Penile torsion is a rare congenital anomaly that is usually characterized by a counterclockwise rotation of the penile shaft or glans. Although several surgical techniques for its correction have been proposed, the consensus of choosing the most efficient technique remains controversial. Herein, we report our operational approach that successfully corrected a severe (>90 degrees) isolated penile torsion in the form of penile degloving and dorsal dartos flap rotation surgery.

Breast cancer was traditionally not considered a particularly immunogenic tumor. However, recent developments have shown that some aggressive triple-negative breast cancers are immunogenic, exhibit a resistance to chemotherapy and have a poor prognosis. These cancers have been shown to express molecules identified as targets for immunotherapy. Despite the advances, the challenges are many, and include identifying the patients that may benefit from immunotherapy. The best methods to analyze these samples and to evaluate immunogenicity are also major challenges. Therefore, the most accurate and reliable assessment of immune cells as potential targets is one of the most important aims in the current research in breast immunotherapy. In the present review, we briefly discuss the mechanisms of the regulation of checkpoint inhibitors (PD-1/PD-L1) in breast cancer and explore the predictive aspects in the PD-L1 testing.

Breast cancer consists of several intrinsic molecular subtypes, providing the basis for clinical treatment decisions. Lately, it is becoming increasingly recognized that factors other than the intrinsic cancer characteristics, such as immune components’ activity in the tumor microenvironment, have important effects on treatment choices and efficacy. bioSyntagma has developed a method, the Molecular Fingerprint (mPrint®), that enables multiplexed analysis of spatially defined regions in formalin-fixed, paraffin-embedded (FFPE) tumor samples allowing for analysis of the gene signatures unique to the tumor microenvironment. This method was applied to molecularly defined sets of breast cancers and used to evaluate four different tumor regions of interest (ROIs): 1) viable carcinoma proper (>90% cancer cells), 2) fibrotic tumor center (sparse cellularity), 3) interface between viable tumor and inflammatory component (tumor and inflammatory microenvironment) and 4) tissue away from the tumor (normal breast tissue). This was compared to the whole tissue scrapes from each patient block. Each ROI and tissue scrape was analyzed by high throughput qPCR for a panel of 248 genes using SmartChip technology (Takara Bio, USA). Sequential tissue slices from each patient were also analyzed using immunohistochemistry (IHC) for three targets and investigated for correlation with qPCR results for validation of the method. Overall, reasonable concordance was observed in general expression trends between selected IHC and RNA expression. qPCR data were further analyzed using hierarchical clustering analysis and showed that morphologically defined ROI’s cluster completely differently than traditional clustering of entire tissue scrapes. Notably, patient clustering based on morphological regions was independent of the intrinsic cancer subtype, as determined by molecular profiling of whole tissue scrapes, as well as independent of trends in Tumor Mutational Burden (TMB) and Microsatellite Instability (MSI). These findings suggest that current methods of patient stratification based on whole tumor molecular subtyping may be inferior to stratification based on molecular characteristics of the tumor microenvironment. Citation Format: Colleen Ziegler, Isaiah Slemons, Chris DeSilva, Barbara Witkowski, Alain Mir, Sangeetha Anandakrishnan, Andrew Farmer, Elma Contreras, David Richardson, Semir Vranic, Zoran Gatalica, Dmitry N. Derkach. Novel method for patient stratification in breast carcinoma based upon spatial analysis of tumor microenvironment [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B094. doi:10.1158/1535-7163.TARG-19-B094

Dishevelled family proteins (DVL1, DVL2, and DVL3) are cytoplasmic mediators involved in canonical and non‐canonical Wnt signaling that are important for embryonic development. Since Wnt signaling promotes cell proliferation and invasion, its increased activation is associated with cancer development as well. To get deeper insight into the behavior of Dishevelled proteins in cancer, we studied their expression in serous ovarian carcinomas [both low‐ (LGSC) and high‐grade (HGSC)], and HGSC cell lines OVCAR5, OVCAR8, and OVSAHO. DVL protein expression in serous ovarian carcinomas tissues was analyzed using immunohistochemistry, while DVL protein and mRNA expressions in HGSC cell lines were analyzed using Western blot and quantitative real‐time PCR. DVL1 protein expression was significantly higher in LGSC compared with normal ovarian tissue, while DVL3 was overexpressed in both LGSC and HGSC. DVL2 and DVL3 protein expression was higher in HGSC cell lines when compared with normal control cell line FNE1, while DVL1, DVL2, and DVL3 mRNA expression was significantly increased only in OVSAHO cell line. Survival analysis revealed no significant impact of DVL proteins on patients’ outcome. Our data show an active involvement of Dishevelled family proteins in serous ovarian carcinomas. Further studies should confirm the clinical relevance of these observations.

