Molecular characterization and survival analysis of a cohort of glioblastoma, IDH-wildtype.

Glioblastoma, IDH-wild type, the most common malignant primary central nervous system tumor, represents a formidable challenge in clinical management due to its poor prognosis and limited therapeutic responses. With an evolving understanding of its underlying biology, there is an urgent need to identify prognostic molecular groups that can be subject to targeted therapy. This study established a cohort of 124 sequential glioblastomas from a tertiary hospital and aimed to find correlations between molecular features and survival outcomes. Comprehensive molecular characterization of the cohort revealed prevalent alterations as previously described, such as TERT promoter mutations and involvement of the PI3K-Akt-mTOR, CK4/6-CDKN2A/B-RB1, and p14ARF-MDM2-MDM4-p53 pathways. MGMT promoter methylation is a significant predictor of improved overall survival, aligned with previous data. Conversely, age showed a marginal association with higher mortality. Multivariate analysis to account for the effect of MGMT promoter methylation and age showed that, in contrast to other published series, this cohort demonstrated improved survival for tumors harboring PTEN mutations, and that there was no observed difference for most other molecular alterations, including EGFR amplification, RB1 loss, or the coexistence of EGFR amplification and deletion/exon skipping (EGFRvIII). Despite limitations in sample size, this study contributes data to the molecular landscape of glioblastomas, prompting further investigations to examine these findings more closely in larger cohorts.

A Multicenter Study of Genotype Variation/Demographic Patterns in 2475 Individuals Including 1444 Cases With Breast Cancer in Turkey.

Objective: Breast cancer (BC) is the most common cancer type in women and may be inherited, mostly in an autosomal dominant pattern. The clinical diagnosis of BC relies on the published diagnostic criteria, and analysis of two genes, BRCA1 and BRCA2, which are strongly associated with BC, are included in these criteria. The aim of this study was to compare BC index cases with non-BC individuals in terms of genotype and diagnostic features to investigate the genotype/demographic information association. Materials and Methods: Mutational analyses for the BRCA1/BRCA2 genes was performed in 2475 individuals between 2013-2022 from collaborative centers across Turkey, of whom 1444 with BC were designated as index cases. Results: Overall, mutations were identified in 17% (421/2475), while the percentage of mutation carriers in cases of BC was similar, 16.6% (239/1444). BRCA1/BRCA2 gene mutations were detected in 17.8% (131/737) of familial cases and 12% (78/549) of sporadic cases. Mutations in BRCA1 were found in 4.9%, whereas 12% were in BRCA2 (p<0.05). Meta-analyses were performed to compare these results with other studies of Mediterranean-region populations. Conclusion: Patients with BRCA2 mutations were significantly more common than those with BRCA1 mutations. In sporadic cases, there was a lower proportion with BRCA1/BRCA2 variants, as expected, and these results were consistent with the data of Mediterranean-region populations. However, the present study, because of the large sample size, revealed more robust findings than previous studies. These findings may be helpful in facilitating the clinical management of BC for both familial and non-familial cases.

EGFR and ERBB2 exon 20 insertion/duplication in advanced non-small cell lung cancer: genomic profiling and clinicopathologic features.

