The human papillomavirus (HPV) is a non-enveloped double-stranded DNA virus capable of infecting skin and mucosa epithelial cells. Commonly, HPV infection is associated with sexually transmitted diseases and is considered the leading cause of cervical cancer and other carcinomas of the anogenital tract. However, several studies reported their involvement in cancers of non-sexual regions, including colorectal, head and neck, and breast cancers. There are several studies from the Middle East and North Africa (MENA) regions on the potential association between high-risk HPVs and cancer; nevertheless, there are limited studies that address the significance of HPV vaccination as a potential guard against these cancers. In the current review, we present a comprehensive description of the current HPV-associated cancers prevalence rates in the MENA region, demonstrating their steady increase with time, especially in African regions. Moreover, we discuss the potential impact of vaccination against HPV infections and its outcome on human health in this region.

The Hedgehog (Hh) signaling pathway is essential for normal embryonic development, while its hyperactivation in the adult organism is associated with the development of various cancers. The role of the Hh signaling pathway in ovarian cancer has not been sufficiently investigated. Therefore, the present study investigated the role of protein patched homolog 1 (PTCH1), a component of the Hh signaling pathway, and changes in the promoter methylation status of the corresponding gene in a cohort of low-(LGSC) and high-grade serous ovarian carcinomas (HGSC) and HGSC cell lines (OVCAR8 and OVSAHO). PTCH1 protein expression level was analyzed using immunohistochemistry in tissue samples and immunofluorescence and western blotting in cell lines. DNA methylation patterns of the PTCH1 gene were analyzed using methylation-specific PCR. PTCH1 protein expression was significantly higher in HGSCs and LGSCs compared with controls (healthy ovaries and fallopian tubes). Similarly, ovarian cancer cell lines exhibited significantly higher PTCH1 protein expression compared with a normal fallopian tube non-ciliated epithelial cell line (FNE1). PTCH1 protein fragments of different molecular weights were detected in all cell lines, indicating possible proteolytic cleavage of this protein, resulting in the generation of soluble N-terminal fragments that are translocated to the nucleus. DNA methylation of the PTCH1 gene promoter was exclusively detected in a proportion of HGSC (13.5%) but did not correlate with protein expression. PTCH1 protein was highly expressed in serous ovarian carcinoma tissues and cell lines, while PTCH1 promoter methylation was only detected in HGSC. Further investigation is required to elucidate the possible mechanisms of PTCH1 activation in serous ovarian carcinomas.

Acinic cell carcinoma of the breast is a rare special subtype of breast cancer in the category of salivary gland-type tumors. It is morphologically similar to acinic cell carcinomas of salivary glands and pancreas and has a triple-negative phenotype (estrogen receptor-negative, progesterone receptor-negative, and Her-2/neu negative). Its molecular genomic features are more similar to triple-negative breast cancer of no special type than to its salivary gland counterpart. However, the clinical course of the mammary acinic cell carcinoma appears to be less aggressive than the usual triple-negative breast carcinomas. This review comprehensively summarizes the current literature on the clinicopathologic, immunohistochemical, and molecular features of this rare and distinct subtype of breast cancer.

In the present review, we briefly discuss the breakthrough advances in precision medicine using a tumor-agnostic approach and focus on BRAF treatment modalities, the mechanisms of resistance and the diagnostic approach in cancers with BRAF mutations. Tumor-type agnostic drug therapies work across cancer types and present a significant novel shift in precision cancer medicine. They are the consequence of carefully designed clinical trials that showed the value of tumor biomarkers, not just in diagnosis but in therapy guidance. Six tumor-agnostic drugs (with seven indications) have been approved through October 2022 by FDA. The first tumor-agnostic treatment modality was pembrolizumab for MSI-H/dMMR solid tumors, approved in 2017. This was followed by approvals of larotrectinib and entrectinib for cancers with NTRK fusions without a known acquired resistance mutation. In 2020, pembrolizumab was approved for all TMB-high solid cancers, while a PD-L1 inhibitor dostarlimab-gxly was approved for dMMR solid cancers in 2021. A combination of BRAF/MEK inhibitors (dabrafenib/trametinib) was approved as a tumor-agnostic therapy in June 2022 for all histologic types of solid metastatic cancers harboring BRAFV600E mutations. In September 2022, RET inhibitor selpercatinib was approved for solid cancers with RET gene fusions. Conclusion. Precision cancer medicine has substantially improved cancer diagnostics and treatment. Tissue type-agnostic drug therapies present a novel shift in precision cancer medicine. This approach rapidly expands to provide treatments for patients with different cancers harboring the same molecular alteration.

