Cervical cancer screening is currently based on high-risk human papillomavirus (HR-HPV) molecular testing, Pap cytology testing, and histologic evaluation of cervical biopsies. As primary HPV screening for cervical cancer becomes widely used, some of the recommended screening guidelines propose colposcopy and biopsies following positivity for HPV16/18 without cytologic triage. In such instances, a biopsy would be the only tissue sample available for informing further management. The use of additional histologic levels on cervical biopsies is commonly employed to achieve a diagnosis, although no set criteria for when to obtain additional levels exist. In this study, we evaluated the value of additional sections in cervical biopsy and endocervical curetting, as well as clinical and histologic features that should be considered when ordering additional levels. Additional levels were obtained for the following scenarios: benign mucosa with Pap discrepancy (HSIL or ASC-H interpretation), size discrepancy with the gross description, suspicious atypia for a high-grade lesion, and long-standing high-risk HPV infection. A change in diagnosis was observed in 21.4% of the cases, with an upgrade to a high-grade squamous intraepithelial lesion (CIN2-3) in 12.1% of cases. An initial impression of atypia significantly correlated with both a change in diagnosis and an upgrade to CIN2-3. In the era of primary HPV screening, when evaluating tissue samples following positive HPV test, small, atypical foci should be followed by additional levels. We recommend six (6) initial levels on all cervical biopsies, particularly if there is no loss of tissue between the levels, to ensure an accurate interpretation. This will be crucial in the timely and accurate identification of HPV-related intraepithelial lesions and proper subsequent management.

Apocrine carcinoma of the breast is a rare malignancy. According to 2019 WHO classification, apocrine cellular features and a characteristic steroid receptor profile (Estrogen receptor (ER)-negative and androgen receptor (AR)-positive) define apocrine carcinoma. Her-2/neu protein expression is reported in ∼30-50% of apocrine carcinomas, while NGS analysis showed frequent PIK3CA/PTEN/AKT and TP53 mutations Followed by deregulation in the mitogen-activated protein kinase pathway components (mutations of KRAS, NRAS, BRAF). A recent miRNA study indicates various miRNAs (downregulated hsa-miR-145-5p and upregulated 14 miRNAs such as hsa-miR-182-5p, hsa-miR-3135b, and hsa-miR-4417) may target the commonly altered pathways in apocrine carcinomas such as ERBB2/HER2 and mitogen-activated protein kinase signaling pathway. Although AR expression is a hallmark of apocrine carcinoma, little is known regarding the efficacy/resistance to antiandrogens. Success of bicalutamide, a non-steroidal anti-androgen, was reported in a case of Her2-negative apocrine carcinoma. Two recent studies, however, described presence of anti-androgen resistance biomarkers (a splice variant ARv7 and AR/NCOA2 co-amplification) in a subset of AR+ apocrine carcinomas, cautioning the use of anti-androgens in AR+ triple-negative breast carcinomas. Apocrine carcinomas rarely show biomarkers predictive of response to immune checkpoint inhibitors (PD-L1 expression, MSI-H status, and TMB-high). Therefore, a comprehensive cancer profiling of apocrine carcinomas is necessary to identify potential therapeutic targets for a truly individualized treatment approach.

Abstract The adrenal abscess is a rare complication of adrenal hemorrhage in the neonatal period. Due to its rare occurrence and non-specific signs, diagnosing and treating an adrenal abscess in the neonatal period might be challenging. We present herein a 3-week-old male neonate with an adrenal abscess associated with Escherichia coli sepsis, which was successfully treated by open surgery (using the minimal posterior lumbar approach) following an unsuccessful ultrasound-guided percutaneous drainage.

