FibroMeter scores are predictive noninvasive markers of advanced and significant liver fibrosis in patients with chronic viral hepatitis or metabolic dysfunction-associated steatotic liver disease.

Background: FibroMeter and FibroMeter vibration-controlled transient elastography (FibroMeter VCTE) were assessed in a Greek cohort of patients with chronic viral hepatitis (CVH) B and C or metabolic dysfunction-associated steatotic liver disease (MASLD) to evaluate their accuracy in predicting advanced liver fibrosis against other well-validated noninvasive markers. Methods: Group 1: n=83 CVH and group 2: n=38 MASLD patients underwent liver biopsy and transient elastography (TE) on the same day as sera collection. FibroMeter scores APRI and FIB-4 were calculated in all 121 patients, while MASLD fibrosis score (MFS) was also calculated in group 2. Results: In CVH, FibroMeter VCTE performed equivalently to TE and better than the other markers in predicting advanced (≥F3) and significant (≥F2) fibrosis (area under the receiver operating characteristic curve [AUC] 0.887, P<0.001 for F3; AUC 0.766 P<0.001 for F2). FibroMeter Virus (cutoff 0.61) had lower sensitivity (20%) but performed equivalently to APRI and FIB-4. In MASLD, all markers but APRI performed equivalently in predicting advanced fibrosis. FibroMeter VCTE >0.2154 had the same sensitivity (100%) and specificity (81%) as TE (cutoff >7.1 kPa). FibroMeter MASLD >0.25 performed equivalently to MFS and FIB4, but with higher specificity (100%). Both FibroMeter and FibroMeter VCTE correlated with liver histology but not with liver enzymes. Conclusions: FibroMeter VCTE predicts accurately advanced fibrosis in CVH and MASLD, irrespectively of transaminase levels. FibroMeter Virus can be applied only as an alternative marker in CVH, while FibroMeter MASLD performs equally to TE and calculated scores (MFS, FIB-4) in predicting advanced fibrosis in MASLD patients.

Investigation of Clinically Significant Molecular Aberrations in Patients with Prostate Cancer: Implications for Personalized Treatment, Prognosis and Genetic Testing.

The data on tumor molecular profiling of European patients with prostate cancer is limited. Our aim was to evaluate the prevalence and prognostic and predictive values of gene alterations in unselected patients with prostate cancer. The presence of gene alterations was assessed in patients with histologically confirmed prostate cancer using the ForeSENTIA® Prostate panel (Medicover Genetics), targeting 36 clinically relevant genes and microsatellite instability testing. The primary endpoint was the prevalence of gene alterations in homologous recombination repair (HRR) genes. Overall, 196 patients with prostate cancer were evaluated (median age 72.2 years, metastatic disease in 141 (71.9%) patients). Gene alterations were identified in 120 (61%) patients, while alteration in HRR genes were identified in 34 (17.3%) patients. The most commonly mutated HRR genes were ATM (17, 8.7%), BRCA2 (9, 4.6%) and BRCA1 (4, 2%). The presence of HRR gene alterations was not associated with advanced stage (p = 0.21), age at diagnosis (p = 0.28), Gleason score (p = 0.17) or overall survival (HR 0.72; 95% CI: 0.41-1.26; p = 0.251). We identified clinically relevant somatic gene alterations in European patients with prostate cancer. These molecular alterations have prognostic significance and therapeutic implications and/or may trigger genetic testing in selected patients. In the era of precision medicine, prospective research on the predictive role of these alterations for innovative treatments or their combinations is warranted.

The impact of cryopreservation on both sperm HPV-negative and positive subtypes.

