Malignant uterine perivascular epithelioid cell tumor: histopathologic and immunohistochemical characterization of a rare tumor in a post-menopausal woman

Background: Perivascular epithelioid cell tumors (PEComas) are rare, mesenchymal neoplasms composed of epithelioid cells exhibiting myogenic and melanocytic differentiation. The uterus is an infrequent site of involvement. The most common histopathologic mimics include leiomyosarcoma, endometrial stromal sarcoma, undifferentiated uterine sarcoma, and malignant melanoma. Rendering an accurate histopathologic diagnosis is essential, owing to the prognostic and therapeutic implications. Case: A 65-years-old post-menopausal woman presented with post-menopausal bleeding, abdominal pain, and heaviness for the last four months. Ultrasound abdomen revealed a large uterine mass replacing the endometrial cavity. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy. Result: Microscopically, a circumscribed tumor with tumor cells arranged in sheets and interlacing fascicles, with interspersed fine capillary network, was seen. The individual tumor cells were epithelioid to spindle with moderate pleomorphism, round nuclei, vesicular chromatin, prominent macronucleoli, and moderate cytoplasm. Mitosis was 2-3/50 HPFs. On immunohistochemistry, tumor cells were positive for HMB-45, Melan-A, and smooth muscle actin and were negative for h-caldesmon, TFE3, S-100, CD10, and pan-cytokeratin. Based on the histopathologic and immunohistochemical features, a final diagnosis of malignant uterine PEComa was rendered. Conclusions: This index report describes the characteristic histopathologic and immunohistochemical features of malignant uterine PEComa and highlights the salient features that distinguish it from other commonly encountered histopathologic mimics.     

Neutrophil gelatinase-associated lipocalin: a novel suppressor of invasion and angiogenesis in pancreatic cancer

Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa secreted acute phase protein, which is also up-regulated in multiple cancers, including breast, lung, and pancreas. Recently, NGAL has been proposed as an early biomarker in pancreatic cancer (PaCa). However, its biological role in PaCa is unknown. In this study, we examined in vitro and in vivo the functional role of NGAL in PaCa. Well- to moderately differentiated PaCa cells (AsPC-1, BxPC-3, and Capan-2) expressed high levels of NGAL but moderately to poorly differentiated PaCa cells (PANC-1 and MIAPaCa-2) expressed undetectable NGAL levels. Immunohistochemistry of untreated tissue microarray showed specific NGAL staining in resected PaCa specimens (P = 0.0167). Stable NGAL overexpression (MIAPaCa-2 and PANC-1) significantly blocked PaCa cell adhesion and invasion in vitro and vice versa with stable PaCa clones (BxPC-3 and AsPC-1). Moreover, NGAL overexpression reduced focal adhesion kinase (FAK) tyrosine-397 phosphorylation in PaCa cells. Furthermore, NGAL overexpression potently decreased angiogenesis in vitro partly through reduced vascular endothelial growth factor (VEGF) production and vice versa. Stable NGAL overexpression or underexpression had no effect on PaCa cell survival, viability, and response to chemotherapeutic drugs. Finally, MIAPaCa-2 cells overexpressing NGAL reduced tumor volume (P = 0.012), local and distant metastasis (P = 0.002), and angiogenesis (P = 0.05) with no effect on K-67 proliferation index (P > 0.1) in an orthotopic nude mouse PaCa model. Collectively, our results suggest that NGAL reduces adhesion/invasion partly by suppressing FAK activation and inhibits angiogenesis partly by blocking VEGF production in PaCa cells. Thus, NGAL is a potential suppressor of invasion and angiogenesis in advanced PaCa.     

Understanding utero-placental blood flow in normal and hypertensive pregnancy through a mathematical model

Normal development of utero-placental circulation is crucial not only for the survival and growth of the fetus in utero, but also for maternal well-being. Any disturbance or abnormality may reflect underlying pathology. Geometric conversion of a pre-pregnant spiral vessel into a divergent low-resistance vessel is believed to be responsible for the increased utero-placental blood flow in normal pregnancy. Known biomedical investigative techniques have failed to explain many such underlying haemodynamic changes taking place in the utero-placental system. Therefore, proper understanding of the system using a mathematical model has been found to be useful. The physiological fluid dynamic study is the first in this branch of physiology. Abnormal pressure gradient, axial velocity, volume flow and shear rate are obtained for various slowly changing geometries such as, tapering, divergence, local constrictions and sinusoidal tube for low Womersley parameters. The model can explain many enhanced patho-physiological changes, such as persistence or the appearance of local constriction in the utero-placental vessels. Such pathological changes are considered to be responsible for very high utero-placental resistance, leading to blood flow insufficiency in pre-eclampsia or intra-uterine growth retardations. It is believed that these changes may be caused by low shear rate on the pre-existing deranged or abnormal endothelium. Furthermore, this derangement is caused by an abnormal proliferation of either spiral vessels or the invading non-villous trophoblasts. Doppler flow study can explain and validate some of the theoretically derived flow velocity results. The study opens up a new area of research into utero-placental physiological fluid dynamics.     

