Human Epidermal Growth Factor Receptor 2 Overexpression/Amplification in Primary Ovarian Endometrioid Carcinoma.

Human epidermal growth factor receptor 2 (HER2) expression has become increasingly helpful in predicting responses to anti-HER2 agents in gynecological cancers. This study retrospectively analyzed HER2 expression in 48 primary ovarian endometrioid carcinomas. HER2 immunohistochemistry was performed using the Ventana platform (Clone 4B5 monoclonal predilute) following the manufacturer's protocol. HER2 expression was equivocal (score 2+) by image analysis in 2 cases (4.17%) based on the breast cancer criteria. Fluorescence in situ hybridization was negative for HER2amplification in one case (International Federation of Gynecology and Obstetrics, grade 1) and positive in the other (International Federation of Gynecology and Obstetrics, grade 3). Our findings contribute to the growing evidence that HER2 is overexpressed in a small proportion of ovarian endometrioid carcinoma, and thus may serve as a potential therapeutic target in selected cases.

TRPS1 Is Differentially Expressed in a Variety of Malignant and Benign Cutaneous Sweat Gland Neoplasms.

Neoplasms of sweat glands and the breast may be morphologically and immunophenotypically similar. A recent study showed that TRPS1 staining is a highly sensitive and specific marker for breast carcinoma. In this study, we analyzed TRPS1 expression in a spectrum of cutaneous sweat gland tumors. We stained five microcystic adnexal carcinomas (MACs), three eccrine adenocarcinomas, two syringoid eccrine carcinomas, four hidradenocarcinomas, six porocarcinomas, one eccrine carcinoma-NOS, 11 hidradenomas, nine poromas, seven cylindromas, three spiradenomas, and 10 syringomas with TRPS1 antibodies. All of the MACs and syringomas were negative. Every cylindroma and two of the three spiradenomas demonstrated intense staining in cells lining the ductular spaces, with negative to relatively weak expression in surrounding cells. Of the 16 remaining malignant entities, 13 were intermediate to high positive, one was low positive, and two were negative. From the 20 hidradenomas and poromas, intermediate to high positivity was revealed in 14 cases, low positivity in three cases, and negative staining in three cases. Our study demonstrates a very high (86%) expression of TRPS1 in malignant and benign adnexal tumors that are mainly composed of islands or nodules with polygonal cells, e.g., hidradenomas. On the other hand, tumors with small ducts or strands of cells, such as MACs, appear to be completely negative. This differential staining among types of sweat gland tumors may represent either differential cells of origin or divergent differentiation and has the potential to be used as a diagnostic tool in the future.

Two distinct pathogenic pathways of digital papillary adenocarcinoma - BRAF mutation or low-risk HPV infection.

Digital papillary adenocarcinoma (DPA) is a rare neoplasm that can exhibit local recurrence and distant metastasis. We present a series of eight cases of DPA showing two distinct clinical presentations, morphologies, immunophenotypes, and molecular features. Four cases were characterized by painless, slow-growing nodules located on the digits. The lesions were small, well-defined, and confined in the dermis. Histopathologically, these tumors were composed of glandular structures lined by cuboidal epithelium with luminal papillary infoldings. Only rare mitotic figures and minimal squamoid differentiation were present, and cellular necrosis was absent. All four cases were positive for the BRAF V600E immunohistochemistry but negative for p16, low-risk and high-risk HPV in situ hybridization (ISH). In contrast, the remaining four cases were characterized by painful, rapidly growing masses on the digits. These four lesions were located in the deep dermis and consisted of a solid, tightly packed papillary architecture lined by atypical epithelioid cells with inconspicuous nucleoli. Cellular necrosis, numerous mitotic figures, and prominent squamoid differentiation were seen. All cases were negative for the BRAF V600E IHC. However, they showed strong, patchy to diffuse reactivity for p16 and were positive for low-risk HPV ISH and negative for high-risk HPV ISH. Our findings suggest that the current classification of DPA encompasses tumors that show two discrete pathogenic pathways - BRAF mutation or low-risk HPV infection. DPAs with low-risk HPV infection exhibit aggressive clinical features, high-grade morphology, marked squamoid differentiation, and wild-type BRAF. DPAs with BRAF V600E have less aggressive clinical features, low-grade morphologic findings, mild to absent squamoid differentiation, and negative HPV infection.

Multiply Recurrent Composite Hemangioendothelioma of Penis with Histologic Progression to High-Grade Features.

Composite hemangioendothelioma (CHE) is a very rare low-grade malignant vascular neoplasm. Here, we present the first case of it occurring on a penis with two local recurrences over a 9 year span and its progression to a high-grade morphology.

Claudin-4 Upregulation in Acantholytic and Autoimmune-Mediated Bullous Disorders.