It is well known that various human papillomavirus (HPV) genotypes are present in semen specimens. Also, it has been demonstrated that sperm parameters are negatively affected when HPV infection is present in the sperm sample. Besides all these, the effect of cryopreservation on HPV sensitivity and resistance is not known. The aim of the present study is to evaluate first the prevalence of HPV and secondly to elucidate whether cryopreservation of sperm HPV-positive samples has any effect on the viability of HPV. For this purpose, a cohort of 78 sperm specimens was used from a respective number of patients. After giving informed consent, semen analysis was performed. Each sperm sample was divided into four equal aliquots. The first one (fresh) was evaluated for the prevalence of HPV, while the other three aliquots were cryopreserved by adding an equal quantity of cryoprotectant and plunged into the LN. Each of the three aliquots was thawed 3, 6, and 12 months later, respectively, so as to evaluate whether there is a time-resistance period of HPV prevalence. HPV infection was found to be in eleven sperm samples, demonstrating a 14.1% (11/78) HPV prevalence. Among the HPV-positive samples, six of them were high-risk and the remaining were low-risk genotypes. Moreover, the high-risk fresh samples demonstrated higher motility values than the low-risk samples (60% ± 2.7 vs 45.6% ± 3.7, p < .05), while semen volume in the high-risk samples was significantly lower than the respective volume in the low-risk samples (2.26 ± 0.2ml vs 3.5 ± 0.6ml, p < .05). Interestingly, cryopreservation of the HPV-positive samples resulted in the sustainability and time-resistance of HPV in all high-risk HPV-positive samples, something that was not the case with the low-risk HPV-positive samples. Conclusively, sperm samples infected with high-risk HPV, demonstrate lower sperm parameters and time-resistance activity during cryopreservation.

Mutational profile of primary clear cell renal cell carcinoma predicts recurrence and potential candidacy for adjuvant immune checkpoint inhibition.

Background: The risk of recurrence after nephrectomy for primary clear cell renal cell carcinoma (ccRCC) is estimated in daily practice solely based on clinical criteria. The aim of this study was to assess the prognostic relevance of common somatic mutations with respect to tumor aggressiveness and outcomes of ccRCC patients after definitive treatment. Methods: Primary tumors from 37 patients with ccRCC who underwent radical nephrectomy were analyzed for presence of somatic mutations using a 15-gene targeted next-generation sequencing (NGS) panel. Associations to histopathologic characteristics and outcomes were investigated in the study cohort (n=37) and validated in The Cancer Genome Atlas (TCGA) ccRCC cohort (n=451). Results: VHL was the most frequently mutated gene (51%), followed by PBRM1 (27%), BAP1 (13%), SETD2 (13%), KDM5C (5%), ATM (5%), MTOR (5%), and PTEN (3%). One-third of patients did not have any somatic mutations within the 15-gene panel. The vast majority of tumors harboring no mutations at all or VHL-only mutations (51%) were more frequently of smaller size (pT1-2) and earlier stage (I/II), whereas presence of any other gene mutations in various combinations with or without VHL was enriched in larger (pT3) and higher stage tumors (III) (p=0.02). No recurrences were noted in patients with unmutated tumors or VHL-only mutations as opposed to three relapses in patients with non- VHL somatic mutations (p=0.06). Presence of somatic mutations in PBRM1, BAP1, SETD2, KDM5C, ATM, MTOR, or PTEN genes in 451 TCGA ccRCC patients was associated with a significantly shorter disease-free survival (DFS) compared to those with unaltered tumors (q=0.01). Conclusions: Preliminary findings from this ongoing study support the prognostic value of non- VHL mutations including PBRM1, BAP1, SETD2, KDM5C, ATM, MTOR, and PTEN in primary ccRCC tumors as surrogates of earlier recurrence and potential selection for adjuvant immune checkpoint inhibition.

Hemophagocytic lymphohistiocytosis diagnosed by bone marrow trephine biopsy in living post-COVID-19 patients: case report and mini-review.

