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.

Background Encapsulating Peritoneal Sclerosis (EPS) is a rare phenomenon in paediatric patients with kidney failure treated with peritoneal dialysis (PD). This study highlights clinical challenges in the management of EPS, with particular emphasis on peri-operative considerations and surgical technique. Methods Retrospective analysis of all paediatric patients with EPS treated at the Manchester Centre for Transplantation. Results Four patients were included with a median duration of 78 months on PD. All patients had recurrent peritonitis (> 3 episodes), and all had symptoms within three months of a change of dialysis modality from PD to haemodialysis or transplant. In Manchester, care was delivered by a multi-disciplinary team, including surgeons delivering the adult EPS surgical service with a particular focus on nutritional optimisation, sepsis control, and wound management. The surgery involved laparotomy, lavage, and enterolysis of the small bowel + / − stoma formation, depending on intra-abdominal contamination. Two patients had a formal stoma, which were reversed at three and six months, respectively. Two patients underwent primary closure of the abdomen, whereas two patients had re-look procedures at 48 h with secondary closure. One patient had a post-operative wound infection, which was managed medically. One patient’s stoma became detached, leading to an intra-abdominal collection requiring re-laparotomy. The median length of stay was 25 days, and patients were discharged once enteral feeding was established. All patients remained free of recurrence with normal gut function and currently two out of four have functioning transplants. Conclusions This series demonstrates 100% survival and parenteral feed independence following EPS surgery. Post-operative morbidity was common; however, with individualised experience-based decision-making and relevant additional interventions, patients made full recoveries. Health and development post-surgery continued, allowing the potential for transplantation. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

The Discoidin Domain Receptor 1 (DDR1) is one of the two members of a unique family of receptor tyrosine kinase receptors that signal in response to collagen, which has been implicated in cancer progression. Here, we examined the expression of DDR1 in prostate cancer (PCa), and assessed its potential value as a prognostic marker, as a function of grade, stage and other clinicopathologic parameters. We investigated the association between the expression level and subcellular localization of DDR1 protein and PCa aggressiveness by immunohistochemistry, using tissue microarrays (TMAs) encompassing 200 cases of PCa with various Gleason scores (GS) and pathologic stages with matched normal tissue, and a highly specific monoclonal antibody. DDR1 was found to be localized in the membrane, cytoplasm, and nuclear compartments of both normal and cancerous prostate epithelial cells. Analyses of DDR1 expression in low GS (≤ 7[3 + 4]) vs high GS (≥ 7[4 + 3]) tissues showed no differences in nuclear or cytoplasmic DDR1in either cancerous or adjacent normal tissue cores. However, relative to normal-matched tissue, the percentage of cases with higher membranous DDR1 expression was significantly lower in high vs. low GS cancers. Although nuclear localization of DDR1 was consistently detected in our tissue samples and also in cultured human PCa and normal prostate-derived cell lines, its presence in that site could not be associated with disease aggressiveness. No associations between DDR1 expression and overall survival or biochemical recurrence were found in this cohort of patients. The data obtained through multivariate logistic regression model analysis suggest that the level of membranous DDR1 expression status may represent a potential biomarker of utility for better determination of PCa aggressiveness.

Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide. Human papillomaviruses (HPVs) and Epstein–Barr virus (EBV) have been reported to be present in different types of human cancers, including CRCs, where they can play a key role in the onset and/or progression of these cancers. Thus, we herein explored the prevalence of high-risk HPVs and EBV in a cohort of 94 CRC tissue samples and 13 colorectal normal tissues from the Lebanese population using polymerase chain reaction, immunohistochemistry, and tissue microarray methodologies. We found that high-risk HPVs are present in 64%, while EBV is present in 29% of our CRC samples. Additionally, our data showed that high-risk HPV types (16, 18, 35, 58, 51, 45, 52, 31, and 33) are the most frequent in CRC in the Lebanese cohort, respectively. Our data point out that HPVs and EBV are copresent in 28% of the samples. Thus, this study clearly suggests that high-risk HPVs and EBV are present/copresent in CRCs, where they could play an important role in colorectal carcinogenesis. Nevertheless, further investigations using a larger cohort are needed to elucidate the possible cooperation between these oncoviruses in the development of CRC.