Immunotherapy, based on immune checkpoint inhibitors (ICIs) targeting the programmed cell death ligand 1 (PD-L1) and/or programmed death receptor 1 (PD-1), has substantially improved the outcomes of patients with various cancers. However, only ~30% of patients benefit from ICIs. Tumor PD-L1 expression, assessed by immunohistochemistry (IHC), is the most widely validated and used predictive biomarker to guide the selection of patients for ICIs. PD-L1 assessment may be challenging due to the necessity of different companion diagnostic assays for required specific ICIs and a relatively high level of inter-assay variability in terms of performance and cutoff levels. In this review, we discuss the role of PD-L1 IHC as a predictive test in immunotherapy (immuno-oncology), highlight the complexity of the PD-L1 testing landscape, discuss various preanalytical, analytical, and clinical issues that are associated with PD-L1 assays, and provide some insights into optimization of PD-L1 as a predictive biomarker in immuno-oncology.

Alpha-methylacyl-CoA racemase (AMACR/P504S) is a mitochondrial and peroxisomal enzyme involved in the branched-chain fatty acid and bile acid metabolism. AMACR is a useful diagnostic biomarker for prostate carcinomas and several other malignancies. Its expression in apocrine breast lesions had been previously reported, but its role in breast cancer progression has not been fully investigated. One hundred fifty breast samples (80 with invasive carcinomas) were studied. The expression of AMACR protein was analyzed using the immunohistochemical method (IHC). Lesions were considered positive if AMACR was detected in ≥10% of the cells at any intensity comprising a histologically defined normal epithelial structure or a pathologic lesion. In addition, AMACR mRNA relative expression was calculated from the whole-transcript RNA-Seq performed on >20,000 diverse tumor samples using a 20,000+ hybrid-capture NGS assay with the transcript capture panel based on the Agilent SureSelect Human All ExonV7. Expression of AMACR protein was restricted to epithelia. It was uncommon in the normal breast (7/81 samples, 9%). Increasing AMACR expression was observed with proliferative epithelial lesions (18% of usual ductal hyperplasias/adenosis, 70% of atypical lesions and 72% of DCIS/LCIS). Invasive ductal carcinomas NST and invasive lobular carcinomas expressed AMACR in 64% and 46%, respectively. The highest AMACR expression was observed in luminal B and HER2-positive breast carcinomas (86-100%). Triple-negative breast carcinomas exhibited AMACR in 50% of the cases. Apocrine lesions showed strong, nearly uniform overexpression of AMACR (100% of metaplasias, hyperplasias and in situ carcinomas and 88% of invasive apocrine carcinomas were positive). RNA-Seq analysis also confirmed AMACR expression in breast carcinomas, although its median value was substantially lower with a lower standard deviation than in prostate carcinomas. Over-expression of AMACR characterizes various proliferative, preinvasive and invasive breast lesions and is not specific to the apocrine morphology. It points to altered lipid metabolism (branched fatty acids) as one of the general characteristics of breast carcinogenesis, like several other malignancies. Its early detection may represent a potential target for cancer progression intervention.

No abstract available.

Aim A standardized assessment for the optimal repair of hypospadias remains elusive. The aim of this study was to assess a postoperative cosmetic outcome of hypospadias repair using a validated questionnaire, Hypospadias Objective Scoring Evaluation (HOSE). Methods During the period between January 2016 and May 2019, 40 patients who underwent hypospadias repair were identified and they agreed to a follow-up using the HOSE. Distal hypospadias repairs underwent a cross-sectional assessment of the cosmetic outcome. Cosmetic assessment was performed by an independent physician using the HOSE scoring system. Results The native meatus was coronal in 10 (25%), subcoronal in eight (20%), and distal penile in 22 (55%) patients. Mean followup was 35.90 months (SD ±29.58) postoperatively (range 12-162 months). Complications occurred in one (2.5%) patient. Out of 40 uncomplicated repairs, 39 (97.5%) were satisfactory. A vertical slit-like meatus located at the distal glans was created in 33 (82.5%) boys, and at the proximal glans in seven (17.5%). The urinary stream was single and straight in 39 and spray in one patient. A straight erection was observed in 39 (97.5%) boys. The median HOSE score was 16 (range 12-16). One patient had a small, single coronal fistula. The technique used included tubularised incised plate urethroplasty. Conclusion The HOSE score is simple, easy, non-invasive and non-expensive tool for objective assessment of long-term outcomes of hypospadias repair.