Hemophagocytic lymphohistiocytosis (HLH) constitutes a life-threatening inflammatory syndrome. Postmortem histological findings of bone marrow (BM) from COVID-19 patients showed histiocytosis and hemophagocytosis and supported the hypothesis that secondary HLH (sHLH) may be triggered by SARS-CoV-2 infection. However, there are a limited number of sHLH cases in which trephine has been performed in living post-COVID-19 patients. Here we present a recent case and a mini-review of sHLH diagnosed by trephine biopsy in living patients after COVID-19. An 81-year-old man with a past medical history of hypertension, diabetes, ischemic stroke, was referred to the hospital to evaluate leukocytosis, pyuria, and elevation of inflammatory markers four weeks after recovering from COVID-19. Computed tomography of the abdomen did not reveal focal signs of infection or hepatosplenomegaly. The patient received intravenous meropenem and two packed red blood cell units. Leukocytes and C-reactive protein were gradually decreased. A BM biopsy was performed and the patient was discharged on cefixime. BM smear revealed severe anemia, lymphopenia, and dysplastic morphologic findings of erythroblasts, neutrophils, and megakaryocytes. Trephine biopsy revealed hypercellular marrow dyserythropoiesis, plasmacytosis, lymphocytosis, histiocytosis, hemophagocytosis, and the absence of granulomas or carcinoma. Immunohistochemistry documented a mixed population of T lymphocytes (CD3+) and B lymphocytes (CD20+). Strong positivity for CD68 confirmed histiocytosis. CD138 κ, λ staining proved polyclonal plasmacytosis. Perl's staining showed excess hemosiderin deposits. Based on our findings, we document sHLH in trephine BM biopsy of a living post-COVID-19 patient and persistent leukocytosis, underscoring the diagnostic value of trephine biopsy in preventing life-threatening conditions such as COVID-19.

Altered DNA methylation pattern characterizes the peripheral immune cells of patients with autoimmune hepatitis.

BACKGROUND AND AIMS: Little is known about the impact of DNA methylation modifications on autoimmune hepatitis (AIH) pathogenesis and therapeutic response. We investigated the potential alterations of DNA methylation in AIH peripheral lymphocytes at diagnosis and remission. METHODS: Ten AIH patients at diagnosis (time-point 1; AIH-tp1), 8/10 following biochemical response (time-point 2; AIH-tp2), 9 primary biliary cholangitis (PBC) and 10 healthy controls (HC) were investigated. Peripheral CD19(+) and CD4(+) cells were isolated. Global DNA methylation (5m C)/hydroxymethylation (5hm C) was studied by ELISAs. mRNA of DNA methylation (DNMT1/3A/3B) and their counteracting hydroxymethylation enzymes (TET1/2/3) was determined by quantitative RT-PCR. Epigenome wide association study (EWAS) was performed in CD4(+) cells (Illumina HumanMethylation 850 K array) in AIH and HC. Total 5m C/5hm C was also assessed by immunohistochemistry (IHC) on paraffin-embedded liver sections. RESULTS: Reduced TET1 and increased DNMT3A mRNA levels characterized CD19(+) and CD4(+)-lymphocytes from AIH-tp1 compared to HC and PBC, respectively, without affecting global DNA 5m C/5hm C. In AIH-tp1, CD4(+) DNMT3A expression was negatively correlated with serum IgG (P = .03). In remission, DNMT3A decreased in both CD19(+) and CD4(+) cells compared to AIH-tp1 (P = .02, P = .03 respectively). EWAS in CD4(+) cells from AIH patients confirmed important modifications in genes implicated in immune responses (HLA-DP, TNF, lnRNAs and CD86). IHC showed increased 5hm C staining of periportal infiltrating lymphocytes in AIH-tp1 compared to HC and PBC. CONCLUSION: Altered TET1 and DNMT3A expressions, characterize peripheral lymphocytes in AIH. DNMT3A was associated with disease activity and decreased following remission. Gene DNA methylation modifications affect immunological pathways that may play an important role in AIH pathogenesis.

Patient with prostatic adenocarcinoma with plasmacytoid features and an aberrant immunohistochemical phenotype diagnosed by biopsy and a mini-review of plasmacytoid features in the genitourinary system: A case report.