Antibody-drug conjugates represent a new class of highly potent antineoplastic drugs built by attaching a small molecule of an anticancer drug (payload) or another therapeutic agent to an antibody recognizing an epitope on the targeted cells. Trophoblast cell-surface antigen-2 (Trop-2) was originally described in trophoblasts and fetal tissues, but subsequently its overexpression has been demonstrated in various solid malignancies. Sacituzumab govitecan (SG), a conjugate of anti-Trop-2 antibody and SN-38 payload (an active metabolite of irinotecan), is the first in the class that has been clinically validated and approved by the Food and Drug Administration for the treatment of metastatic triple-negative breast (2020) and urothelial carcinomas (2021). In the current review, we summarize and critically appraise the most recent advances with regard to SG, emphasizing the predictive biomarker analysis.

Purpose The acute scrotum (AS) in the pediatric population is a medical emergency. The most common causes of AS include testicular torsion (TT) and torsion of the appendix testis (TAT). Their distinction may be clinically challenging. The purpose of our study was to compare demographic and clinical characteristics of the pediatric cases of TT and TAT and thus provide clinical evidence for distinguishing these two conditions. Methods We retrospectively analyzed all children ≤ 16 years who underwent surgical exploration for AS. The patients were divided into Group 1 or TT and Group 2 or TAT groups. Results Ninety patients were included in the study (24 with TT and 66 with TAT). Patients with TT were significantly older than those with TAT (p < 0.001). The peak incidence of TT was in the age of 12–16 years (p < 0.001), whereas the peak of TAT was in the age group of 7–11 years (p < 0.001). Scrotal pain was more prevalent in patients with TAT (p = 0.02), whereas systemic signs (nausea/vomiting and abdominal pain) affected more frequently the TT patients (p = 0.003 and p < 0.001, respectively). The mean duration of symptoms was significantly longer in the TAT group than in the TT group (p < 0.001). Color-Doppler Ultrasound (CDUS) findings of absent or decreased testicular blood flow in the affected testis strongly favored the diagnosis of TT (p < 0.001). Conclusion Our data indicate that the older age, shorter duration of symptoms, systemic signs (nausea/vomiting and abdominal pain), and characteristics CDUS findings can help distinguish between the two most common acute scrotum causes.

High-risk human papillomaviruses (HPVs) are present and can cooperate with Epstein–Barr virus (EBV) to initiate and/or enhance the progression of several types of human carcinomas including cervical as well as head and neck; in parallel, it has been recently pointed out that these oncoviruses can be detected in human breast cancers. Thus, we herein explored the presence/co-presence of high-risk HPVs and EBV in breast cancer in Lebanese women. A cohort of 102 breast cancer samples and 14 normal breast tissues were assessed for the presence of HPVs and EBV. Polymerase chain reaction (PCR) and immunohistochemistry (IHC) analysis in addition to tissue microarray (TMA) platform were used in this study. We found the presence of HPV in 66/102 (65%) of our samples, while EBV is present in 41/102 (40%) of the cohort. Additionally, our data showed that high-risk HPV types (52, 35, 58, 45, 16 and 51) are the most frequent in breast cancer in Lebanese women. Meanwhile, we report that high-risk HPVs and EBV are co-present in 30/102 (29%) of the samples; more significantly, our results indicate that their co-presence is associated with tumor grade (p = 0.03). Our data revealed that HPVs and EBV are present/co-present in human breast cancer where they may play an important role in its development and/or progression; thus, we believe that further investigations are essential to confirm and elucidate the presence/co-presence of these oncoviruses and the underlying mechanisms of their interaction in breast carcinogenesis.

