Ai Mogi

Pathology of soft-tissue tumors: Daily diagnosis, molecular cytogenetics and experimental approach

This article reviews problems in diagnostic pathology and molecular cytogenetics of soft‐tissue tumors. Also discussed are the origin of soft‐tissue sarcomas and the molecular basis of effective target therapy for sarcomas. Molecular cytogenetic analysis of tumor‐specific chromosomal translocations and associated fusion gene transcripts offers a useful adjunct to the diagnosis of soft‐tissue tumors, but recent studies have indicated a growing number of fusion gene variations in each tumor type. In pleomorphic sarcoma/malignant fibrous histiocytoma, the alternative lengthening of telomeres (ALT) mechanism may result in formation of anaphase bridges and marked nuclear pleomorphism. The histogenesis of soft‐tissue sarcomas has been a matter of controversy. In the present experimental model using s.c. injection of 3‐methylcholanthrene in C57BL/6 mice pretreated with bone marrow‐transplantation from green fluorescent protein (GFP)‐positive green mice, the bone marrow‐derived mesenchymal stem cells as well as the tissue‐resident mesenchymal cells in the peripheral soft tissues are possible originators of sarcomagenesis. Little is known about a molecular basis of target therapy for sarcomas. Platelet‐derived growth factor‐BB (PDGF‐BB) enhances the invasive activity of malignant peripheral nerve sheath tumor (MPNST) cells through platelet‐derived growth factor receptor (PDGFR) phosphorylation, whereas imatinib mesylate inhibited such activity, suggesting that targeting PDGFR‐β may result in the establishment of novel treatment for MPNST. In addition, emmprin is a transmembrane glycoprotein on tumor cells that stimulates peritumoral fibroblasts to produce matrix metalloproteinases (MMP), playing a crucial role in tumor progression, invasion and metastasis. The MMP upregulation mechanism mediated by tumor‐associated emmprin may be a potentially useful target in anti‐tumor invasion therapy for sarcomas.

Pleural malignant mesothelioma with invasive micropapillary component and its association with pulmonary metastasis

The micropapillary pattern (characterized by papillary structure with tufts lacking a central fibrovascular core) is a predictor of aggressive carcinoma. The purpose of the present study was to review 34 pleural malignant mesotheliomas (21 epithelioid, five sarcomatoid, seven biphasic and one lymphohistiocytoid), with special reference to the presence of invasive micropapillary component. Two invasive micropapillary pattern‐positive tumors were identified. The invasive micropapillary pattern was seen to have a focal distribution in 15–20% of the tumor tissues. The majority of the invasive micropapillary clusters expressed MUC1 along the outer cell surface. Analysis of pleural malignant mesotheliomas with epithelioid features and with or without invasive micropapillary pattern (21 epithelioid and seven biphasic subtypes) indicated pulmonary micrometastases in only the invasive micropapillary‐positive tumors (P < 0.015), and the spread was probably via the lymphatics. Lymphatic involvement (confirmed on immunohistochemistry with D2‐40 antibody) and lymph node metastasis were found in both of the invasive micropapillary‐positive tumor patients, whereas they were noted in only one of 10 (10%, P < 0.046) and three of nine (30%) invasive micropapillary‐negative patients. To the authors’ knowledge this is the first study to indicate the presence of invasive micropapillary component in pleural malignant mesothelioma. This component can predict more aggressive lymphatic spread, similar to that of carcinomas in other organs with micropapillary pattern.

Expression and role of GLUT-1, MCT-1, and MCT-4 in malignant pleural mesothelioma.

Malignant cells supply their energy needs through increased glucose consumption, producing large quantities of lactic acid via glycolysis. Glucose transporters (GLUTs) and monocarboxylate transporters (MCTs) are therefore commonly up-regulated in human malignancies to mediate glucose influx and lactic acid efflux, respectively. However, their roles in malignant pleural mesothelioma (MPM) have not been fully elucidated. Here, we evaluated GLUT-1, MCT-1, and MCT-4 expression in human MPM and reactive mesothelial hyperplasia (RMH) and elucidated their biological role in vitro. GLUT-1, MCT-1, and MCT-4 expression was determined in human MPM (n = 35) and RMH (n = 20) specimens by immunohistochemistry and in frozen tissue, and MPM cell lines, by real-time reverse transcription-polymerase chain reaction and western blot analysis. GLUT-1, MCT-1, and MCT-4 functions in MPM were evaluated by transfection with small interfering RNA. Immunohistochemical analysis revealed higher levels of GLUT-1, MCT-1, and MCT-4 in MPM than in RMH. Additionally, GLUT-1, MCT-1, and MCT-4 mRNA levels were higher in MPM than in non-neoplastic mesothelial cell lines. The siRNA-mediated knockdown of GLUT-1 or MCT-1 significantly suppressed tumor cell proliferation, and MCT-1 silencing inhibited invasion and induced apoptosis. Taken together, these results indicate that combined application of GLUT-1, MCT-1, and MCT-4 immunohistochemistry might be useful in differentiating MPM from RMH and suggest that MCT-1plays an important biological role.