Prostate cancer is one of the most commonly diagnosed malignancies in men. Most of these tumors are adenocarcinomas. Plasmacytoid is a rare variant of adenocarcinoma described by previous studies in the genitourinary system and is characterized by the plasmacytoid appearance of tumor cells with abundant cytoplasm and abnormally placed hyperchromatic nuclei. However, to the best of our knowledge, plasmacytoid adenocarcinoma has rarely been described in the prostate. This report describes a new case of plasmacytoid adenocarcinoma of the prostate diagnosed by biopsy and summarizes the known literature on plasmacytoid features in the genitourinary system. A 62-year-old male patient presented to the hospital with urinary retention, hematuria, weakness and weight loss. The digital rectal examination revealed an irregular enlargement. Laboratory findings showed elevated levels of prostate specific antigen (PSA; 43.6 ng/ml). Transrectal ultrasound showed invasion of the right seminal vesicle. Prostate tumor core biopsies were collected and sent for diagnosis. Histological examination revealed a high-grade prostatic adenocarcinoma Gleason score of 5+5 (total score 10). The tumor cells had a plasmacytoid appearance with abundant cytoplasm and abnormally placed hyperchromatic nuclei. The immunohistochemical phenotype was characterized by abundant positivity for cytokeratin (CK)AE1/AE3 and PSA. By contrast, tumor cells were negative for p63, CK 34BE12 and GATA binding protein 3 (urothelial markers), synaptophysin (neuroendocrine marker). Tumor cells were also negative for E-cadherin, which is particularly indicative of CDH1 alterations. To the best of our knowledge, this is the first description of a plasmacytoid adenocarcinoma of the prostate diagnosed by biopsy, showing an irregular immunophenotype that may indicate somatic CDH1 alterations. The presentation of a novel rare variant of prostatic carcinoma that differs from other neoplasms of the genitourinary system may contribute to an improved understanding of this uncommonly found histological pattern that may also be mandatory due to the clinical and prognostic implications of this diagnosis.

Renin-Angiotensin System Single Nucleotide Polymorphisms Are Associated with Bladder Cancer Risk.

The renin-angiotensin system (RAS), besides being a major regulator of blood pressure, is also involved in tumor angiogenesis. Emerging evidence suggests a correlation between the use of pharmacologic RAS inhibitors and a delay in urothelial bladder cancer (BC) progression. However, it is unknown whether RAS gene variants may predispose to the development of BC. This study examined the association of RAS single nucleotide polymorphisms (SNPs) including AT1R rs5186, AT2R rs11091046, REN rs12750834, ANG rs4762, and ANG rs699 with the risk of developing non-invasive BC. Peripheral blood samples from 73 patients with T1 urothelial BC (66 men, seven women) and an equal number of healthy subjects (control group) were collected. The TT genotype of the REN rs12750834 SNP (OR: 2.8 [1.3-6.05], p = 0.008) and to a lesser extent the presence of the T allele (OR: 2.3 [1.2-4.48], p = 0.01) conferred a higher risk of BC. The highest risk for BC within SNP carriers of the RAS system was associated with the presence of the CC genotype (OR: 17.6 [7.5-41.35], p < 0.001) and C allele (OR: 17.7 [8.8-35.9], p < 0.001) of the ANG rs699 SNP. The presence of the AT2R rs11091046 SNP, particularly the AA genotype, was associated with a protective effect against developing BC (OR: 0.268 [0.126-057], p < 0.001). In conclusion, these results support the clinical utility of RAS gene SNPs AT2R rs11091046, REN rs12750834, and ANG rs699 in the genetic cancer risk assessment of patients and families with BC.

Bursitis of the coccyx in an adult with rheumatoid arthritis mimicking a sacrococcygeal meningocele.

BACKGROUND: Bursitis is a chronic inflammatory condition characterized by the deposition of cholesterol, macrophage infiltration, and bursal wall calcification. Bursitis is, however, rarely found in the sacrococcygeal region where it may present as a space-occupying mass. CASE DESCRIPTION: A 64-year-old male with rheumatoid arthritis presented with 3 years' duration of difficulty sitting and walking due to a soft-tissue mass involving the coccyx region. Once the patient's MR demonstrated a cystic lesion with erosion of the coccyx, the patient underwent gross total resection of the lesion that proved to be pathologically consistent with bursitis. Postoperatively, the patient's complaints fully resolved. CONCLUSION: Bursitis may present as a soft-tissue tumor-like lesion in the coccyx that favorably responds to gross total surgical excision.