A congenital hernia into the umbilical cord (CHUM) is often misinterpreted as a mild form of omphalocele. Herniated content in CHUM can be either the solitary intestinal loop or persistent omphalomesenteric duct (POMD) with the potential for traumatic injury in a case of inadequate examination of the umbilical cord and its clamping in the delivery room. Herein, we report a case of a male newborn with a functional bowel obstruction due to peritonitis caused by necrosis of iatrogenically clamped POMD in the CHUM. A 2-day-old full-term male infant was referred to the emergency department with a 1 day history of bilious vomiting, a gradual increase in abdominal distension, and absence of passage of meconium. The infant was born at 38 weeks’ gestation with a birthweight of 2,885 g. The baby was born following an uncomplicated pregnancy and a normal spontaneous vaginal delivery. The Apgar scores were eight at both 1 and 5 min. On physical examination, his abdomen was slightly distended by an umbilical ligation clip placed approximately 2.5 cm from the enlarged base of the umbilical cord (Fig. 1a). The stump of the umbilical cord was thickened and red. The baby was pale and dehydrated. An abdominal radiograph showed dilated small bowel loops due to small bowel obstruction (Fig. 1b). After resuscitation, a surgical exploration via a circumumbilical incision revealed a clamped POMD in the umbilical cord. The top of the POMD was crushed by the umbilical cord clamp (Fig. 1c). The POMD was resected at its base on the ileal loop. The ileal loop was closed transversely using 5-0 Vicryl by single-layer extra mucosal-interrupted sutures. The postoperative recovery was uneventful at a follow up of 8 years. Evaluation of the umbilical cord is a routine part of every newborn examination in the delivery room. Any suspected abnormal thickening of the base of the umbilical cord or any other malformations found should be further evaluated by a neonatologist or pediatric surgeon. Congenital hernia into the umbilical cord is a type of ventral abdominal wall defect in which the bowel usually herniates into the base of normally inserted umbilical cord through a patent umbilical ring. The condition results from a failure of return of intestine loops following the physiological gut herniation around 10–12 weeks of gestation. Due to similar morphologic features, characterized by coverage of eviscerated abdominal contents with a sac comprising outer amnion and inner peritoneal lining, CHUM may be easily misdiagnosed as a small omphalocele. Unlike an omphalocele, CHUM has an intact abdominal wall with adequate muscle development and a complete umbilical ring covered by a small cuff of skin about ~2.5 cm. Congenital hernia into the umbilical cord is usually not linked to chromosomal abnormalities but cases of trisomy 13 associated with CHUM have been reported in the literature. However, if missed, this condition can lead to intestinal damage by a low-placed umbilical cord clamp as it is shown in our illustrative case. Although very rare, similar complications have been reported in the literature. The prevention of inadvertent bowel injury during cord clamping at delivery is possible with increased awareness and knowledge regarding CHUM. Primary prevention includes the prenatal sonographic CHUM detection characterized by intestinal protrusion only into the base of the hernia. The most important preventive measure if the umbilical cord is broad based is the umbilical cord clamping at a safe distance from the basis (at least 5 cm from the abdominal wall). In conclusion, a careful inspection of the umbilical cord of all newborns in the delivery room is essential to identify any clinically relevant umbilical abnormality (e.g., a persistence of CHUM with POMD). This would prevent any iatrogenic gut injury during umbilical cord clamping. Although these complications are rare, they should be kept in mind when performing umbilical cord clamping.