Juvenile cystic adenomyoma (JCA) is a rare uterine pathology with <40 cases reported in the current literature since 1996 when Tamura described it. We report a 13-year-old girl with a history of chronic pelvic pain and dysmenorrhea for 12 months. After diagnostic evaluation and identification of the cystic structure ( ∼ 6 cm) within the myometrium, fertility-sparing surgery was successfully performed. Histopathological examination of the uterine cyst was consistent with the diagnosis of JCA. The postoperative course was uneventful, and the patient was disease-free three years after surgery. JCA is a rare condition but should be considered in the differential diagnosis in adolescents with moderate to severe dysmenorrhea. Despite diagnostic advances, the awareness of the disorder remains low. Thus, our case report aims to increase awareness of this rare pathology with unclear etiology.

Simple Summary Recently, the interactions between microbiota and the host have been reported to induce the onset and progression of human cancer via epithelial–mesenchymal transition (EMT). In contrast, some microorganisms can protect against cancer growth, indicating an anticancer therapeutic action of such microbiota. In the review, we summarize findings from the literature, exploring the underlying mechanisms by which pathogenic microorganisms induce EMT. We also highlight the potential of exploiting these complex interactions for developing new biological therapies. Abstract Advancement in the development of molecular sequencing platforms has identified infectious bacteria or viruses that trigger the dysregulation of a set of genes inducing the epithelial–mesenchymal transition (EMT) event. EMT is essential for embryogenesis, wound repair, and organ development; meanwhile, during carcinogenesis, initiation of the EMT can promote cancer progression and metastasis. Recent studies have reported that interactions between the host and dysbiotic microbiota in different tissues and organs, such as the oral and nasal cavities, esophagus, stomach, gut, skin, and the reproductive tract, may provoke EMT. On the other hand, it is revealed that certain microorganisms display a protective role against cancer growth, indicative of possible therapeutic function. In this review, we summarize recent findings elucidating the underlying mechanisms of pathogenic microorganisms, especially the microbiota, in eliciting crucial regulator genes that induce EMT. Such an approach may help explain cancer progression and pave the way for developing novel preventive and therapeutic strategies.

Introduction: Human papillomaviruses (HPVs), Epstein-Barr virus (EBV), and mouse mammary tumor virus-like virus (MMTV-like virus) can be present and contribute to breast cancer development and progression. However, the role of these oncoviruses and their crosstalk in breast cancer is still unclear. Methods: We explored the co-presence of high-risk HPVs, EBV, and MMTV-like virus in 74 breast cancer samples from Qatar using PCR. Results: We found the presence of HPV and EBV in 65% and 49% of our cancer sample cohorts; 47% of the samples are positive for both oncoviruses. The MMTV-like virus alone was detected in 15% of the samples with no significant association with clinicopathological features. The three oncoviruses were co-present in 14% of the cases; no significant association was noted between the co-presence of these viruses and the clinicopathological features. Conclusion: Despite the presence of the oncoviruses, additional studies are necessary to understand their interactions in human breast carcinogenesis.

c-kit is a classical proto-oncogene that encodes a receptor tyrosine kinase (RTK) that responds to stem cell factor (SCF). C-KIT signaling is a critical regulator of cell proliferation, survival, and migration and is implicated in several physiological processes, including pigmentation, hematopoiesis, and gut movement. Accumulating evidence suggests that dysregulated c-KIT function, caused by either overexpression or mutations in c-kit, promotes tumor development and progression in various human cancers. In this review, we discuss the most important structural and biological features of c-KIT, as well as insights into the activation of intracellular signaling pathways following SCF binding to this RTK. We then illustrate how different c-kit alterations are associated with specific human cancers and describe recent studies that highlight the contribution of c-KIT to cancer stemness, epithelial-mesenchymal transition and progression to metastatic disease in different experimental models. The impact of tyrosine kinase inhibitors in treating c-KIT-positive tumors and limitations due to their propensity to develop drug resistance are summarized. Finally, we appraise the potential of novel therapeutic approaches targeting c-KIT more selectively while minimizing toxicity to normal tissue.