DNA Repair Gene Polymorphisms and Susceptibility to Urothelial Carcinoma in a Southeastern European Population.

Single nucleotide polymorphisms (SNPs) in DNA repair genes may predispose to urothelial carcinoma of the bladder (UCB). This study focused on three specific SNPs in a population with high exposure to environmental carcinogens including tobacco and alcohol. A case-control study design was used to assess for presence of XPC PAT +/-, XRCC3 Thr241Met, and ERCC2 Lys751Gln DNA repair gene SNPs in peripheral blood from patients with UCB and healthy individuals. One hundred patients and equal number of healthy subjects were enrolled. The XPC PAT +/+ genotype was associated with a 2-fold increased risk of UCB (OR = 2.16; 95%CI: 1.14-4; p = 0.01). The -/+ and +/+ XPC PAT genotypes were more frequently present in patients with multiple versus single tumors (p = 0.01). No association was detected between ERCC2 Lys751Gln genotypes/alleles, and risk for developing UCB. Presence of the XRCC3 TT genotype (OR = 0.14; 95%CI:0.07-0.25; p < 0.01) and of the T allele overall (OR = 0.26; 95%CI:0.16-0.41; p < 0.01) conferred a protective effect against developing UCB. The XPC PAT -/+ and XRCC3 Thr241Met SNPs are associated with predisposition to UCB. The XPC PAT -/+ SNP is also an indicator of bladder tumor multiplicity, which might require a more individualized surveillance and treatment.

Promyelocytic Leukemia Antigen Expression: a Histological Marker for Primary Biliary Cholangitis Diagnosis?

BACKGROUND AND OBJECTIVES: Distinguishing primary biliary cholangitis (PBC) from other cholestatic diseases at the histological level could be assisted by new methods, such as immunohistochemical staining of specific antigens. METHODS: We evaluated whether the detection of promyelocytic leukemia protein (PML) can serve as a specific and sensitive marker for PBC diagnosis. Liver biopsies from 26 PBC patients, 20 primary sclerosing cholangitis (PSC), 37 viral hepatitis, 11 non-alcoholic steatohepatitis (NASH) and 5 normal patients were investigated after immunostaining with the anti-PML monoclonal PG-M3, IgG1 antibody. RESULTS: Immunoreactivity in bile ducts was expressed by the PML-score (quotient of positive ducts to the total number of portal tracts multiplied by 2). PML-score was higher in PBC as compared to controls (P < 0.001). Using a cutoff of 0.18, PML-score proved highly sensitive (84.6%) and specific (89.7%) for confirming PBC as compared to only 5% of PSC, 9.1% of NASH and 13.5% of viral hepatitis patients (P < 0.001). Irrespective of the underlying disease, patients with PML-score > 0.18 were older (P = 0.007), more often females (P < 0.001) with higher ALP (P < 0.001), γ-GT (P = 0.001) and IgM (P < 0.001) compared to the patients with PML-score < 0.18. CONCLUSIONS: We postulate that a simple PML immunohistochemical test could be sufficient for histopathological discrimination of PBC in problematic cases of undefined cholestatic disorders, including small-duct PSC and AMA-negative PBC cases.

Alcoholic liver disease and autoimmune hepatitis: Sometimes a closer look under the surface is needed.