Claudin-4 is a key component of tight junctions, which play an important role in the formation of the epidermal barrier by forming a circumferential network in the granular layer that serves as a gatekeeper of the paracellular pathway. The aim of this study is to illustrate claudin-4 immunohistochemical staining patterns of different blistering disorders. We collected 35 cases, including two Hailey-Hailey disease, one Darier disease, three Grover disease, one acantholytic acanthoma, two warty dyskeratoma, 11 pemphigus vulgaris (PV) including six mucosal PV, and two pemphigus foliaceus. For comparison, we included five cases of normal skin, five eczema, and three bullous pemphigoid cases. Claudin-4 demonstrated weak-to-moderate expression in keratinocytes located in the stratum granulosum, keratinocytes surrounding hair follicles, and adnexal glands. Further, claudin-4 exhibited moderate-to-strong membranous staining in disrupted keratinocytes surrounding and within the acantholytic and bullous areas in 16/22 of the acantholytic cases (not seen in the six cases of mucosal PV) and all three bullous pemphigoids. This finding suggests that claudin-4 is upregulated in these conditions, which may be a compensatory response to the disrupted barrier function. This finding could shed light on the molecular mechanisms underlying disrupted barrier function in blistering disorders, independent of the specific underlying disease mechanism.

Primary mucoepidermoid carcinoma of the breast arising in adenomyoepithelioma.

Mucoepidermoid carcinoma (MEC) and adenomyoepithelioma (AME) are uncommon neoplasms of the breast that are more commonly noted in the salivary glands. AMEs are benign tumours that are known to undergo malignant transformation. This report describes the first case of a MEC arising in AME in a woman in her 50s.

A Case of Digital Cutaneous Melanocytic Tumor With CRTC1::TRIM11 Fusion.

A cutaneous melanocytic tumor with CRTC1::TRIM11 fusion (CMTCT) was recently described as a novel superficial tumor with melanocytic differentiation and harboring a unique in-frame translocation, CRTC1::TRIM11. This emerging entity can occur at any age and is known to be a low-grade malignant neoplasm with limited follow-up data. There are no available guidelines for the management and treatment of this tumor. This neoplasm has been found in the extremities, head and neck, and trunk. Here, we present the first case occurring on acral digital skin. This case contributes to the growing knowledge surrounding this newly described entity.

Pseudomyogenic Hemangioendothelioma: A Case of a Solitary Lesion With a Very Indolent Clinical Course.

Pseudomyogenic hemangioendothelioma (PMH), also known as epithelioid sarcoma-like hemangioendothelioma, is a rare epithelioid vascular neoplasm predominantly affecting young adult males at an average age of approximately 30 years. This tumor is rare; therefore, detailed information regarding this tumor is still lacking. Here, we report a case of a man in his 20s presenting with left foot pain for about one year. Imaging showed a 2-cm ovoid, cortically based lesion with a lytic defect of the cortex at the fifth metatarsal proximal shaft. Histologically, the lesion presented as an infiltrating proliferation of distinctly myoid-appearing spindled cells with eosinophilic cytoplasm and mildly atypical vesicular nuclei. Scant mitoses were identified with no areas of necrosis. Tumor cells exhibited strong, diffuse cytokeratin expression as well as CD31 and ERG. CD34 was positive in a few tumor cells, and integrase interactor 1 (INI1) retained nuclear expression. No reactivity for S100, desmin, smooth muscle actin (SMA), epithelial membrane antigen (EMA), and CD1a was present. Over half of the patients with PMH develop multifocal lesions, often involving several tissue planes; however, distant metastasis is very infrequent. This patient underwent curettage and internal fixation of the left fifth metatarsal and had no evidence of recurrence or distant metastasis after seven years of follow-up. Our case contributes to the growing knowledge of PMH and sheds light on the prognosis of these lesions.

Lack of PRAME Expression in Cutaneous T-Cell Lymphomas.

Cutaneous T-cell lymphomas (CTCLs) are rare tumors with no established markers that can reliably distinguish between benign and malignant lesions. Preferentially Expressed Antigen in Melanoma (PRAME) is a cancer/testis antigen that is found in many solid and hematologic malignancies. PRAME overexpression typically portends a poor prognosis and lower chemotherapeutic response. To date, no studies have established a role for PRAME in CTCL. An analysis was performed on 47 cases definitively diagnosed as CTCL: 25 cases of mycosis fungoides, 2 of Sezary syndrome, 5 of CD30+ lymphoproliferative disorder, 7 of primary cutaneous anaplastic large T-cell lymphoma, 3 of primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, 1 of subcutaneous panniculitis-like T-cell lymphoma, and 4 of angiocentric T-cell lymphoma. PRAME immunohistochemistry was completely negative in all cases. PRAME expression was not found in any CTCL subtypes, suggesting that the pathogenesis of CTCL is not mediated by PRAME. Further study is required to identify biomarkers that might aid in the diagnosis and prognostication of CTCLs.

Frequency of Alterations in Apheresis-Related Abstracts Prior to Publications as Peer-Reviewed Articles.

