The prognostic and therapeutic implications of distinct patterns of argininosuccinate synthase 1 (ASS1) and arginase-2 (ARG2) expression by cancer cells and tumor stroma in non-small-cell lung cancer

Background Arginine (Arg) is essential for cancer cell growth and also for the activation of T cells. Thus, therapies aiming to reduce Arg utilization by cancer may prove detrimental for the immune response. Methods We examined the expression of two major enzymes involved in arginine depletion and replenishment, namely arginase ARG2 and argininosuccinate synthase ASS1, respectively, in a series of 98 NSCLCs. Their association with immune infiltrates and the postoperative outcome were also studied. Results ARG2 was expressed mainly by cancer-associated fibroblasts (CAFs) (58/98 cases; 59.2%), while ASS1 by cancer cells (75/98 cases; 76.5%). ASS1 and ARG2 expression patterns were not related to hypoxia markers. Auxotrophy, implied by the lack of expression of ASS1 in cancer cells, was associated with high angiogenesis (p < 0.02). ASS1 expression by cancer cells was associated with a high density of iNOS-expressing tumor-infiltrating lymphocytes (iNOS+TILs). ARG2 expression by CAFs was inversely related to the TIL-density and linked with poorer prognosis (p = 0.02). Patients with ASS1 expression by cancer cells had a better prognosis especially when CAFs did not express ARG2 (p = 0.004). Conclusions ARG2 and ASS1 enzymes are extensively expressed in NSCLC stroma and cancer cells, respectively. Auxotrophic tumors have a poor prognosis, potentially by utilizing Arg, thus reducing Arg-dependent TIL anti-tumor activity. ASS1 expression in cancer cells would allow Arg fueling of iNOS+TILs and enhance anti-tumor immunity. However, upregulation of ARG2 in CAFs may divert Arg from TILs, allowing immune escape. Identification of these three distinct phenotypes may be useful in the individualization of Arg-targeting therapies and immunotherapy

Angiogenic Factor Expression in Hepatic Cirrhosis

The pathogenesis of fibrosis in hepatic cirrhosis remains obscure. This study examines the eventual role of angiogenic factors in the fibrotic process. A series of 55 cirrhotic livers was studied for the proliferation state of fibroblasts, and the expression of vascular endothelial growth factor (VEGF), thymidine phosphorylase (TP) and the basic and acidic fibroblast growth factor (bFGF, aFGF) in both fibroblasts and hepatic cells. The angiogenic and/or fibrogenic factors VEGF, TP, bFGF, and aFGF were clearly expressed in regenerative hepatocytes, but not in fibroblasts of diffuse hepatic fibrosis. The immunohistochemical findings suggest that angiogenic factors and factors promoting oxidative stress (i.e., TP) produced by hepatocytes may contribute to the development of fibrous bands in hepatic cirrhosis

Human Papillomavirus in Endometrial Adenocarcinomas: Infectious Agent or a Mere “Passenger”?

Aims. To investigate the possible association of human papillomavirus (HPV) with endometrial hyperplasias and neoplasia. Does HPV play any role in the initiation or prognosis of endometrial adenocarcinomas? Methods. Twenty-five endometrial adenocarcinomas of the endometrioid cell type, with and without squamous differentiation, and twenty-four endometrial hyperplasias of various forms (simple, complex, and atypical) were analyzed for the presence of type 16 and 18 HPV by the polymerase chain reaction (PCR). The results were related to histopathological features of the tumour, and the patients' age, and prognosis. Results. Six of 25 endometrial adenocarcinomas were HPV 16-positive (24%), and 5 of 25 (20%) were HPV 18-positive. Simple endometrial hyperplasias was associated somewhat more commonly with HPV 16 and 18 (2/8 and 1/8 cases, resp.) than hyperplasias progressing to endometrial adenocarcinomas, namely, atypical endometrial hyperplasia (1/8 and 0/8 cases, resp.). None of the positive cases in the series, whether hyperplastic or neoplastic, demonstrated cytological evidence of HPV infection. There was no relation between HPV-positive cases and squamous differentiation, depth of myometrial invasion, lymphatic involvement, lymphocytic response, patients' age, or prognosis. Conclusion. It appears that the presence of HPV in the endometrium, as detected by PCR, does not play any role in the initiation or prognosis of endometrial adenocarcinoma

Acute appendicitis in preschoolers: a study of two different populations of children

