infection. Investigation of the molecular mechanisms suggested that this response was facilitated by a number of unexpected outcomes including an apparent failure of the cells to up-regulate certain anti-viral response gene products in response to interferons. However, more detailed exploration revealed that this lack of response was restricted to molecular targets that were either activated by, or detected with, human-selective reagents. By contrast, and to our surprise, the cells were much more responsive to rodent-selective reagents. Using multiple approaches, we then established that populations of 1.1B4 cells are not homogeneous but that they contain a mixture of rodent and human cells. This was true both of our own cell stocks and those held by the European Collection of Authenticated Cell Cultures. In view of this unexpected finding, we developed a strategy to harvest, isolate and expand single cell clones from the heterogeneous population, which allowed us to establish colonies of 1.1B4 cells that were uniquely human (h1.1.B4). However, extensive analysis of the gene expression profiles, immunoreactive insulin content, regulated secretory pathways and the electrophysiological properties of these cells demonstrated that they did not retain the principal characteristics expected of human beta cells. Our data suggest that stocks of 1.1B4 cells should be evaluated carefully prior to their use as a model human beta-cell since they may not retain the phenotype expected of human beta-cells.

Malignant Gastrointestinal Neuroectodermal Tumor (GNET) with Prolonged Disease-Free Survival after Platinum-Based Chemotherapy.

Malignant gastrointestinal neuroectodermal tumor (GNET) is a rare disease with a handful of cases described in literature. GNET has only become a well-known/widely accepted entity in the recent years, but it is still not listed in the database of rare diseases. Due to the rarity of disease, there are no guidelines on standard therapeutic approaches in the adjuvant or metastatic setting. Here, we describe a unique case of GNET with a 7-year disease-free survival following adjuvant cisplatin and etoposide chemotherapy. This is the longest disease-free survival that has ever been described in literature and may support using this combination in a larger cohort of patients in the context of a global clinical trial. We will also review the histopathologic features of GNET and potential therapeutic options in the metastatic setting.

A Predictive Model for Primary Closure Lengths in Mohs Surgery Based on Skin Cancer Type, Dimensions, and Location.

BACKGROUND: Surgical scar length is a common concern among patients undergoing Mohs micrographic surgery (MMS). OBJECTIVE: This study evaluates 3 metrics of preoperative lesion size to determine which correlates best with primary linear closure lengths for nonmelanoma skin cancers (NMSCs) treated with MMS. This metric is then used to develop predictive models for linear closure lengths in 10 different anatomical regions. MATERIALS AND METHODS: A retrospective study of 4,049 NMSCs treated with MMS and repaired with primary linear closure was conducted. Primary closure lengths were plotted against preoperative lesion circumference, area, and short axis length. Linear regression analysis was performed. RESULTS: Preoperative NMSC circumference correlated best with closure length. Twenty-one of the 28 regression models had coefficients of determination (R) above 0.5. Closure lengths increased by 0.52 to 1.1 mm, depending on location, for every millimeter increase in preoperative NMSC circumference. CONCLUSION: Preoperative lesion circumference is directly proportional to primary closure length and is a better indicator of closure length than preoperative area and short axis for MMS of NMSCs. Closure lengths located on the nasal tip, supratip, or periocular areas are most sensitive to differences in NMSC size. These data might aid Mohs surgeons with preoperative planning for wound reconstruction and patient counseling.

The transcription factor STAT6 plays a critical role in promoting beta cell viability and is depleted in islets of individuals with type 1 diabetes.