AIMS: Differential diagnosis of autoimmune hepatitis (AIH) incorporates various liver diseases, including alcoholic liver disease (ALD). We report on clinical, laboratory and outcome characteristics of AIH patients who were initially referred as ALD based on increased alcohol consumption (AIH/ALD). METHODS: From 2000-2019, we retrospectively identified 12 AIH/ALD patients [9 males, age: 61 (30-73) years] in our prospective data base of 317 AIH patients. RESULTS: AIH diagnosis was based on aminotransferases elevation in 10 patients, high IgG in 8, compatible autoantibody profile in all and typical/compatible histology in all 9 with available biopsy. There were no significant differences of baseline demographics, presentation, cirrhosis at diagnosis, response to treatment and simplified score compared to 45 age- and sex-matched AIH patients without alcohol consumption and 44 age- and sex-matched ALD patients. However, the AIH/ALD cohort was characterized by more frequent progression to cirrhosis, higher liver-related deaths and overall mortality compared to AIH, though similar to the ALD group. AST/ALT ratio>1 seems to bear a good positive (0.84) and negative predictive value (0.88) for ALD and AIH diagnosis, respectively, but cannot help in discriminating the AIH/ALD variant. CONCLUSIONS: AIH should not be forgotten in patients with alcohol use when clinical and laboratory features hint towards the diagnosis of AIH/ALD variant as this group seems to have worse outcome compared to those with AIH alone suggesting the need for closer follow-up and surveillance. Reliable autoantibody testing and cautious interpretation of liver histology appear mandatory for AIH diagnosis in these difficult to diagnose cases.

FibroMeter scores for the assessment of liver fibrosis in patients with autoimmune liver diseases.

INTRODUCTION AND OBJECTIVES: We assessed FibroMeter virus (FMvirus) and FibroMeter vibration-controlled transient elastography (FMVCTE) in 134 patients with autoimmune liver diseases [ALD, autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC)], in order to assess new potential non-invasive biomarkers of liver fibrosis in patients with ALD, as similar data are missing. PATIENTS AND METHODS: The following groups were included: group 1: n = 78 AIH; group 2: n = 56 PBC. FMvirus and FMVCTE were determined in all 134 patients who underwent liver biopsy and TE the same day with sera collection. In addition, APRI and FIB-4 scores were calculated. RESULTS: The AUCs for TE and FMVCTE were significantly better (0.809; p < 0.001 and 0.772; p = 0.001, respectively for AIH and 0.997; p < 0.001 and 1; p < 0.001, for PBC) than the other three markers in predicting ≥ F3 fibrosis irrespective of the biochemical activity. FMVCTE and TE had good diagnostic accuracy (75.6% and 73%, respectively) for predicting severe fibrosis in AIH and performed even better in PBC (94.6% and 96.4%, respectively). The cut-offs of TE and FMVCTE had the best sensitivity and specificity in predicting ≥ F3 fibrosis in both AIH and PBC. CONCLUSIONS: FMVCTE seems to detect severe fibrosis equally to TE in patients with ALD but with better specificity. Biochemical disease activity did not seem to affect their diagnostic accuracy in ALD and therefore, could be helpful for the assessment of fibrosis, especially if they are performed sequentially (first TE with the best sensitivity and then FMVCTE with the best specificity).

Non-alcoholic steatohepatitis or autoimmune hepatitis? Sometimes a closer look under the surface is needed.

Non-alcoholic fatty liver disease (NAFLD) is nowadays the most common liver disease worldwide. Autoimmune hepatitis (AIH) is a relatively rare disease of the liver characterised by female predominance, circulating autoantibodies, polyclonal hypergammaglobulinaemia, interface hepatitis on histology and favourable response to immunosuppression. The possibility of an additional AIH diagnosis in patients with NAFLD (NAFLD/AIH concurrence) or the presence of AIH alone instead of a supposed NAFLD diagnosis represents a challenge for clinicians. We report herein two adult patients (a 33-year-old woman and a 59-year-old man) with a previous NAFLD diagnosis who proved finally to suffer from AIH alone. These two representative cases indicate how difficult and complicated could be sometimes the diagnosis of patients with AIH highlighting the range of disease manifestations and severity while they also underline that although NAFLD is by far the most frequent chronic liver disease this could not be always the case.