BACKGROUND Infantile hypertrophic pyloric stenosis (IHPS) is the most common condition requiring surgery in infancy, but the etiology of IHPS is still unclear. The study aimed to analyze the epidemiological and clinical features of the infants with IHPS in our setting and determine the yearly trends in IHPS incidence in the Sarajevo Canton between 2007 and 2016. METHODS We retrospectively analyzed epidemiologic, clinical, and operative data of all infants undergoing pyloromyotomy for IHPS over ten years in the largest tertiary care facility in Bosnia and Herzegovina. RESULTS Fifty-three IHPS patients were diagnosed, yielding an overall incidence of 1.17 per 1000 live births (1.25 and 1.09 cases in 2007-2011 and 2012-2016, respectively). IHPS was more prevalent among male infants (ratio 6.6:1, p < 0.001). The mean age at onset of symptoms was 39.6 days (range, 17-107 days). The estimated median time from symptoms onset to hospitalization was 11 days (range, 1-17 days). The mean age at diagnosis was significantly longer in premature infants compared with term infants (p = 0.003). Both first-born rank and bottle-feeding were significantly associated with IHPS (p = 0.001 and p = 0.04, respectively). No seasonal variation associated with IHPS was detected (p = 0.25). No evidence was found of differences in the incidence of IHPS related to maternal age (p = 0.24) and smoking (p = 0.59). CONCLUSION Our data indicate a declining trend and provide insights into the clinical characteristics of IHPS in Bosnia and Herzegovina. Most of the obtained results are in line with the published data and could improve the quality of local pediatric services.

Background: Water-pipe smoking (WPS), a predominant method of tobacco consumption, is common amongst young females in the Middle East. WPS smoke consists of toxins analogous to the ones that exist in cigarette smoke and frequently correlates with the onset of several types of human cancers including breast. However, the potential target genes and their underlying mechanisms in the initiation and/ or progression of human cancers, especially breast, due to WPS exposure are still unknown. Materials and Methods: In this investigation, we explored the effect of WPS chronic exposure on human normal mammary epithelial cells and analyzed alterations in the differentially ex-pressed gene (DEG) targets using the NanoString nCounter PanCancer Pathways Panel consisting of 770 gene transcripts and a quantitative real-time polymerase chain reaction (PCR) analysis. Results: Our NanoString analysis identified 13 genes dysregulated under the effect of WPS exposure involved in regulating signal transduction, cell cycle, cell motility, proliferation and migration/invasion as well as the inflammatory response. We further performed an in silico analysis to investigate the effect of the identified genes in the prognosis of breast cancer patients and reported those DEGs that directly correlated with smoking and were upregulated in breast cancer in comparison with normal tissue. Moreover, the Kaplan–Meier curve analysis showed a significant correlation be-tween WPS-dysregulated genes (MX1, CCL8, GNGT1 and MMP9) and relapse-free survival in breast cancer patients. Conclusions: Our data clearly suggest that exposure to WPS can alter the expression of key regulator genes involved in the pathogenesis of breast cancer, thereby affecting the breast cancer prognosis.

Recurrent Respiratory Papillomatosis (RRP) is a rare but severe manifestation of human papillomavirus (HPV). As our knowledge about HPV infections has expanded, it has become possible to understand the course of RRP disease and unravel plausible efficient methods to manage the disease. However, the surge in reports on HPV has not been accompanied by a similar increase in research about RRP specifically. In this paper, we review the clinical manifestation and typical presentation of the illness. In addition, the pathogenesis and progression of the disease are described. On the other hand, we discuss the types of treatments currently available and future treatment strategies. The role of vaccination in both the prevention and treatment of RRP will also be reviewed. We believe this review is essential to update the general knowledge on RRP with the latest information available to date to enhance our understanding of RRP and its management.

Simple Summary Fascin, an actin-binding protein, is upregulated in different types of human cancers. It is reportedly responsible for increasing the invasive and metastatic ability of cancer cells by reducing cell–cell adhesions. This review provides a brief overview of fascin and its interactions with other genes and oncoviruses to induce the onset and progression of cancer. Abstract Fascin is an actin-binding protein that is encoded by the FSCN1 gene (located on chromosome 7). It triggers membrane projections and stimulates cell motility in cancer cells. Fascin overexpression has been described in different types of human cancers in which its expression correlated with tumor growth, migration, invasion, and metastasis. Moreover, overexpression of fascin was found in oncovirus-infected cells, such as human papillomaviruses (HPVs) and Epstein-Barr virus (EBV), disrupting the cell–cell adhesion and enhancing cancer progression. Based on these findings, several studies reported fascin as a potential biomarker and a therapeutic target in various cancers. This review provides a brief overview of the FSCN1 role in various cancers with emphasis on gynecological malignancies. We also discuss fascin interactions with other genes and oncoviruses through which it might induce cancer development and progression.