Abstract Rationale: Pentalogy of Cantrell (POC) is an extremely rare syndrome with an estimated incidence of 1:65,000 to 200,000 live births. Its complete form includes a midline epigastric abdominal wall defect, defects affecting the lower sternum, anterior diaphragm, diaphragmatic pericardium, and various intracardiac defects. Patient concerns: We report a case of complete POC affecting only the first-born of a set of premature dizygotic twins. Diagnosis: A giant omphalocele with an eviscerated liver and bowel on prenatal, obstetric ultrasonography at 24 gestational weeks was observed. At birth, physical examination confirmed a massive (10 × 8 cm) epigastric omphalocele in which a significant part of the liver was seen. A postnatal echocardiogram revealed the presence of an ostium secundum atrial septal defect, perimembranous ventricular septal defect, and moderate pulmonary stenosis. X-ray showed an abnormal intrathoracic positioned stomach, which was confirmed with a plain x-ray of the upper intestinal tract with hydrosoluble contrast. Computed tomography (CT) scan revealed the sternum's absence and a close connection between the pericardial sac and the stomach wall. Interventions: The patient underwent surgical intervention at 18 days of age. Outcomes: Despite adequate and appropriate postoperative treatment, the baby rapidly deteriorated and died 72 hours after surgery. Lessons: POC is a complex, high-mortality syndrome whose management requires a multidisciplinary approach and meticulous planning. Despite all efforts, POC carries a poor prognosis, particularly in patients affected by its complete form.

A 65-year-old woman with a negative family history of breast cancer presented with a palpable mass in the left breast’s central portion. Mammography revealed an oval heteroechogenic, partly solid, partly cystic, sharply demarcated mass, measuring 100×90 mm in greatest diameter, classified as BI-RADS 4c, according to ACR BI-RADS Atlas Fifth Edition (Figure 1A-B). Breast MRI showed a lobulated mass with smooth margins appearing hypointense on T1WI and high signal intensity on T2WI (Figure 1C-D). A core needle biopsy revealed a cellular neoplasm, composed of small, closely packed tubules with spindle cell intervening stroma without prominent atypia and mitotic activity, classified as B3 category according to the UK National Coordinating Committee for Breast Screening Pathology (Figure 2A). The multidisciplinary tumor board discussed the case and recommended a wide surgical excision. With the patient’s approval, a left mastectomy was recommended and performed. The axillary clearance was not performed. The 100×90 mm tumor was grossly well-circumscribed, grayish-white, and predominantly solid, with a smaller cystic component, without necrosis and hemorrhage (Figure 2B). Histopathologic examination revealed a well-circumscribed tumor with two distinct components (tubular adenoma and phyllodes tumor) with the transition to one another (Figure 2C). The larger portion of the tumor was composed of closely packed small round to oval tubules with little intervening spindle cell stroma consistent with tubular adenoma. The smaller component showed a biphasic fibroepithelial tumor with leaf-like projections with moderately cellular stroma (Figure 2D-E). The stromal cells exhibited mild to moderate atypia, and their mitotic activity was up to six mitoses/10 hpf (Figure 2F). Stromal overgrowth was absent, while the malignant heterologous elements were not observed despite the exhaustive tumor sampling (25 paraffin blocks). The final diagnosis was a complex fibroepithelial tumor composed of borderline phyllodes and tubular adenoma. Clinical Science

This review provides a brief overview of the state-of-the-art molecular pathology approaches emphasizing the increasingly important pathology role in clinical precision cancer medicine. Recent advances in molecular biology and genetics have tremendously affected the practice of anatomic pathology, gradually transforming it from a morphology-based into a molecularbased discipline. Molecular diagnostics has a long tradition in pathology, especially in clinical pathology. The improvement of methodology for genomic testing in recent years has made it one of the cornerstones of precision cancer medicine. The decisions related to cancer treatments are no longer solely based on the histopathological diagnosis. Various genomic analyses of human cancers are being incorporated into diagnostic and decision-making algorithms. CONCLUSION: The pathologists continue to play an essential role in developing and implementing molecular and genomic tests in practice and communicate the results and their relevance with clinicians. Such activities are of utmost importance for successfully translating scientific advancements into a benefit to patients ("next-generation pathologists").