Predatory journals refer to journals that recruit articles through aggressive marketing and spam emails, promising a quick, but not robust, review and fast open-access (OA) publication, thus compromising scholarly publishing standards.1–5 Their key motive is a financial benefit via article processing charges (APCs) and other additional fees.1 3 4 The number of OA journals has dramatically risen over the past 15 years,6 reaching 11 376 journals, indexed in the Directory of Open Access Journals (DOAJ) in 2018 (available at https://doaj.org). This expansion was parallel to the increase in the number of predatory publishers.7 8 Predatory journals have become more prevalent than ever due to massive internet expansion and extensive spam email soliciting.2 4 9 Since 2011, when Jeffrey Beall launched his first list of potential predatory OA publishers and journals, predatory journals have come into focus.3 4 Recent studies have highlighted the significant burden of potentially predatory journals in several biomedical specialties, including neuroscience/neurology, urology, emergency medicine, physical medicine, orthopaedics, rehabilitation, as well as anaesthesiology.7 8 10–13 No study on predatory journals in pathology has been conducted so far. As previously suggested, we explored Beall’s list of predatory journals as an initial database of suspected journals related to pathology.2 8 The term predatory was only applied after assessing each journal separately. The assessment was based on the recommended …

Introduction/Background Aberrant Hedgehog (Hh) pathway signaling has been implicated in pathogenesis of several human cancers. Recent studies have indicated its active role in serous ovarian carcinomas. Smoothened protein (SMO), a transmembrane co-receptor in Hh pathway signal transduction, is inhibited in non-dividing cells, thus its disinhibition might be a trigger for uncontrolled cell proliferation and growth. Very few studies have explored the role of SMO in serous ovarian cancers. The aim of the study was to assess the expression of SMO protein and to explore the Smoothened gene promoter methylation in a cohort of serous ovarian carcinomas. Methodology SMO protein expression was immunohistochemically quantified in 40 high-grade serous carcinomas (HGSC), 12 low-grade serous carcinomas (LGSC), 20 normal ovarian and 9 normal fallopian tube samples (controls). SMO gene promoter methylation status was analyzed using methylation-specific polymerase chain reaction (MSP) in randomly selected HGSCs (n=10), LGSCs (n=10), and normal fallopian tube (n=9) samples. Kaplan-Meier survival plots were used to estimate the impact of SMO expression on patients‘ overall survival (OS). Results SMO nuclear expression was significantly higher in HGSCs and LGSCs compared with the fallopian tube samples (p=0.010 and p=0.003, respectively). LGSCs, compared with normal ovarian tissue, exhibited higher total, cytoplasmic/membrane and nuclear expression (p=0.000, p=0.001 and p=0.000, respectively). Comparing HGSCs and LGSCs, significantly higher total and cytoplasmic/membrane expression was found in HGSC (p=0.026 and p=0.030, respectively). SMO gene promoter was unmethylated in both LGSCs and HGSCs as well as in fallopian tube. In addition, the SMO protein expression had no significant impact on patients‘ OS (p=0.07). Conclusion Our data indicate the lack of SMO gene promoter methylation while a significant overexpression (particularly nuclear) of SMO protein characterized a substantial proportion of serous ovarian carcinomas. Further functional studies should elucidate the clinical relevance of these findings. Disclosure Nothing to disclose.

As the majority of cancers and gestational diseases are prognostically stage- and grade-dependent, the ultimate goal of ongoing studies in precision medicine is to provide early and timely diagnosis of such disorders. These studies have enabled the development of various new diagnostic biomarkers, such as free circulating nucleic acids, and detection of their epigenetic changes. Recently, extracellular vesicles including exosomes, microvesicles, oncosomes, and apoptotic bodies have been recognized as powerful diagnostic tools. Extracellular vesicles carry specific proteins, lipids, DNAs, mRNAs, and miRNAs of the cells that produced them, thus reflecting the function of these cells. It is believed that exosomes, in particular, may be the optimal biomarkers of pathological pregnancies and cancers, especially those that are frequently diagnosed at an advanced stage, such as ovarian cancer. In the present review, we survey and critically appraise novel epigenetic biomarkers related to free circulating nucleic acids and extracellular vesicles, focusing especially on their status in trophoblasts (pregnancy) and neoplastic cells (cancers).