AIMS/HYPOTHESIS: In type 1 diabetes, selective beta cell loss occurs within the inflamed milieu of insulitic islets. This milieu is generated via the enhanced secretion of proinflammatory cytokines and by the loss of anti-inflammatory molecules such as IL-4 and IL-13. While the actions of proinflammatory cytokines have been well-studied in beta cells, the effects of their anti-inflammatory counterparts have received relatively little attention and we have addressed this. METHODS: Clonal beta cells, isolated human islets and pancreas sections from control individuals and those with type 1 diabetes were employed. Gene expression was measured using targeted gene arrays and by quantitative RT-PCR. Protein expression was monitored in cell extracts by western blotting and in tissue sections by immunocytochemistry. Target proteins were knocked down selectively with interference RNA. RESULTS: Cytoprotection achieved with IL-4 and IL-13 is mediated by the early activation of signal transducer and activator of transcription 6 (STAT6) in beta cells, leading to the upregulation of anti-apoptotic proteins, including myeloid leukaemia-1 (MCL-1) and B cell lymphoma-extra large (BCLXL). We also report the induction of signal regulatory protein-α (SIRPα), and find that knockdown of SIRPα is associated with reduced beta cell viability. These anti-apoptotic proteins and their attendant cytoprotective effects are lost following siRNA-mediated knockdown of STAT6 in beta cells. Importantly, analysis of human pancreas sections revealed that STAT6 is markedly depleted in the beta cells of individuals with type 1 diabetes, implying the loss of cytoprotective responses. CONCLUSIONS/INTERPRETATION: Selective loss of STAT6 may contribute to beta cell demise during the progression of type 1 diabetes.

Unexpected subcellular distribution of a specific isoform of the Coxsackie and adenovirus receptor, CAR-SIV, in human pancreatic beta cells.

AIMS/HYPOTHESIS: The Coxsackie and adenovirus receptor (CAR) is a transmembrane cell-adhesion protein that serves as an entry receptor for enteroviruses and may be essential for their ability to infect cells. Since enteroviral infection of beta cells has been implicated as a factor that could contribute to the development of type 1 diabetes, it is often assumed that CAR is displayed on the surface of human beta cells. However, CAR exists as multiple isoforms and it is not known whether all isoforms subserve similar physiological functions. In the present study, we have determined the profile of CAR isoforms present in human beta cells and monitored the subcellular localisation of the principal isoform within the cells. METHODS: Formalin-fixed, paraffin-embedded pancreatic sections from non-diabetic individuals and those with type 1 diabetes were studied. Immunohistochemistry, confocal immunofluorescence, electron microscopy and western blotting with isoform-specific antisera were employed to examine the expression and cellular localisation of the five known CAR isoforms. Isoform-specific qRT-PCR and RNA sequencing (RNAseq) were performed on RNA extracted from isolated human islets. RESULTS: An isoform of CAR with a terminal SIV motif and a unique PDZ-binding domain was expressed at high levels in human beta cells at the protein level. A second isoform, CAR-TVV, was also present. Both forms were readily detected by qRT-PCR and RNAseq analysis in isolated human islets. Immunocytochemical studies indicated that CAR-SIV was the principal isoform in islets and was localised mainly within the cytoplasm of beta cells, rather than at the plasma membrane. Within the cells it displayed a punctate pattern of immunolabelling, consistent with its retention within a specific membrane-bound compartment. Co-immunofluorescence analysis revealed significant co-localisation of CAR-SIV with zinc transporter protein 8 (ZnT8), prohormone convertase 1/3 (PC1/3) and insulin, but not proinsulin. This suggests that CAR-SIV may be resident mainly in the membranes of insulin secretory granules. Immunogold labelling and electron microscopic analysis confirmed that CAR-SIV was localised to dense-core (insulin) secretory granules in human islets, whereas no immunolabelling of the protein was detected on the secretory granules of adjacent exocrine cells. Importantly, CAR-SIV was also found to co-localise with protein interacting with C-kinase 1 (PICK1), a protein recently demonstrated to play a role in insulin granule maturation and trafficking. CONCLUSIONS/INTERPRETATION: The SIV isoform of CAR is abundant in human beta cells and is localised mainly to insulin secretory granules, implying that it may be involved in granule trafficking and maturation. We propose that this subcellular localisation of CAR-SIV contributes to the unique sensitivity of human beta cells to enteroviral infection.

Auricular Hemosiderosis in a Diabetic Patient.