Belimumab is a promising third-line treatment option for refractory autoimmune hepatitis.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a disease of unknown aetiology with a favourable response to immunosuppression. However, in the clinic, it appears that <50% of patients achieve complete response on standard treatment. Serum B cell-activating factor (BAFF) levels are elevated in patients with AIH and are likely to contribute to disease pathogenesis. Given that belimumab, a BAFF inhibitor, has been shown to be effective in other autoimmune diseases, we investigated its use as a third-line add-on treatment option in patients with advanced AIH who did not respond to conventional treatment. METHODS: Herein, we report for the first time two patients, a 27-year-old female and a 58-year-old male, both with AIH-related compensated cirrhosis at diagnosis, who were refractory to standard immunosuppressive therapies and received add-on third-line therapy with belimumab. RESULTS: Both patients achieved a complete response and remained in remission while receiving low-dose corticosteroids. No adverse events related to belimumab and/or disease decompensation were observed. CONCLUSIONS: These preliminary findings indicate belimumab as a promising treatment option for patients with AIH and refractory and advanced liver-related fibrosis. LAY SUMMARY: A small proportion of patients with autoimmune hepatitis (AIH) are refractory to standard treatments; these patients bear the highest probability of developing decompensated cirrhosis and hepatocellular carcinoma because third-line treatment options are not well established. In this case study, we showed that third-line add-on therapy with belimumab, a B cell-activating factor inhibitor, could be an alternative and promising treatment option in patients with advanced AIH who did not respond to conventional treatment.

Alveolar rhabdomyosarcoma with unusual cytogenetic findings: one more case and review of the literature.

Alveolar rhabdomyosarcoma (ARMS), a histological subtype of rhabdomyosarcoma (RMS), is characterized by an unfavorable clinical outcome. In most ARMS cases, an indicative chromosomal alteration is identified. The recurrent translocation of FKHR with either PAX3 or PAX7 genes results in the encoding of chimeric transcription factors that boost tumorigenesis. Besides structural mutations, the copy number of these genes also contributes to the oncogenic activity. In our case, a 12-year-old female patient was diagnosed with a 4 cm pelvic mass. Histopathological examination indicated an alveolar type of RMS. Subsequent FISH analysis with a dual color break-apart probe identified positive signals of FKHR3 gene break, as well as the rare event of a synchronous aneuploidy and gene deletion of FKHR. Our findings lead to the conclusion that a systematic break-apart probe FKHR FISH analysis in ARMS, confirms the diagnosis and elucidates the full spectrum of genomic alterations of this malignancy.

Implementation of HPV-based Cervical Cancer Screening Combined with Self-sampling Using a Midwifery Network Across Rural Greece: The GRECOSELF Study.

Self-sampling for human papillomavirus (HPV) testing is an alternative to physician sampling particularly for cervical cancer screening nonattenders. The GRECOSELF study is a nationwide observational cross-sectional study aiming to suggest a way to implement HPV-DNA testing in conjunction with self-sampling for cervical cancer screening in Greece, utilizing a midwifery network. Women residing in remote areas of Greece were approached by midwives, of a nationwide network, and were provided with a self-collection kit (dry swab) for cervicovaginal sampling and asked to answer a questionnaire about their cervical cancer screening history. Each sample was tested for high-risk (hr) HPV with the Cobas HPV test. HrHPV-Positive women were referred to undergo colposcopy and, if needed, treatment according to colposcopy/biopsy results. Between May 2016 and November 2018, 13,111 women were recruited. Of these, 12,787 women gave valid answers in the study questionnaire and had valid HPV-DNA results; hrHPV prevalence was 8.3%; high-grade cervical/vaginal disease or cancer prevalence was 0.6%. HrHPV positivity rate decreased with age from 20.7% for women aged 25-29 years to 5.1% for women aged 50-60 years. Positive predictive value for hrHPV testing and for HPV16/18 genotyping ranged from 5.0% to 11.6% and from 11.8% to 27.0%, respectively, in different age groups. Compliance to colposcopy referral rate ranged from 68.6% (for women 25-29) to 76.3% (for women 40-49). For women residing in remote areas of Greece, the detection of hrHPV DNA with the Cobas HPV test, on self-collected cervicovaginal samples using dry cotton swabs, which are provided by visiting midwives, is a promising method for cervical cancer secondary prevention.

