Pathogenic and Prognostic Roles of Paraneoplastic Leukocytosis in Cervical Cancer: Can Genomic-Based Targeted Therapies Have a Role? A Literature Review and an Emblematic Case Report

Tumor-associated leukocytosis has been associated with poor prognosis in cervical cancer. Leukemoid reaction (i.e., white blood cell count > 40,000/µL) is defined paraneoplastic (PLR) when it occurs in the presence of a cytokine-secreting tumor (CST) without neoplastic bone marrow infiltration. Cervical cancers displaying PLR represent a peculiar entity characterized by a rapidly progressive behavior typically associated with chemo-radioresistance. The present paper aims to review the literature about the pathogenetic mechanisms of PLR and its prognostic role in cervical cancer. Moreover, it reports the emblematic case of a patient with an advanced cervical cancer associated with PLR that was chemotherapy resistant. The patient underwent a palliative cytoreductive surgery of high complexity, obtaining a temporary regression of PLR. The tumor sample stained positive for G-CSF and IL-6, thus indicating a CST. Notably, the tumor genomic analysis revealed a PI3CKA mutation. Therefore, at the instrumental evidence of a rapidly progressive disease relapse, which was accompanied by reappearance of PLR, we started a targeted treatment with a selective PIK3 inhibitor alpesilib combined with the JAK1-2 inhibitor ruxolitinib. We achieved a relief of symptoms and leukocytosis; however, severe side effects necessitated the treatment suspension. In conclusion, as therapeutic strategies for cancer with PLR are scarcely reported in literature, our study could contribute to expand our understanding of the topic and provide a basis for further research

Different Thymosin Beta 4 Immunoreactivity in Foetal and Adult Gastrointestinal Tract

Background: Thymosin beta 4 (T beta(4)) is a member of beta-thymosins, a family of peptides that play essential roles in many cellular functions. A recent study from our group suggested a role for T beta(4) in the development of human salivary glands. The aim of this study was to analyze the expression of T beta(4) in the human gut during development, and in the adult. Methodology/Principal Findings: Immunolocalization of T beta(4) was studied in autoptic samples of tongue, oesophagus, stomach, ileum, colon, liver and pancreas obtained from two human foetuses and two adults. T beta(4) appeared unevenly distributed, with marked differences between foetuses and adults. In the stomach, superficial epithelium was positive in foetuses and negative in adults. Ileal enterocytes were strongly positive in the adult and weakly positive in the foetuses. An increase in reactivity for T beta(4) was observed in superficial colon epithelium of adults as compared with the foetuses. Striking differences were found between foetal and adult liver: the former showed a very low reactivity for T beta(4) while in the adult we observed a strong reactivity in the vast majority of the hepatocytes. A peculiar pattern was found in the pancreas, with the strongest reactivity observed in foetal and adult islet cells. Significance: Our data show a strong expression of T beta(4) in the human gut and in endocrine pancreas during development. The observed differential expression of T beta(4) suggests specific roles of the peptide in the gut of foetuses and adults. The observed heterogeneity of T beta(4) expression in the foetal life, ranging from a very rare detection in liver cells up to a diffuse reactivity in endocrine pancreas, should be taken into account when the role of T beta(4) in the development of human embryo is assessed. Future studies are needed to shed light on the link between T beta(4) and organogenesis

Thymosin β 4 in colorectal cancer is localized predominantly at the invasion front in tumor cells undergoing epithelial mesenchymal transition.

Thymosin β 4 (Tβ(4)) is a ubiquitous peptide that plays pivotal roles in the cytoskeletal system and in cell differentiation during embryogenesis. Recently, a role for Tβ(4) has been proposed in experimental and human carcinogenesis. This study was aimed at evaluating the correlation between Tβ(4) immunoractivity and colorectal cancer, with particular attemption to tumor cells undergoing epithelial-mesenchymal transition.86 intestinal biopsies were retrospectively analyzed including 76 colorectal adenocarcinomas with evident features of epithelial-mesenchymal transition, and 10 samples of normal colorectal mucosa. Paraffin sections were immunostained for Tβ(4) and for E-cadherin. Total RNA was isolated from frozen specimens obtained, at surgery, from the normal colon mucosa, the deeper regions and the superficial tumor regions in four cases of colon cancer. Tβ(4) immunoreactivity was detected in the vast majority (59/76) of colon carcinomas, showing a patchy distribution, with well differentiated areas significantly more reactive than the less differentiated tumor zones. We also noted a zonal pattern in the majority of tumors, characterized by a progressive increase in immunostaining for Tβ(4) from the superficial toward the deepest tumor regions. The strongest expression for Tβ(4) was frequently detected in invading tumor cells with features of epithelial-mesenchymal transition. The increase in reactivity for Tβ(4) matched with a progressive decrease in E-cadherin expression in invading cancer cells. At mRNA level, the differences in Tβ(4) expression between the surrounding colon mucosa and the tumors samples were not significant.Our data show that Tβ(4) is expressed in the majority of colon cancers, with preferential immunoreactivity in deep tumor regions. The preferential expression of the peptide and the increase in intensity of the immunostaining at the invasion front suggests a possible link between the peptide and the process of epithelial mesenchymal transition, suggesting a role for Tβ(4) in colorectal cancer invasion and metastasis

“Physiological” renal regenerating medicine in VLBW preterm infants: could a dream come true?

