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Abstract Background Whereas the antimicrobial peptides hBD-2 and -3 are related to inflammation, the constitutively expressed hBD-1 might function as 8p tumour suppressor gene and thus play a key role in control of transcription and induction of apoptosis in malignant epithelial tumours. Therefore this study was conducted to characterise proteins involved in cell cycle control and host defence in different benign and malignant salivary gland tumours in comparison with healthy salivary gland tissue. Methods 21 paraffin-embedded tissue samples of benign (n = 7), and malignant (n = 7) salivary gland tumours as well as healthy (n = 7) salivary glands were examined immunohistochemically for the expression of p53, bcl-2, and hBD-1, -2, -3. Results HBD-1 was distributed in the cytoplasm of healthy salivary glands and benign salivary gland tumours but seems to migrate into the nucleus of malignant salivary gland tumours. Pleomorphic adenomas showed cytoplasmic as well as weak nuclear hBD-1 staining. Conclusion HBD-1, 2 and 3 are traceable in healthy salivary gland tissue as well as in benign and malignant salivary gland tumours. As hBD-1 is shifted from the cytoplasm to the nucleus in malignant salivary gland tumours, we hypothesize that it might play a role in the oncogenesis of these tumours. In pleomorphic adenomas hBD-1 might be connected to their biologic behaviour of recurrence and malignant transformation.

Objectives: Image-based detection of intralesional fat in focal liver lesions has been established in diagnostic guidelines as a feature indicative of hepatocellular carcinoma (HCC) and associated with a favorable prognosis. Given recent advances in MRI-based fat quantification techniques, we investigated a possible relationship between intralesional fat content and histologic tumor grade in steatotic HCCs., Methods: Patients with histopathologically confirmed HCC and prior MRI with proton density fat fraction (PDFF) mapping were retrospectively identified. Intralesional fat of HCCs was assessed using an ROI-based analysis and the median fat fraction of steatotic HCCs was compared between tumor grades G1-3 with non-parametric testing. ROC analysis was performed in case of statistically significant differences (p < 0.05). Subgroup analyses were conducted for patients with/without liver steatosis and with/without liver cirrhosis., Results: A total of 57 patients with steatotic HCCs (62 lesions) were eligible for analysis. The median fat fraction was significantly higher for G1 lesions (median [interquartile range], 7.9% [6.0─10.7%]) than for G2 (4.4% [3.2─6.6%]; p = .001) and G3 lesions (4.7% [2.8─7.8%]; p = .036). PDFF was a good discriminator between G1 and G2/3 lesions (AUC .81; cut-off 5.8%, sensitivity 83%, specificity 68%) with comparable results in patients with liver cirrhosis. In patients with liver steatosis, intralesional fat content was higher than in the overall sample, with PDFF performing better in distinguishing between G1 and G2/3 lesions (AUC .92; cut-off 8.8%, sensitivity 83%, specificity 91%)., Conclusions: Quantification of intralesional fat using MRI PDFF mapping allows distinction between well- and less-differentiated steatotic HCCs., Clinical Relevance: PDFF mapping may help optimize precision medicine as a tool for tumor grade assessment in steatotic HCCs. Further investigation of intratumoral fat content as a potential prognostic indicator of treatment response is encouraged., Key Points: • MRI proton density fat fraction mapping enables distinction between well- (G1) and less- (G2 and G3) differentiated steatotic hepatocellular carcinomas. • In a retrospective single-center study with 62 histologically proven steatotic hepatocellular carcinomas, G1 tumors showed a higher intralesional fat content than G2 and G3 tumors (7.9% vs. 4.4% and 4.7%; p = .004). • In liver steatosis, MRI proton density fat fraction mapping was an even better discriminator between G1 and G2/G3 steatotic hepatocellular carcinomas., (© 2023. The Author(s).)