A carcinoma with apocrine differentiation arising from the sweat glands. It presents as single or multiple nodular lesions which may be ulcerated or hemorrhagic and is usually in the axilla and less often in the anogenital region. It grows in the dermis and infiltrates subcutaneous tissues. It is characterized by the presence of large cells with abundant eosinophilic cytoplasm and large often vesicular nuclei. Most cases are slow growing tumors and have a prolonged course. Qeios · Definition, February 7, 2020

Salivary duct carcinoma (SDC) is a rare, aggressive salivary gland malignancy, which often presents at an advanced stage. A proportion of SDC are characterized by HER2 amplification and/or overexpression of androgen receptor (AR), which could be targeted in a subset of patients, but the presence of AR splice variant‐7 (AR‐V7) in some SDC cases could result in resistance to anti‐androgen therapy. We evaluated a cohort of 28 cases of SDC for potentially targetable biomarkers and pathways using immunohistochemistry (IHC) and next‐generation sequencing (DNA and RNA) assays. Pathogenic genetic aberrations were found in all but 1 case and affected TP53 (n = 19), HRAS (n = 7), PIK3CA, ERBB2 (HER2), and NF1 (n = 5 each); KMT2C (MLL3) and PTEN (n = 3 each); BRAF (p.V600E), KDM5C and NOTCH1 (n = 2 each). Androgen receptor was expressed in all cases and 13 of 27 harbored the AR‐V7 splice variant (including a case without any other detectable genetic alteration). HER2 IHC was expressed in 11 of 28 cases. The majority of SDC cases had no biomarkers predictive of immunotherapy response: 5 cases exhibited low (1%‐8%) programmed death ligand 1 (PD‐L1) expression in tumor cells, 2 cases exhibited elevated TMB, and no samples exhibited microsatellite instability. Notably, the pre‐treatment biopsies from 2 patients with metastatic disease, who demonstrated clinical responses to anti‐androgen therapy, showed AR expression and no AR splice variants. We conclude that comprehensive molecular profiling of SDCs can guide the selection of patients for targeted therapies involving AR, HER2, PD‐L1, mitogen‐activated protein kinase, and PIK3CA pathways.

Abstract Background Neuroendocrine carcinoma of the uterine cervix (NEC) is a rare cervical malignancy, accounting for 0.9% of all cervical carcinomas. Cervical NEC is a high-grade cancer with an aggressive clinical course and poor outcome. Given that no target therapy has been approved yet for NEC, we explored novel targetable biomarkers in a large cohort of NEC of the cervix. Methods Sixty-two NEC of the cervix were profiled for biomarkers of targeted therapy including antibody-drug conjugates (DLL3, TROP-2, and FOLR1), tropomyosin receptor kinases (NTRK1/2/3 gene fusions), and immune checkpoint inhibitors (PD-L1, TMB, and MSI) using immunohistochemistry and DNA/RNA next-generation sequencing assays. Results The study included 36 primary and 26 metastatic cervical NEC. The mean patient’s age was 43.6 years (range, 24-82 years). DLL3 expression was observed in 81% of the cases with 49% of cases expressing diffusely (≥50% of positive cancer cells) DLL3 protein. DLL3 expression was inversely correlated with commonly observed mutations: PIK3CA (7/47) (p = 0.018) and PTEN mutations (5/40) (p = 0.006). Other frequently seen mutations (TP53 17%, KRAS 11% and CTTNB1 5%) were not associated with DLL3 expression. PD-L1 expression, high TMB and MSI-H were seen in single cases. Although NTRK protein expression was observed in 21% of the cases, none of these had confirmatory NTRK gene fusions. TROP-2 and FOLR1 were negative in all tested cases. Conclusions DLL3 protein and PIK3CA/PTEN pathway genes may be potential therapeutic targets for a substantial proportion of the patients NEC of the cervix. Based on I-O biomarkers status, the patients with cervical NEC are less likely to benefit from immune checkpoint inhibitors. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure D. Arguello: Full / Part-time employment: Caris Life Sciences. E. Contreras: Full / Part-time employment: Caris Life Sciences. Z. Gatalica: Full / Part-time employment: Caris Life Sciences. All other authors have declared no conflicts of interest.