An emerging hypothesis from the recent literature explain how specific adverse factors related with growth retardation as well as of low birth weight (LBW) might influence renal development during fetal life and then the insurgence of hypertension and renal disease in adulthood. In this article, after introducing a brief overview of human nephrogenesis, the most important factors influencing nephron number at birth will be reviewed, focusing on the "in utero" experiences that lead to an increased risk of developing hypertension and/or kidney disease in adult. Since nephrogenesis in preterm human newborns does not stop at birth, but it continues for 4-6 weeks postnatally, a better knowledge of the mechanisms able to accelerate nephrogenesis in the perinatal period, could represent a powerful tool in the hands of neonatologists. We suggest to define this approach to a possible therapy of a deficient nephrogenesis at birth "physiological renal regenerating medicine". Our goal in preterm infants, especially VLBW, could be to prolong the nephrogenesis not only for 6 weeks after birth but until 36 weeks of post conceptual age, allowing newborn kidneys to restore their nephron endowment, escaping susceptibility to hypertension and to renal disease later in life

10 questions: a Belgian pathologist, Peter Van Eyken, on the future of pathology. Interview by Sonia Nemolato

Prof. Peter Van Eyken, a renowned Belgian pathologist, answers to the following 10 questions: 1. You are a pupil of Valeer Desmet, one of the leading liver pathologists in the world. What was it like spending so many years with him? 2. Your first research project focused on cytokeratins: how has your research changed liver biopsy interpretation in clinical practice? 3. What are the most important innovations in pathology of the last years? What is changing in your approach to histology and to cytology? 4. What is the role of pathologists in pediatric pathology? How is their relationship with pediatricians is changing? 5. How is the role of the pathologist changing in neonatal and in perinatal medicine? 6. As a young researcher, you published many articles on liver development and on bile duct atresia: did your studies change the way you approach liver biopsy interpretation in a newborn? 7. After years of involvement in kidney biopsy interpretation in adults, recently, you became involved in studies on nephrogenesis. Which is the relationship between renal development and adult kidney pathology? 8. What is your opinion on networks in medicine? Should pathology be integrated with “omic” sciences and informatics ? 9. What about the future of pathology? New techniques or new eyes in the interpretation of H&E-stained sections? What is the role of immunohistochemistry? And of of molecular pathology? 10. Could you advise young medical doctors to become pathologists? What are your suggestions

World Journal of Gastroenterology ISSN 1007-9327

doi:10.3748/wjg.14.469

ColitisA Practical Approach to Colon Biopsy Interpretation /

XII, 200 p. 90 illus. in color.online resource

Lymphoepithelioma-like hepatocellular carcinoma: A case report and a review of the literature

Lymphoepithelioma is a particular form of undifferentiated carcinoma, characterized by a prominent lymphoid stroma, originally described in the nasopharynx. Lymphoid stroma-rich carcinomas arising in other organs have been termed lymphoepithelioma-like carcinoma (LELC). In the liver, primary LELCs are very rare, and the majority has been identified as cholangiocarcinomas. Here a rare case of lymphoepithelioma-like hepatocellular carcinoma (HCC) is described. A 47-year old woman presented with abdominal pain. Ultrasonography revealed a liver nodule, 2.2 cm in diameter, localized in the right lobe, adjacent to the gallbladder. Viral markers for hepatic B virus (HBV), hepatic C virus (HCV) and Epstein-Barr virus (EBV) were negative. The nodule was hypoechogenic. The patient underwent surgery, with resection of the nodule. Histology showed hepatocellular carcinoma, characterized by a prominent lymphoid infiltrate. At immunocytochemistry, tumor cells were reactive for Hep Par1 and glypican 3. Immunophenotyping of tumor infiltrating lymphocytes evidenced the predominance of CD8+ cytotoxic suppressor T cells. The postoperative clinical outcome was favorable and the patient was recurrence-free 15 mo after resection. This case, to the best of our knowledge, is the first reported non EBV and non cirrhosis-associated lymphoepithelioma-like hepatocellular carcinoma. The association between the lack of EBV infection, the absence of cirrhosis, a “cytotoxic profile” of the inflammatory infiltrate and a good prognosis could identify a variant of lymphoepithelioma-like HCC with a favorable clinical outcome