Background: The hTERT promoter mutation represents a common and early event in hepatocarcinogenesis, but its linkage to the morphological status of the underlying liver tissue is poorly understood. We analyzed the connection between the histopathological changes in tumor-bearing liver tissue and the occurrence of the hTERT promoter mutation in hepatocellular carcinoma (HCC), correlated with clinical data., Methods: The study cohort comprised 160 histologically confirmed HCC in patients with or without cirrhosis that were investigated for the hTERT promoter mutation. We evaluated the frequency of the hTERT promoter mutation in patients with HCC with or without cirrhosis and correlated it with potential clinical and histopathological drivers. In particular, we examined tumor-bearing noncirrhotic liver tissue regarding inflammation; the modified histological activity index (mHAI), fibrosis, and steatosis; and its correlation with the frequency of the hTERT promoter mutation in HCC. We evaluated overall survival with multivariate Cox regression. Furthermore, we compared hTERT antibody immunohistochemistry and molecular hTERT promoter mutation analysis of both HCC and background liver tissue., Results: The hTERT promoter mutation was especially related to HCC in cirrhotic compared with noncirrhotic liver ( p < 0.001) and independently of cirrhosis in patients ≥ 60 years ( p = 0.005). Furthermore, the hTERT promoter mutation was associated with cirrhosis caused by alcohol toxicity and hepatitis C virus infection. In noncirrhotic liver tissue, the frequency of hTERT -promoter-mutated HCC increased with the degree of inflammation and fibrosis. Nevertheless, 25% of the hTERT -promoter-mutated HCC developed in normal liver tissue without HCC risk factors. Multivariate Cox regression analysis did not reveal an influence of the hTERT promoter mutation in HCC on overall survival at 3, 5, and 16 years. Immunohistochemical analysis with the hTERT antibodies LS-B95 and 2D8 in hTERT -promoter-mutated HCC and hTERT -wildtype HCC showed a mildly stronger immunoreaction compared with the tumor-bearing liver tissue (LS-B95: p < 0.01, 2D8: p < 0.01)., Conclusions: Our study reveals a connection between pathological changes in tumor-bearing liver tissue and the hTERT promoter mutation in most HCC, even in noncirrhotic liver tissue. Immunohistochemical hTERT antibodies do not discriminate between hTERT -promoter-mutated and wildtype HCC., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023 Anne Kristin Fischer et al.)

Objective: The aim of the study was to introduce our new modification of the Indiana pouch with a refluxing ureteral anastomosis in a tubular afferent ileal segment of the ileo-caecal urinary reservoir., Patients and Methods: Between February 2008 and December 2020, we performed a total of 37 modified continent ileo-caecal pouches for urinary diversion when orthotopic bladder substitution was not possible. Hereby, we modified the Indiana pouch procedure with a new refluxing end-to-end ureteral anastomosis into an 8-cm afferent tubular ileal segment., Results: We performed the modified Indiana pouch in 27 women (73%) and 10 men (27%). The median age of the patients at time of operation was 64 years (43-80 years). To date, the average follow-up is 69 months (3-156 months). In 32/37 cases, we performed the new pouch procedure after radical cystectomy for muscle-invasive bladder cancer and in 1/37 cases after radical cystectomy for locally advanced prostate cancer. In 4 cases, the procedure was performed after total exenteration of the pelvis due to locally advanced bladder, colorectal, or gynaecological cancers. Ureteral anastomotic strictures were seen in 2/37 patients (5.4%) or 2/72 (2.8%) of renal units., Conclusions: Our modification of the Indiana pouch cutaneous continent urinary diversion with the ureteral anastomosis to a tubular segment of the pouch is easy to perform and effective in reducing the rate of ureteral anastomotic strictures. By lengthening, the afferent tubular ileal segment, it additionally allows easy ureteral replacement., (© 2021 S. Karger AG, Basel.)

The early and definitive diagnosis of malignant bile duct stenoses is essential for a timely and adequate therapy. However, tissue sampling with transpapillary brush cytology (BC) or forceps biopsy (FB) remains challenging. With this study, we aimed to compare the effectiveness and safety of different tissue sampling modalities (BC, FB without/after previous balloon dilatation). Standardized database research identified all patients, who underwent endoscopic retrograde cholangiography with BC and/or FB for indeterminate bile duct stenosis between January 2010 and April 2018 and with a definitive diagnosis. 218 patients were enrolled (149 cases with malignant and 69 with benign disease). FB had a significant higher sensitivity than BC (43% vs. 16%, p < 0.01). Prior balloon dilatation of the stenosis improved the sensitivity of FB from 41 to 71% (p = 0.03), the NPV from 36 to 81% (p < 0.01) and the accuracy from 55 to 87% (p < 0.01). The complication rates did not differ significantly between the modalities. In our center FB turned out to be the diagnostically more effective procedure. Balloon dilatation of the stenosis before FB had a significant diagnostic benefit and was not associated with a higher complication rate.