<p>Abstract</p> <p>Objective</p> <p>To assess the incidence and the risk factors implicated in acute appendicitis in preschoolers in our region.</p> <p>Methods</p> <p>Over a 7-year period, 352 children underwent appendectomy for suspected acute appendicitis. Of these, data for 23 children were excluded because no inflammation of the appendix was found on subsequent histology. Of the remaining 329, 82 were ≤ 5 years old (i.e., preschool children) and 247 were 5-14 years old. These two groups of children were further divided according to their religion into Muslims and Christian Orthodox: 43 of the children aged ≤ 5 years were Muslims and 39 were Christian Orthodox. A household questionnaire was designed to collect data concerning age, gender, type of residence area, living conditions, vegetable consumption, and family history of surgery for acute appendicitis as preschool children. The removed appendices were also assessed histologically for the amount of lymphoid tissue.</p> <p>Results</p> <p>Acute appendicitis of preschoolers developed more frequently in Muslims (39.4%) than in Christians (17.7%; <it>p </it>< 0.001). The lack of inside toilet facilities at home, overcrowded living conditions, living in rural areas, and the amount of appendix lymphoid tissue were significantly more frequent among the Muslim preschool children (<it>p </it>< 0.05), while there were no statistically significant differences between Muslim and Christian children with regard to gender, the family history of acute appendicitis, or the vegetable consumption (<it>p </it>> 0.05).</p> <p>Conclusions</p> <p>In our region, the percentage of preschool-aged Muslim children with acute appendicitis was remarkably high. One possible explanation for this finding could be the higher amount of lymphoid tissue in the wall of the appendix in Muslim preschool children together with their low standard of hygiene.</p

Omental infarction in an obese 10-year-old boy

Primary omental infarction (POI) has a low incidence worldwide, with most cases occurring in adults. This condition is rarely considered in the differential diagnosis of acute abdominal pain in childhood. Herein, we present a case of omental infarction in an obese 10-year-old boy who presented with acute abdominal pain in the right lower abdomen. The ultrasound (US) examination did not reveal the appendix but showed secondary signs suggesting acute appendicitis. The child was thus operated on under the preoperative diagnosis of acute appendicitis but the intra-operative finding was omental infarct. Since the omental infarct as etiology of acute abdominal pain is uncommon, we highlight some of the possible etiologies and emphasize the importance of accurate diagnosis and appropriate treatment of omental infarction

Clear cell sarcoma of the scapula. A case report and review of the literature

BACKGROUND: Clear cell sarcoma of tendons and aponeuroses (CCSTA) appears usually in the extremities and rarely in the trunk. CASE PRESENTATION: We present an unusual case of CCSTA overlying the scapular region and with secondary osseous extension in the lower scapula. The patient underwent a wide local excision with removal of the tumor and the lower two thirds of the scapula. He had no local recurrences but he developed lung metastases after 5 months in spite of postoperative chemotherapy. He finally died ten months later. CONCLUSION: The patients with CCSTA have a variable unpredictable course. Despite treatment the overall prognosis is poor

Concurrent Hypofractionated Radiotherapy and 5-Fluorouracil for Advanced Sarcomas of the Bone

Purpose. 5-Fluorouracil (5-FU) has shown radiosensitizing properties in vitro. This paper reports the effects of radiotherapy and concomitant intravenous 5-FU radiosensitization in the treatment of advanced bone sarcomas

A Case Report of Urinary Bladder Carcinosarcoma and Review of the Literature

Carcinosarcoma of the bladder is an unusual tumour characterized by a combination of malignant epithelial and soft tissue elements. Most of the reported cases have been case reports or small series. Optimal treatment is uncertain. We herein report our experience in such a case treated with transurethral resection followed by radiotherapy with adverse final outcome. Treatment of bladder carcinosarcomas should be aggressive and multimodal but optional treatment is still unknown. Radiotherapy alone is insufficient as a treatment option of these aggressive tumors

Pyruvate Dehydrogenase and Pyruvate Dehydrogenase Kinase Expression in Non Small Cell Lung Cancer and Tumor-Associated Stroma

AbstractPyruvate dehydrogenase (PDH) catalyzes the conversion of pyruvate to acetyl-coenzyme A, which enters into the Krebs cycle, providing adenosine triphosphate (ATP) to the cell. PDH activity is under the control of pyruvate dehydrogenase kinases (PDKs). Under hypoxic conditions, conversion of pyruvate to lactate occurs, a reaction catalyzed by lactate dehydrogenase 5 (LDH5). In cancer cells, however, pyruvate is transformed to lactate occurs, regardless of the presence of oxygen (aerobic glycolysis/Warburg effect). Although hypoxic intratumoral conditions account for HIFia stabilization and induction of anaerobic metabolism, recent data suggest that high pyruvate concentrations also result in HIFia stabilization independently of hypoxia. In the present immunohistochemical study, we provide evidence that the PDH/PDK pathway is repressed in 73% of non small cell lung carcinomas, which may be a key reason for HIFia stabilization and “aerobic glycolysis.” However, about half of PDHdeficient carcinomas are not able to switch on the HIF pathway, and patients harboring these tumors have an excellent postoperative outcome. A small subgroup of clinically aggressive tumors maintains a coherent PDH and HIF/LDH5 expression. In contrast to cancer cells, fibroblasts in the tumor-supporting stroma exhibit an intense PDH but reduced PDK1 expression favoring maximum PDH activity. This means that stroma may use lactic acid produced by tumor cells, preventing the creation of an intolerable intratumoral acidic environment at the same time