Background: Exon 20 (ex20) in-frame insertions or duplications (ins/dup) in epidermal growth factor receptor (EGFR) and its analog erb-b2 receptor tyrosine kinase 2 (ERBB2) are each detected in 1.5% of non-small cell lung cancer (NSCLC). Unlike EGFR p.L858R or ex19 deletions, ex20 ins/dup is associated with de novo resistance to classic EGFR inhibitors, lack of response to immune checkpoint inhibitors, and poor prognosis. US Food and Drug Administration has approved mobocertinib and amivantamab for targeting tumors with this aberration, but the number of comprehensive studies on ex20 ins/dup NSCLC is limited. We identified 18 cases of NSCLCs with EGFR/ERBB2 ex20 ins/dup and correlated the findings with clinical and morphologic information including programed death-ligand 1 (PD-L1) expression. Methods: A total of 536 NSCLC cases tested at our institution between 2014 and 2023 were reviewed. A custom-designed 214-gene next-generation sequencing panel was used for detecting DNA variants, and the FusionPlex CTL panel (ArcherDx) was used for the detection of fusion transcripts from formalin-fixed, paraffin-embedded tissue. Immunohistochemistry (IHC)for PD-L1 was performed using 22C3 or E1L3N clones. Results: Nine EGFR and nine ERBB2 ex20 ins/dup variants were identified from an equal number of men and women, 14 were non- or light smokers, and 15 had stage IV disease. All 18 cases were adenocarcinomas. Seven of the 11 cases with available primary tumors had acinar predominant pattern, two had lepidic predominant pattern, and the remainder had papillary (one case) and mucinous (one case) patterns. Ex20 ins/dup variants were heterogenous in-frame one to four amino acids spanning A767-V774 in EGFR and Y772-P780 in ERBB2 and were clustered in the loop following the C-helix and α C-helix. Twelve cases (67%) had co-existing TP53 variants. Copy number variation in CDK4 amplification was identified in one case. No fusion or microsatellite instability was identified in any case. PD-L1 was positive in two cases, low positive in four cases, and negative in 11 cases. Conclusions: NSCLCs harboring EGFR/ERBB2 ex20 ins/dup are rare and tend to be acinar predominant, negative for PD-L1, more frequent in non- or light smokers, and mutually exclusive with other driver mutations in NSCLC. The correlation of different EGFR/ERBB2 ex20 ins/dup variants and co-existing mutations with response to targeted therapy and the possibility of developing resistant mutations after mobocertinib treatment warrants further investigation.

Tumor to Tumor Metastasis: A Case Report of Metastatic Angiosarcoma to an Ovarian Brenner Tumor and Review of the Literature.

While angiosarcoma metastatic to the ovary is rare, metastatic angiosarcoma to an ovarian tumor has never been reported in the literature, so far. We report a case of a 61-yr-old postmenopausal woman with history of breast cancer, presenting with metastatic angiosarcoma to an ovarian Brenner tumor. Initially at the frozen section examination, on limited sampling, and without knowledge of the patient's history, a diagnosis of at least proliferating Brenner tumor was rendered. Upon review of permanent sections, an intermixed angiosarcoma component was identified within Brenner tumor. Tumor to ovarian tumor metastasis is a rare phenomenon, with only 18 cases reported in the last 50 yr. It poses diagnostic challenges during sampling and histopathologic interpretation. Detailed clinical history, careful gross examination and sampling are important to recognize the separate tumor components.

Anatomic pathology quality assurance: Developing an LIS based tracking and documentation module for intradepartmental consultations.

Background: An electronic intradepartmental consultation system for anatomic pathology (AP) was conceived and developed in the laboratory information system (LIS) in 2019. Previously, all surgical pathology intradepartmental consultative activities were initiated and documented with paper forms which circulated with the pertinent microscopic slides and were eventually filed. In this study, we discuss the implementation and utilization of an electronic intradepartmental AP consultation system. Methods: Workflows and procedures were developed to organize intradepartmental surgical pathology consultations from the beginning to the end point of the consultative activities entirely using a paperless system that resided in the LIS. Results: The electronic consult system allowed electronic documentation of all steps of intradepartmental consultative activities. The system provided tracking ability for consulted cases and improved access to consult discussion for all departmental personnel, staff, and trainees. Consultation work queue was created for each pathologist and a summary of individual consultative workload was possible. Documentation of anatomic pathology quality assurance for intradepartmental consultative activity was easily assessed. Conclusions: The electronic intradepartmental consult system has allowed our department to electronically track intradepartmental consult cases, store the consultative opinion text with the case, record the pathologists involved, and document the consultation for internal quality assurance review as well as for accrediting organizations. Summarization of pathologist workload related to consultative activity was quantifiable and optimization of the consultative process was maximized for education in an academic setting.