Autoimmune liver diseases comprise a spectrum of progredient idiopathic inflammatory diseases. Typical histological features of autoimmune hepatitis (AIH) include the pattern of chronic hepatitis with predominant plasma cell-rich interface activity, rosetting of hepatocytes, and emperipolesis. Florid bile duct lesions are the key feature of primary biliary cholangitis (PBC); onion-like periductal fibrosis characterizes the primary sclerosing cholangitis (PSC). Variants of AIH, or overlap syndromes, show intersecting histomorphologic findings with PBC or PSC. The diagnosis of the different autoimmune inflammatory liver diseases is based on clinical presentation, a hepatitic or cholestatic pattern of liver enzymes, immuno-serological findings, image analysis in PSC, and liver biopsy as a facultative or obligatory adjunct. Liver biopsy plays a major role in the diagnosis of AIH, small-duct PSC, AMA-negative PBC, IgG4-related diseases, overlap syndrome, and in the recognition of concurrent liver diseases, especially drug-induced liver diseases. Herewith pathologists can help clinicians find adequate therapy for different autoimmune inflammatory liver diseases.

This review covers a spectrum of pathologic changes and diseases involving hepatic sinusoids. In the majority of patients, clinical findings are rather uncharacteristic such as hepatomegaly, portal hypertension, or lingering liver failure of unknown origin. In contrast to more common hepatic disorders, characteristic clinical, serological, immunoserological, and radiographical findings are lacking. In these cases, biopsy findings may be crucial to guide treatment decisions. This review covers a variety of hepatic disorders that practicing pathologists may encounter in their clinical routine.

Aim: The prostate-specific membrane antigen (PSMA) is currently being established as a potent diagnostic marker in many tumor types. So far, its evidence in hepatocellular carcinoma (HCC) is sparse. The aim of our study was a comprehensive evaluation of PSMA expression and its prognostic role in patients with hepatocellular carcinoma as well as feasibility test of PSMA as an agent for diagnostic imaging., Methods: The cohort for immunohistochemistry consisted of 153 patients with HCC. For validation purposes the HCC cohort (n = 359) of The Cancer Genome Atlas was analyzed on transcript level as well., Results: On immunohistochemistry, non-tumorous liver tissue showed PSMA expression on canalicular membranes in all cases. In tumor tissue two patterns of expression, with a canalicular (41.1% of tumors) and a neovascular (89.9% of tumors) staining were seen. Completely negative for both two patterns were only 4.1% of tumors; conversely, 79.2% of the tumors showed high levels of PSMA protein expression at any location. At mRNA level higher FOLH1 (PSMA) expression rates were statistically significant and independently associated with longer overall survival times.Additionally, a case report of successful diagnostic 68 Ga-PSMA-11 PET/CT in a patient with HCC progression on multiple therapy lines is provided., Conclusions: Majority of hepatocellular carcinomas show high levels of PSMA expression on tumor vessels and on canalicular membrane of the tumor cells. Putative diagnostic, prognostic and therapeutic value of PSMA in HCC warrants further clinically oriented investigations., Competing Interests: CONFLICTS OF INTEREST All authors declare that they have no conflicts of interest.

Musculoskeletal hydatidosis is a rare but severe disease in central Europe. This case report presents the incidental finding of an osseous hydatidosis after cementless revision total hip arthroplasty in a patient without a preoperative history of hydatidosis or any clinical symptoms. Revision total hip arthroplasty had been necessary due to a septic osteonecrosis of the femoral head 2 years after osteosynthesis of a traumatic proximal femur fracture with a sliding hip screw. The positive sample was taken out of the greater trochanter in the area of the possible former entry point for the lag screw, which was macroscopic inconspicuous. Sero-analysis could afterwards confirm the suspected diagnosis. Postoperative chemotherapy with albendazole was performed for 6 months. A full-body MRI did not reveal any further cysts. This case demonstrates a possible impact of migration on the expected pathogens in revision arthroplasty. This demonstrates that in revision arthroplasty, an infection with this parasite also has to be taken into account, if the patients come from an area endemic for hydatidosis.

High resolution cross-sectional imaging techniques means that even small, well-differentiated hepatocellular tumors can also be diagnosed with biopsy. In cirrhotic liver tissue, macroregenerative and dysplastic nodules must be discriminated from hepatocellular cancer (HCC). In non-cirrhotic liver tissue the differential diagnosis includes hepatocellular adenoma, macroregeneratory nodules, fibrolamellar carcinoma, as well as primary tumors and metastases. The diagnostic procedure includes matrix diagnosis of the tumor-bearing liver tissue, cyto- and histomorphologic analysis including capillarization of vascular bed, and adapted immunohistological testing with antibodies which underline possible malignancy or hepatocellular differentiation. A flow chart for the diagnosis of hepatocellular carcinomas and their mimics on liver biopsies is presented.