Introduction: Both Dasatinib (DA), a tyrosine kinase inhibitor that is used for targeted cancer therapy, and programmed death-ligand 1 (PD-1/PD-L1) inhibitor that is an immune checkpoint therapy, play a vital role in the management of several types of solid tumors, including breast. Nevertheless, the combined outcome of DA and PD-1/PD-L1 inhibitors in human carcinomas has not been explored yet. Materials and methods: We herein compared the individual impact of DA and PD-1/PD-L1 inhibitors (BMS-202) with their combination on two human HER2-positive breast cancer cell lines, SKBR3 and ZR75. Results: Our data revealed that the combination of DA and BMS-202 significantly inhibits cell proliferation in both cell lines as compared to mono treatment and/or untreated cells. Moreover, we observed that combination treatment prevents the progression of “epithelial-mesenchymal transition” (EMT), which is a hallmark of cell invasion and cancer progression. Our data reveal that DA and BMS-202 together dramatically inhibit cell invasion of SKBR3 and ZR75 cells; this is accompanied by the up-regulation of E-cadherin and its restoration along with b-catenin on the cell membrane and its undercoat, respectively, in addition to the downregulation of vimentin, which are major markers of EMT. Additionally, we found that the synergistic treatment of DA and BMS-202 inhibits colony formation of both cell lines in comparison with their matched control. Conclusion: Our findings implicate that, in comparison to monotreatment, combination of DA and BMS-202 could have a significant impact on the management of HER2-positive breast cancer via HER2 inactivation and specifically b-catenin signaling pathways.

ABSTRACT Breast cancer, the most frequent disease amongst women worldwide, accounts for the highest cancer-related mortality rate. Triple-negative breast cancer (TNBC) subtype encompasses ~15% of all breast cancers and lack estrogen, progesterone, and HER2 receptors. Although risk factors for breast cancer are well-known, factors underpinning breast cancer onset and progression remain unknown. Recent studies suggest the plausible role of oncoviruses including human papillomaviruses (HPVs), Epstein-Barr virus (EBV), and mouse mammary tumor virus (MMTV) in breast cancer pathogenesis. However, the role of these oncoviruses in TNBC is still unclear. In the current study, we explored the status of high-risk HPVs, EBV, and MMTV in a well-defined TNBC cohort from Croatia in comparison to 16 normal/non TNBC samples (controls) using polymerase chain reaction assay. We found high-risk HPVs and EBV present in 37/70 (53%) and 25/70 (36%) of the cases, respectively. The most common HPV types are 52, 45, 31, 58 and 68. We found 16% of the samples positive for co-presence of high-risk HPVs and EBV. Moreover, our data revealed that 5/70 (7%) samples are positive for MMTV. In addition, only 2/70 (3%) samples had co-presence of HPVs, EBV, and MMTV without any significant association with the clinicopathological variables. While, 6/16 (37.5%) controls were positive for HPV (p = .4), EBV was absent in all controls (0/16, 0%) (p = .01). In addition, we did not find the co-presence of the oncoviruses in the controls (p > .05). Nevertheless, further investigations are essential to understand the underlying mechanisms of multiple-oncogenic viruses’ interaction in breast carcinogenesis, especially TNBC.

Gold nanorods have been implicated in several biomedical applications. Herein, the effect of two surface-modified gold nanorods on the early stages of embryogenesis and angiogenesis was investigated using avian embryos at three days and their chorioallantoic membrane (CAM) at five days of incubation. We found that gold nanorods (GNR) modified with PEGylated phospholipid moiety show a high mortality rate in embryos after four days of exposure compared to GNR modified with PEGylated cholesterol moiety. Meanwhile, our data revealed that surface modified-GNR significantly inhibit the formation of new blood vessels in the treated CAM model after 48 h of exposure. Moreover, we report that surface-modified GNR significantly deregulate the expression of several genes implicated in cell proliferation, invasion, apoptosis, cellular energy metabolism, and angiogenesis. On the other hand, our data point out that GNR treatments can modulate the expression patterns of JNK1/2/3, NF-KB/p38, and MAPK, which could be the main molecular pathways of the nanorods in our experimental models.