Clinicopathologic Features of Facial Dermatofibromas, a Cohort Study, and a Systematic Review of Literature.

BACKGROUND: Dermatofibromas are common skin tumors that typically occur on the extremities and trunk and demonstrate benign behavior, frequent recurrences, and very rare metastasis. Facial dermatofibromas are rare and not well studied . We analyzed clinicopathologic features of facial dermatofibromas. DESIGN: Considering the rarity of the condition, we conducted a cohort study and a systematic review. We queried medical records of a single tertiary care center for dermatofibromas from January 1, 2000, to July 1, 2021. A systematic review of multiple databases was conducted through October 27, 2021, to include studies reporting facial dermatofibromas. Random-effects meta-analysis was used to estimate pooled odds ratio and proportions with associated 95% confidence interval (CI). RESULTS: The cohort study identified 2858 cases of dermatofibromas, of which, 23 cases from 18 patients were on the face (1%). The mean age was 52.7 ± 17.8 years. Fifty-six percent of the cases were women. The most common location was the forehead (6 cases). The mean follow-up was 54 months. Forty-four percent of the cases had subcutaneous involvement, and 39% were the cellular type. Margins were positive in 89% of the cases, recurrence rate was 22%, and no metastases were observed. The systematic review included 10 studies (119 patients). Meta-analyses showed that facial dermatofibromas were 2% of all dermatofibromas (95% CI: 1%-3%). The local recurrence rate was 14% (95% CI: 6%-26%). Facial dermatofibromas with subcutaneous involvement were more likely to recur [odds ratio 4.53 (95% CI: 1.12-18.24)]. Before histopathologic examination, clinical differential diagnosis included dermatofibromas in only 9% of the cases (95% CI: 2%-19%). CONCLUSION: Facial dermatofibromas are rare and are difficult to fully excise. Cellular type and subcutaneous or muscular involvement are common in these cases and tend to have higher local recurrence rate than other nonfacial dermatofibromas. Wider excisions might be necessary for complete excision.

Clinical and molecular evaluation of MEFV gene variants in the Turkish population: a study by the National Genetics Consortium.

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder with recurrent fever, abdominal pain, serositis, articular manifestations, erysipelas-like erythema, and renal complications as its main features. Caused by the mutations in the MEditerranean FeVer (MEFV) gene, it mainly affects people of Mediterranean descent with a higher incidence in the Turkish, Jewish, Arabic, and Armenian populations. As our understanding of FMF improves, it becomes clearer that we are facing with a more complex picture of FMF with respect to its pathogenesis, penetrance, variant type (gain-of-function vs. loss-of-function), and inheritance. In this study, MEFV gene analysis results and clinical findings of 27,504 patients from 35 universities and institutions in Turkey and Northern Cyprus are combined in an effort to provide a better insight into the genotype-phenotype correlation and how a specific variant contributes to certain clinical findings in FMF patients. Our results may help better understand this complex disease and how the genotype may sometimes contribute to phenotype. Unlike many studies in the literature, our study investigated a broader symptomatic spectrum and the relationship between the genotype and phenotype data. In this sense, we aimed to guide all clinicians and academicians who work in this field to better establish a comprehensive data set for the patients. One of the biggest messages of our study is that lack of uniformity in some clinical and demographic data of participants may become an obstacle in approaching FMF patients and understanding this complex disease.

A Rare Inflammatory Myofibroblastic Tumor of the Mitral Valve With Systemic Embolism in a Child.

Inflammatory myofibroblastic tumors (IMTs) represent mesenchymal tumors that occur in the lungs, abdomen, or pelvis. Cardiac IMTs are rare, usually right-sided, and when left-sided can cause sudden cardiac death by coronary occlusion. We report a child with symptoms of embolization to the right kidney and the femoral artery, and a mobile mass in the left atrium attached to the mitral valve. Upon surgical removal, histopathology revealed IMT. Our case illustrates a unique presentation of systemic thromboembolism.