Sarcopenia in hepatocellular carcinoma: Current knowledge and future directions

Liver cancer is the second most occurring cancer worldwide and is one of the leading causes of cancer-related deaths.Hepatocellular carcinoma(HCC)is the most common(80%-90%)type among malignant liver cancers.Sarcopenia occurs very early in HCC and can predict and provide an opportunity to improve muscle health before engaging in the treatment options such as loco-regional,systemic,and transplant management.Multiple prognostic stating systems have been developed in HCC,such as Barcelona Clinic Liver Cancer,Child-Pugh score and Albumin-Bilirubin grade.However,the evaluation of patients’performance status is a major limitation of these scoring systems.In this review,we aim to summarize the current knowledge and recent advances about the role of sarcopenia in cirrhosis in general,while focusing specifically on HCC.Additionally,the role of sarcopenia in predicting clinical outcomes and prognostication in HCC patients undergoing loco-regional therapies,liver resection,liver transplantation and systematic therapy has been discussed.A literature review was performed using databases PubMed/MEDLINE,EMBASE,Cochrane,Web of Science,and CINAHL on April 1,2021,to identify published reports on sarcopenia in HCC.Sarcopenia can independently predict HCC-related mortality especially in patients undergoing treatments such as loco-regional,surgical liver transplantation and systemic therapies.Basic research is focused on evaluating a balance of anabolic and catabolic pathways responsible for muscle health.Early clinical studies have shown promising results in methods to improve sarcopenia in HCC which can potentially increase prognosis in these patients.As sarcopenia occurs very early in HCC,it can predict and provide an opportunity to improve muscle health before engaging in the treatment options such as loco-regional,systemic,and transplant management.Further,sarcopenia measurement can obviate the confounding caused by the abdominal ascites in these patients.The use of sarcopenia can add to the existing scoring systems to better prognosticate the HCC.     

The impact of Human Papilloma Virus status on the prediction of head and neck cancer chemoradiotherapy outcomes using the pre-treatment apparent diffusion coefficient

Objective:To determine the impact of Human Papilloma Virus (HPV) oropharyngeal cancer (OPC) status on the prediction of head and neck squamous cell cancer (HNSCC) chemoradiotherapy (CRT) outcomes with pre-treatment quantitative diffusion-weighted magnetic resonance imaging (DW-MRI).Methods:Following ethical approval, 65 participants (53 male, age 59.9 ± 7.86) underwent pre-treatment DW-MRI in this prospective cohort observational study. There were 46 HPV OPC and 19 other HNSCC cases with Stage III/IV HNSCC. Regions of interest (ROIs) (volume, largest area, core) at the primary tumour (n = 57) and largest pathological node (n = 59) were placed to analyse ADC_mean and ADC_min. Unpaired t-test or Mann–Whitney test evaluated the impact of HPV OPC status and clinical parameters on their prediction of post-CRT 2 year locoregional and disease-free survival (LRFS and DFS). Multivariate logistic regression compared significant variables with 2 year outcomes.Results:On univariate analysis of all participants, the primary tumour area ADC_mean was predictive of 2 year LRFS (p = 0.04). However, only the HPV OPC diagnosis (LFRS p = 0.03; DFS p = 0.02) predicted outcomes on multivariate analysis. None of the pre-treatment ADC values were predictive of 2 year DFS in the HPV OPC subgroup (p = 0.21–0.68). Amongst participants without 2 year disease-free survival, HPV-OPC was found to have much lower primary tumour ADC_mean values than other HNSCC.Conclusion:Knowledge of HPV OPC status is required in order to determine the impact of the pre-treatment ADC values on post-CRT outcomes in HNSCC.Advances in knowledge:Pre-treatment ADC_mean and ADC_min values acquired using different ROI methods are not predictive of 2 year survival outcomes in HPV OPC.     

Community Health Worker Perspectives on Engaging Unhoused Peer Ambassadors for COVID-19 Vaccine Outreach in Homeless Encampments and Shelters

BackgroundCOVID-19 vaccination is a priority for people experiencing homelessness. However, there are barriers to vaccine access driven in part by mistrust towards clinicians and healthcare. Community health workers (CHWs) and Peer Ambassadors (PAs) may be able to overcome mistrust in COVID-19 vaccine outreach. An unhoused PA program for COVID-19 vaccine outreach by CHWs was implemented in Los Angeles using a participatory academic-community partnership.ObjectiveThe purpose of this study was to evaluate CHW perspectives on an unhoused PA COVID-19 vaccine outreach program in Los Angeles.DesignThis study used a participatory community conference and qualitative focus groups to understand CHW perspectives on the PA program. The one-day conference was held in November 2021.ParticipantsOf the 42 conference participants, 19 CHWs participated in focus groups for two-way knowledge exchange between CHWs and researchers.ApproachFour focus groups were held during the conference, with 4-6 CHWs per group. Each group had a facilitator and two notetakers. Focus group notes were then analyzed using content analysis to derive categories of findings. CHWs reviewed the qualitative analysis to ensure that findings represented their experiences with the PA program.Key ResultsThe five categories of findings from focus groups were as follows: (1) PAs were effective liaisons to their peers to promote COVID-19 vaccines; (2) CHWs recognized the importance of establishing genuine trust and equitable working relationships within CHW/PA teams; (3) there were tradeoffs of integrating unhoused PAs into the existing CHW workflow; (4) CHWs had initial misgivings about the research process; and (5) there were lingering questions about the ethics of “exploiting” the invaluable trust unhoused PAs have with unhoused communities.ConclusionsCHWs were in a unique position to empower unhoused PAs to take a leadership role in reaching their peers with COVID-19 vaccines and advocate for long-term employment and housing needs.