Glycogenic hepatopathy as a cause of severe deranged liver enzymes in a young patient with type 1 diabetes mellitus.

Glycogenic hepatopathy (GH) is a rare complication of poorly controlled type 1 diabetes mellitus (T1DM). We present a 19-year-old woman with T1DM and autoimmune thyroiditis who admitted to our department because of abrupt onset intermittent abdominal pain in the right upper quadrant accompanied by laboratory evidence of acute anicteric hepatitis. Physical examination revealed significant hepatomegaly but the common imagining studies were negative. Following exclusion of common causes of acute hepatitis and because of the presence of smooth muscle antibodies in a young female patient with already established two autoimmune diseases, a liver biopsy was performed in order to exclude the potential presence of autoimmune hepatitis. However, liver histology showed typical findings of GH. Intense treatment targeting strict glycemic control resulted in normalisation of liver biochemistry. This case underlines that GH should be considered as a rare cause of acute hepatitis in T1DM patients with poor glycemic control.

Prognostic significance of tumor genotypes and CD8+ infiltrates in stage I-III colorectal cancer.

BACKGROUND: We explored the clinical significance of tumor genotypes and immunophenotypes in non-metastatic colorectal cancer (CRC). METHODS: In primary tumors (paraffin blocks) from 412 CRC patients treated with adjuvant chemotherapy, we examined pathogenic mutations (panel NGS; 347 informative); mismatch repair (MMR) immunophenotype (360 informative); and CD8+ lymphocyte density (high - low; 412 informative). The primary outcome measure was disease-free survival (DFS). RESULTS: We evaluated 1713 pathogenic mutations (median: 3 per tumor; range 0-49); 118/412 (28.6%) tumors exhibited high CD8+ density; and, 40/360 (11.1%) were MMR-deficient. Compared to MMR-proficient, MMR-deficient tumors exhibited higher CD8+ density (chi-square, p<0.001) and higher pathogenic mutation numbers (p=0.003). High CD8+ density was an independent favorable prognosticator (HR=0.49, 95%CI 0.29-0.84, Wald's p=0.010). Pathogenic BRCA1 and ARID1A mutations were inversely associated with each other (p<0.001), were not associated with MMR-deficiency or CD8+ density, but both independently predicted for unfavorable DFS (HR=1.98, 95%CI 1.12-3.48, p=0.018 and HR=1.99, 95%CI 1.11-3.54, p=0.020, respectively). CONCLUSION: In non-metastatic CRC, high CD8+ lymphocyte density confers a favorable prognosis and may be developed as a single marker in routine diagnostics. The unfavorable prognostic effect of pathogenic BRCA1 and ARID1A mutations is a novel observation that, if further validated, may improve treatment selection.

Human Papilloma Virus (HPV) and Fertilization: A Mini Review.

Human papilloma virus (HPV) is one of the most prevalent viral sexually transmitted diseases. The ability of HPV to induce malignancy in the anogenital tract and stomato-pharyngeal cavity is well documented. Moreover, HPV infection may also affect reproductive health and fertility. Although, the impact of HPV on female fertility has not been thoroughly studied it has been found also to have an impact on semen parameters. Relative information can be obtained from studies investigating the relationship between HPV and pregnancy success. Furthermore, there is an ongoing debate whether HPV alters the efficacy of assisted reproductive technologies. An association between HPV and assisted reproductive technologies (ART) programs has been reported. Nevertheless, due to conflicting data and the small number of existing studies further research is required. It remains to be clarified whether HPV detection and genotyping could be included in the diagnostic procedures in couples undergoing in vitro fertilization (IVF)/intrauterine insemination (IUI) treatments. Vaccination of both genders against HPV can reduce the prevalence of HPV infection and eliminate its implications on human fertility. The aim of the present mini-review is to reiterate the association between HPV and human fertility through a systematic literature review.