A 74-year-old Caucasian man with poorly controlled diabetes and hypertension was seen in the dermatology clinic for treatment of a nodular basal cell carcinoma on his right temple. He had poorly controlled diabetes for decades and had been insulin dependent for 20 to 25 years. He had not been on any anticoagulation therapy in the past or present and had no history of a hematologic disorder. He was retired and did woodworking as a hobby. During a routine presurgical head and neck skin examination, he was noted to have macular bluegray dyspigmentation of the central portion of the anterior portion of his ear lobes, bilaterally (Figure 1). He had first noticed this color change approximately 2 years ago and thought the pigmentation was darkening. It was not symptomatic. A punch biopsy was obtained.

Aggressive Skin Cancers Occurring in Patients Treated With the Janus Kinase Inhibitor Ruxolitinib.

The Food and Drug Administration approved Ruxolitinib in 2011 for the treatment of primary myelofibrosis. Five-year safety data showed a higher incidence of skin cancer in patients treated with Ruxolitinib compared to best available therapy for myelofibrosis. This report presents a series of five patients with history of myelofibrosis treated with Ruxolitinib who subsequently developed numerous skin cancers with aggressive biological behavior. Each patient in this report was treated by a Mohs surgeon affiliated with an academic institution. All patients had a history of myelofibrosis and were exposed to Ruxolitinib. Some patients were exposed to other immunomodulatory medications such as Hydroxyurea and Rituximab. The total number of skin cancers and skin cancers with particularly aggressive behavior were noted. All five patients in this series developed numerous skin cancers with aggressive biological behavior during or after therapy with Ruxolitinib. Also, one patient developed lentigo maligna melanoma and another developed metastatic undifferentiated pleomorphic sarcoma. The repeat observation of skin cancers with aggressive features during JAK inhibitor treatment suggests that these medications may promote cutaneous malignant transformation in at risk patients. Further surveillance and testing of JAK kinases regarding the risk of skin cancers is indicated.

J Drugs Dermatol. 2017;16(5):508-511.

Basal Cell Carcinoma Arising in a Breast Augmentation Scar.

We report a case of a 46-year-old female who presented with a persistent lesion on the inferior right breast. The lesion was located within the scar from a breast augmentation procedure 12 years ago. The lesion had been treated as several conditions with no improvement. Biopsy revealed a superficial and nodular basal cell carcinoma, and the lesion was successfully removed with Mohs micrographic surgery. Basal cell carcinoma arising in a surgical scar is exceedingly rare with only 13 reported cases to date. This is the first reported case of basal cell carcinoma arising in a breast augmentation scar. We emphasize the importance of biopsy for suspicious lesions or those refractory to treatment, particularly those lesions that form within a scar. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The subcellular distribution of cyclin-D1 and cyclin-D3 within human islet cells varies according to the status of the pancreas donor.

AIMS/HYPOTHESIS: In humans, the rate of beta cell proliferation declines rapidly during the postnatal period and remains low throughout adult life. Recent studies suggest that this may reflect the distribution of cell cycle regulators which, unusually, are located in the cytosolic compartment of beta cells in islets isolated from adults. In the present work, we examined whether the localisation of cyclin-D molecules is also cytosolic in the islet cells of pancreatic samples studied in situ. METHODS: Immunohistochemical approaches were employed to examine the subcellular localisation of cyclin-D1, -D2 and -D3 in human pancreatic samples recovered either from heart-beating donors or post mortem. Immunofluorescence methods were used to reveal the cellular localisation of cyclin-D1 and -D3. RESULTS: The distribution of cyclin-D2 was invariably cytosolic in islet cells, whereas the localisation of cyclin-D1 and -D3 varied according to the status of the donor. In pancreatic sections from heart-beating donors these molecules were primarily nuclear. By contrast, in samples collected post mortem, they were mainly cytosolic. Cyclin-D1 was detected only in beta cells whereas cyclin-D3 was detected in both alpha and beta cells. The proportion of donors who were immunopositive for cyclin-D1 declined from 71% in controls to 30% in those with type 1 diabetes. Cyclin-D3 was present in the islets of the majority of donors in both groups. CONCLUSIONS/INTERPRETATION: The subcellular localisation of cyclin-D molecules varies according to the status of the donor. Both cyclin-D1 and -D3 can be found in the nuclei of human islet cells in situ.