Retrospective analysis of the efficacy and safety of eribulin therapy for metastatic breast cancer in daily practice

Evidence of eribulin therapy for metastatic breast cancer (MBC) in clinical practice is not well documented.

Patient perceptions of symptoms and concerns during cancer chemotherapy: ‘affects my family’ is the most important

BackgroundCancer chemotherapy is associated with a variety of side effects/adverse events. It is very important that patients adhere to the planned chemotherapy regimen, which necessitates a minimum of side effects and that these side effects be kept under control. We have investigated patients’ concerns and symptoms during chemotherapy with the aim to seek solutions that will improve patients’ quality of life during chemotherapy.MethodsForty-nine patients with malignant diseases on parenteral antineoplastic agents were sequentially enrolled in this study. These patients completed a questionnaire consisting of 42 items related to non-physical concerns and 52 items of physical symptoms related to chemotherapy. Each patient was also asked to select the three items among these 94 items which affected him/her the most. ResultsThe median age of the cancer patients was 62 years and the male-to-female ratio was 18:31. Among the non-physical concerns, the most frequently chosen concern was ‘affects my family or partner,’ followed by anxiety related to treatment. Regarding the physical symptoms, the most frequent complaints were fatigue, alopecia and constipation, while the most troublesome symptoms were nausea, poor taste and paresthesia. Overall, the most frequently expressed concerns were ‘affects my family or partner’ and anxiety related to treatment. Male patients suffered most from fever, fatigue and nausea, and female patients complained more of poor taste and gastrointestinal problems.ConclusionPatient perceptions of adverse events associated with cancer chemotherapy apparently have changed from physical symptoms to non-physical concerns. In our patient cohort ‘affects my family or partner’ was the most important concern. One important point to note is that female patients often complained of poor taste because this meant they were unable to cook well.

Difference in Neutropenia due to Administration Schedule of TAS-102

TAS-102 significantly improves overall survival in patients with metastatic colorectal cancer. The most common adverse event of TAS-102 is bone marrow suppression, which leads to neutropenia. The incidence of neutropenia is high, and there is no known effective prevention method. Furthermore, the administration method of TAS-102 is complicated. We reported that neutropenia could be avoided by changing to a simple administration method of TAS-102.

Subjective and objective assessment of oxaliplatin-induced peripheral neuropathy.

772 Background: Oxaliplatin-induced peripheral neuropathy (PN), for which no therapy has been firmly established, is a critical factor that makes the continuation of chemotherapy difficult. Numbnes...

1608PCHEMOTHERAPY FOR DIHYDROPYRIMIDINE DEHYDROGENASE-DEFICIENT PATIENT

ABSTRACT Aim: 5-FU is metabolized by thymidine phosphorylase and orotate phosphoribosyl transferase and is principally degraded in the blood or liver by dihydropyrimidine dehydrogenase (DPD). DPD, the catalyzing enzyme in the first and rate-limiting step of the degradation process, degrades approximately 85% of the administered 5-FU. DPD activity in peripheral blood mononuclear cells has been reported to correlate inversely with 5-FU clearance. In reports of DPD deficiency, the prognosis is poor, and approximately 60% patients die. With a reported high mortality rate, chemotherapy is generally contraindicated for patients with DPD deficiency, and there have been no reports of continued chemotherapy in patients with a DPD activity level of Methods: Chemotherapy for a 73-year old man with jejunal cancer was initiated. Capecitabine was administered in incrementally increasing doses, beginning with a single pill (dose-escalation method), while monitoring plasma 5-FU concentration, leukocyte, neutrophil, and platelet counts. Results: DPD protein measurement in the peripheral blood mononuclear cells yielded a level of 2.35 U/mg using the ELISA method (the same method yielded DPD measurements ranging from 33.6 to 183.6 U/mg in peripheral blood mononuclear cells from 10 healthy individuals). Ultimately, after increasing the Capecitabine dose to 1800 mg, oxaliplatin and bevacizumab were added and XELOX+bevacizumab treatment was initiated. Subsequent DPD protein measurement showed that the level had increased to approximately 10-fold the level before chemotherapy. Furthermore, the peritoneal metastases disappeared following chemotherapy. Conclusions: Because of serious adverse events, the chemotherapy-associated mortality rate among DPD-deficient patients is high, and there have been no reports of continuous chemotherapy in patients with DPD activity levels of Disclosure: All authors have declared no conflicts of interest.