High-quality evidence supporting clinical practice is lacking in apheresis. A potential source of evidence is provided by abstracts submitted to the Annual Meetings of the American Association of Blood Banks (AABB) and the American Society for Apheresis (ASFA). However, there is potential for study conclusions to be altered significantly following abstract presentations prior to publications in peer-reviewed journals. Therefore, we evaluated the discordance rate between apheresis-related meeting abstracts and their corresponding published articles. Abstracts accepted to either AABB or ASFA Annual Meetings from 2005 to 2012 and corresponding PubMed-indexed peer-reviewed articles' abstracts published prior to 9/2014 were reviewed for altered methods, results, and conclusions. When present, changes were evaluated for clinical significance. During the 8-year period, 198 out of 1152 abstracts were published as peer-reviewed articles. Of these, 36 (18.2%) presented discordant results, six of which (16.7%) were potentially clinically significant. An alteration in results (58.3%) was the leading reason for discordance. The discordance rate for ASFA abstracts was significantly higher (HR = 4.69, P = 0.0028) than the AABB ones. However, clinically significant alterations occurred more frequently among AABB abstracts (P = 0.025). Approximately 18% of meeting abstracts demonstrated alterations prior to publication in peer-reviewed journals. Given that approximately one in six changes represented clinically significant alterations, potentially affecting clinical practice, we recommend caution when modifying one's clinical practice based on abstract presentations at Annual Meetings. Future studies involving abstracts from both the International Society for Apheresis and the World Apheresis Association should also be performed.

aPCC vs. rFVIIa for the treatment of bleeding in patients with acquired haemophilia - a cost-effectiveness model.

BACKGROUND: Acquired haemophilia A (AHA) is an autoimmune bleeding disorder with significant morbidity and mortality. Bleeding AHA patients with high titre inhibitors can be treated with either activated prothrombin complex concentrate (aPCC) or recombinant activated factor VII (rFVIIa). Given that both replacement therapies have inherent benefits and limitations, a cost-effectiveness analysis (CEA) was performed in this population to compare rFVIIa with aPCC. METHODS: In high-titered AHA patients with bleeding treated with either aPCC or rFVIIa, during a 5-day study period, a Markov model was developed such that these patients were transitioned into four different health states: (1) continuous bleeding, (2) thrombosis, (3) stop bleeding and (4) death, with states (2), (3) and (4) modelled as absorbing states. Model parameters, including probabilities, health utility index and costs, were gathered from the medical literature, except for the costs of aPCC and rFVIIa, which were obtained from our institutional data. RESULTS: During the 5-day period, the total treatment cost of rFVIIa was substantially more than the cost of aPCC ($13 635 vs. $1741). The average quality-adjusted life days (QALDs) gained for rFVIIa were slightly lower compared to aPCC (4·08 vs. 4·09). Overall, aPCC prevailed over rFVIIa. Sensitivity analysis confirmed the robustness of the model across tested ranges of all input variables. CONCLUSION: In high-titered AHA patients with bleeding, aPCC is a cost-effective treatment option when compared to rFVIIa. Thus, aPCC may be considered in these patients, if available, and provided there is no clinical contraindication.

Characterising routes of H5N1 and H7N9 spread in China using Bayesian phylogeographical analysis.

Avian influenza H5N1 subtype has caused a global public health concern due to its high pathogenicity in poultry and high case fatality rates in humans. The recently emerged H7N9 is a growing pandemic risk due to its sustained high rates of human infections, and recently acquired high pathogenicity in poultry. Here, we used Bayesian phylogeography on 265 H5N1 and 371 H7N9 haemagglutinin sequences isolated from humans, animals and the environment, to identify and compare migration patterns and factors predictive of H5N1 and H7N9 diffusion rates in China. H7N9 diffusion dynamics and predictor contributions differ from H5N1. Key determinants of spatial diffusion included: proximity between locations (for H5N1 and H7N9), and lower rural population densities (H5N1 only). For H7N9, additional predictors included low avian influenza vaccination rates, low percentage of nature reserves and high humidity levels. For both H5N1 and H7N9, we found viral migration rates from Guangdong to Guangxi and Guangdong to Hunan were highly supported transmission routes (Bayes Factor > 30). We show fundamental differences in wide-scale transmission dynamics between H5N1 and H7N9. Importantly, this indicates that avian influenza initiatives designed to control H5N1 may not be sufficient for controlling the H7N9 epidemic. We suggest control and prevention activities to specifically target poultry transportation networks between Central, Pan-Pearl River Delta and South-West regions.

Does influenza pandemic preparedness and mitigation require gain-of-function research?

The risk and benefits of gain-of-function studies on influenza A have been widely debated since 2012 when the methods to create two respiratory transmissible H5N1 mutant isolates were published. Opponents of gain-of-function studies argue the biosecurity risk is unacceptable, while proponents cite potential uses for pandemic surveillance, preparedness and mitigation. In this commentary, we provide an overview of the background and applications of gain-of-function research and argue that the anticipated benefits have yet to materialize while the significant risks remain.