Fibrous dysplasia is a benign bone disease, presenting as monostotic or polyostotic lesions, or as part of a syndrome (McCune-Albright/Mazabraud). Its clinical course shows a variegated picture and the progression of its growth is unpredictable. In the workup of 39 fibrous dysplasia cases in the cranio-facial area, four cases presented fast growth tendencies, of which two patients with McCune-Albright syndrome showed malignant-like rapid growth. This local aggressive form is extremely rare, and the concept of this issue has not been clearly defined. With regard to the speed of growth a volumetric-time analysis in one of our cases demonstrated a 74 days tumor doubling rate with an exponential growth curve. According to the literature the aggressive form presented extra-cranially mainly at an adult age, whereas its appearance in our cranio-facial patient collective was much younger. Distinguishing nonmalignant and malignant aggressive forms is difficult and highly inconsistent in the literature. We therefore implemented a quantitative growth measure analysis to define aggressive forms based on progression and speed of growth and impartial of type of FD, localization or functional incapacity. Due to our study findings and literature review we state a prevalence of an aggressive form might be possibly about 5 %., (Copyright © 2018 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Anti-PD-1 treatment increases anti-tumour immune responses in animal models of hepatocellular carcinoma (HCC). Sorafenib, the mainstay of treatment of HCC patients, however, leads to tumour hypoxia and thereby abrogates the efficacy of anti-PD-1 treatment. This served as a rationale to implement CXCR4 inhibition as adjunct to sorafenib and anti-PD-1 treatment in murine HCC models. We studied the relationship between tumour hypoxia, PD-L1 and CXCL12 expression in human HCC, aiming to test the rationale for triple therapy combining sorafenib, PD-1 immune checkpoint inhibitors and CXCR4 inhibitors. Expression of CXCL12, PD-L1 and of surrogate markers for tumour hypoxia was evaluated at messenger RNA (mRNA) level in a cohort of HCC patients from The Cancer Genome Atlas and immunohistochemically in an independent cohort from the University Hospital of Bonn. Retrospective survival analyses were conducted. CXCL12 mRNA level significantly correlated with markers indicating tumour hypoxia in HCC (HIF1-α ρ = 0.104, p = 0.047). PD-L1 expression was significantly increased in tumours with a high number of tumour-infiltrating lymphocytes (ρ = 0.533, p < 0.001). In Cox proportional hazard analyses, high PD-L1 expression and loss of nuclear CXCL12 expression showed significant prognostic value in terms of overall survival (hazard ratio (HR) = 3.35 [95%CI 1.33-8.46], p = 0.011 for PD-L1; HR = 2.64 [95%CI 1.18-5.88], p = 0.018 for CXCL12, respectively). This study supports the rationale to combine CXCR4 inhibitors and PD-1 immune checkpoint inhibitors in patients with HCC, as sorafenib-induced tumour hypoxia leads to upregulation of PD-L1 and CXCL12.

Background: Non-cirrhotic idiopathic portal hypertension (NCIPH) is characterized by splenomegaly, anemia and portal hypertension, while liver function is preserved. However, no animal models have been established yet. This study assessed a rat model of NCIPH and characterized the hemodynamics, and compared it to human NCIPH., Methods: Portal pressure (PP) was measured invasively and coloured microspheres were injected in the ileocecal vein in rats. This procedure was performed weekly for 3 weeks (weekly embolization). Rats without and with single embolization served as controls. After four weeks (one week after last embolization), hemodynamics were investigated, hepatic fibrosis and accumulation of myofibroblasts were analysed. General characteristics, laboratory analyses and liver histology were collected in patients with NCIPH., Results: Weekly embolization induced a hyperdynamic circulation, with increased PP. The mesenteric flow and hepatic hydroxyproline content was significantly higher in weekly embolized compared to single embolized rats (mesenteric flow +54.1%, hydroxyproline +41.7%). Mesenteric blood flow and shunt volumes increased, whereas splanchnic vascular resistance was decreased in the weekly embolization group. Fibrotic markers αSMA and Desmin were upregulated in weekly embolized rats., Discussion: This study establishes a model using repetitive embolization via portal veins, comparable with human NCIPH and may serve to test new therapies., Competing Interests: The authors have declared that no competing interests exist.

An 82-year-old male patient presented with a salmon-pink colored conjunctival tumor of the left eye. A circumscribed, dense and whitish portion was detected by clinical examination. The histophological and immunhistochemical examination of the biopsy tissue revealed a CD20+ marginal zone lymphoma of the conjunctiva with amyloid deposits. Extranodal marginal zone lymphoma at this site is the most common lymphoma of the ocular adnexa and accounts for 5-10% of malignant diseases. An association with amyloid production is very rare and according to the current state of knowledge has no known impact on the outcome.