Metastatic Leydig cell tumors (LCT) are rare, difficult to treat malignancies without known underlying molecular-genetic events. We profiled 27 LCT cases using NGS and immunohistochemistry. Our study identified TERT gene fusions as a main genetic alteration and a potential therapeutic target in LCT. TOP1 and AR expressions may guide decisions on chemo- and/or hormone therapy for selected individual patients. Objective: Metastatic Leydig cell tumors (LCT) are rare, difficult-to-treat malignancies without known underlying molecular–genetic events. An index case of metastatic LCT showed an LDLR–TERT gene fusion upon routine genetic profiling for detection of therapeutic targets, which was then followed by an investigation into a cohort of additional LCTs. Patients and Methods: Twenty-nine LCT (27 male and 2 female patients) were profiled using next-generation sequencing and immunohistochemistry. Results: TERT gene fusions were detected only in testicular metastatic LCTs, in 3 of 7 successfully analyzed cases (RMST:TERT,LDLR:TERT, and B4GALT5:TERT). TOP1 and CCND3 amplifications were identified in the case with a B4GALT5:TERT fusion. A TP53 mutation was detected in 1 metastatic tumor without a TERT fusion. Five primary (4 testicular and 1 ovarian) LCTs showed multiple gene amplifications, without a consistent pattern. A single metastatic ovarian LCT showed BAP1 mutation and copy number amplifications affecting the NPM1, PCM1, and SS18 genes. At the protein level, 4 of 7 metastatic and 6 of 10 primary testicular LCTs overexpressed Topo1. Androgen receptor was overexpressed in 10 of 13 primary testicular tumors and 2 of 5 metastatic testicular LCTs (without detectable ARv7 messenger RNA or ARv7 protein). Only 1 metastatic testicular LCT exhibited a high tumor mutational burden; all tested cases were microsatellite instability stable and did not express programmed cell death ligand 1. Conclusions: Our study for the first time identified TERT gene fusions as a main genetic alteration and a potential therapeutic target in metastatic LCTs. Topo1 and androgen receptor may guide decisions on chemotherapy and/or hormone therapy for selected individual patients.

Supplemental Digital Content is available in the text. The breast is a rare site for metastases, and their molecular characteristics have not been studied yet. Intrinsic molecular genetics, cancer characteristics, and breast tissue immune responses in diverse metastases to the breast have not been previously studied. We identified 64 patients with cancers metastatic to the breast: 51 carcinomas and 13 melanomas. Programmed death ligand 1 (PD-L1), steroid receptors, and HER2/neu expressions were evaluated using immunohistochemistry. Gene sequencing, copy number alterations, microsatellite instability, and tumor mutational burden were performed using next-generation sequencing platforms. The 3 most common primary sites for metastatic carcinomas were lung (37%), ovary (29%), and fallopian tubes/peritoneum (14%). TP53 mutations were commonly (50%) observed among the carcinoma cases, while other mutations were characteristic for the primary cancers (VHL in renal, BRCA1 in the fallopian tube, and BRAF in melanomas). High tumor mutational burden was detected in 5/14 carcinomas and 3/7 melanomas. Tumor cell PD-L1 expression was detected in 6 carcinomas, but not in any of the melanomas, whereas immune cells’ expression of PD-L1 was seen in 17 carcinomas and 6 melanomas. Estrogen receptor status was positive in 13/49 carcinomas including 12 adenocarcinomas originating from the ovary and fallopian tube or peritoneum and 1 duodenal neuroendocrine carcinoma. No carcinoma was HER2/neu positive. Intrinsic genetic characteristics of the metastases to the breast followed the pattern commonly seen in primary tumors. Biomarkers of potential benefit to immune checkpoint inhibition therapy were limited to PD-L1-positive non–small cell lung cancer. No common characteristics of the heterogeneous group of tumor metastases to this organ were identified.

Abstract Rationale: Appendiceal mucocele is a rare entity of mucinous cystic dilatation of the appendix. It has no typical clinical presentation and is considered a potentially premalignant condition. Patient concerns: We present a case of accidental intraoperative finding of an appendiceal mucocele in a 54-year old woman that clinically presented with an exacerbated chronic tubo-ovarian abscess. Diagnoses: Trans-vaginal ultrasonography showed an encapsulated, oval, unilocular mass above the uterus with a heteroechogenic structure, homogeneous fluid content, and smooth regular walls without inner proliferation. The histopathologic diagnosis was consistent with an appendiceal cystadenoma. Interventions: The patient underwent a simple appendectomy. Outcomes: There were no clinical, biochemical or imaging signs of the disease recurrence at 6 months follow up. Lessons: To our knowledge, this is the only well-documented case of appendiceal mucocele mimicking exacerbated chronic tubo-ovarian abscess reported in the literature. Awareness of a rare entity such as an appendiceal mucocele, which is frequently misdiagnosed as a potential cause of acute abdomen, is necessary for the appropriate management strategy in order to prevent complications.