Abstract Rationale: Peutz-Jeghers syndrome (PJS), a rare autosomal dominant disorder, is characterized by mucocutaneous pigmentations, hamartomatous polyps in the gastrointestinal tract, and a high risk of developing various malignancies. To the best of our knowledge, only 1 case of appendiceal carcinoid associated with PJS has been previously reported in the pediatric population. Patient concerns: We report a 7-year-old girl who was admitted for severe, intermittent abdominal pain and cramps, nausea, and vomiting. Multiple brown melanotic macules on the lips, buccal mucosa, and the tongue were noted. Diagnosis: A plain abdominal X-ray in a standing position revealed dilated intestinal loops with multiple air-fluid levels. A computed tomography scan of the abdomen showing a “coffee bean” appearance of the jejunal loop with a transition point to the duodenal loop. Axial-contrast-enhanced computed tomography scan of the abdomen showing dilated jejunum loops, filled with fluid with the swirled appearance of mesentery typical for volvulus. The diagnosis of PJS was based on clinical findings along with the histopathologic confirmation of the hamartomatous polyps. Interventions: An emergency laparotomy was performed, revealing a jejunojejunal intussusception starting 40 cm from the duodenojejunal flexure. Jejunotomy revealed that a lead-point intussusception was a necrotic hamartomatous polyp. After resecting the involved jejunal necrotic segment, including the polyp, end-to-end jejuno-jejunal anastomosis was performed. Further exploration revealed the presence of a jejunal mass 80 cm from the duodenojejunal flexure identified as another hamartomatous pedunculated polyp. The polyp was resected, and the enterotomy was then closed transversely. The grossly normal appendix was also removed. Outcomes: Clinical findings along with the histopathologically confirmed hamartomatous polyps were consistent with PJS. An appendiceal carcinoid (well-differentiated neuroendocrine tumor, European Neuroendocrine Tumor Society stage pT2) was incidentally detected during histological examination of the appendix. The patient and parents were counseled accordingly, focusing on active surveillance and control of symptoms. Two additional hamartomatous polyps (gastric and jejunal) were detected endoscopically and resected in the fourth postoperative week. A regular, 1-year follow-up and surveillance revealed no complications or recurrences. Lessons: Unusual neoplasms can occasionally be encountered in well-defined syndromes such as PJS. Therefore, active follow-up and surveillance are mandatory for all patients with PJS.

Nuclear protein of testis (NUT), a protein product of the NUTM1 gene (located on the long arm of chromosome 15) with highly restricted physiologic expression in post-meiotic spermatids, is the oncogenic driver of a group of emerging neoplasms when fused with genes involved in transcription regulation. Although initially identified in a group of lethal midline carcinomas in which NUT forms fusion proteins with bromodomain proteins, NUTM1-rearrangement has since been identified in tumors at non-midline locations, with non-bromodomain partners and with varied morphology. The histologic features of these tumors have also expanded to include sarcoma, skin adnexal tumors, and hematologic malignancies that harbor various fusion partners and are associated with markedly different clinical courses varying from benign to malignant. Most of these tumors have nondescript primitive morphology and therefore should be routinely considered in any undifferentiated neoplasm. The diagnosis is facilitated by the immunohistochemical use of the monoclonal C52 antibody, fluorescence in situ hybridization (FISH), and, recently, RNA-sequencing. The pathogenesis is believed to be altered expression of oncogenes or tumor suppressor genes by NUT-mediated genome-wide histone modification. NUTM1-rearranged neoplasms respond poorly to classical chemotherapy and radiation therapy. Targeted therapies such as bromodomain and extraterminal domain inhibitor (BETi) therapy are being developed. This current review provides an update on NUTM1-rearranged neoplasms, focusing on the correlation between basic sciences and clinical aspects.

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