Microvascular Decompression versus Stereotactic Radiosurgery for Trigeminal Neuralgia: A Single-Institution Experience.

OBJECTIVE: Microvascular decompression (MVD) is the standard surgical procedure for patients with medically refractory trigeminal neuralgia (TN). Stereotactic radiosurgery (SRS) has gained increasing popularity as a less invasive technique. We report our institution's outcome in the surgical treatment of TN (MVD vs. SRS), taking patient's age and gender into consideration. METHODS: We retrospectively reviewed a prospectively collected database of patients undergoing MVD or SRS for type 1 idiopathic TN between 2004 and 2019 at the University of Iowa. Standardized data collection focused on preoperative clinical characteristics and postoperative outcomes including the Barrow Neurological Institute (BNI) Pain Intensity Score. RESULTS: A total of 111 patients underwent MVD and 103 patients underwent SRS for TN. Patients were younger in the MVD (median, 60 years) than SRS (median, 72 years) group. More females (58%) than males (42%) had TN. Multivariate ordinal regression analysis showed that an outcome of BNI score I-II (P = 0.365) and III (P = 0.736) can be achieved with either MVD or SRS; however, BNI score IV (P = 0.031) and V (P = 0.022) were more associated with SRS. Six percent of patients in the MVD group and 26% in the SRS group developed pain recurrence and required a second operation. Nine of 10 patients who underwent MVD after failed SRS had complete pain relief. CONCLUSIONS: Factoring in patients' age and gender, both MVD and SRS can achieve a favorable outcome for medically refractory TN, although BNI scores of IV and V were more common with SRS.

Methods for in vitro modeling of glioma invasion: Choosing tools to meet the need.

Widespread tumor cell invasion is a fundamental property of diffuse gliomas and is ultimately responsible for their poor prognosis. A greater understanding of basic mechanisms underlying glioma invasion is needed to provide insights into therapies that could potentially counteract them. While none of the currently available in vitro models can fully recapitulate the complex interactions of glioma cells within the brain tumor microenvironment, if chosen and developed appropriately, these models can provide controlled experimental settings to study molecular and cellular phenomena that are challenging or impossible to model in vivo. Therefore, selecting the most appropriate in vitro model, together with its inherent advantages and limitations, for specific hypotheses and experimental questions achieves primary significance. In this review, we describe and discuss commonly used methods for modeling and studying glioma invasion in vitro, including platforms, matrices, cell culture, and visualization techniques, so that choices for experimental approach are informed and optimal.

Sarcoidosis with Multiorgan Involvement and Cutaneous Manifestations after Colonic Adenocarcinoma Resection.

Sarcoidosis is a systemic chronic granulomatous disease. It mostly involves the lungs and hilar lymph nodes and produces epithelioid granulomas. Granulomatous (sarcoid) reaction is known to be associated with malignancies; however, it is uncommonly seen with colon carcinomas. Furthermore, systemic sarcoidosis following cancer diagnosis is less commonly seen. To the best of our knowledge, cutaneous sarcoidosis related with an underlying colon carcinoma has not been reported previously in the literature. In this report, we present a very rare case with sarcoidosis development after resection of sigmoid adenocarcinoma, presenting with multiorgan involvement including the skin, eye, joints, and lymph nodes. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) images showed the skin, lung, spleen, mediastinal, and hilar lymph node involvement. Histopathological examination of skin lesions demonstrated granulomatous dermatitis. This case demonstrates that sarcoidosis can cause intensely FDG-avid lesions on 18F-FDG-PET/CT scans, mimicking metastasis in colon cancer patients. Histopathological evaluation is essential for confirming the diagnosis. 18F-FDG-PET/CT scan provides important information for evaluation of disease extension, progression, and clinical follow-up.