The Impact of Metformin on Tumor-Infiltrated Immune Cells: Preclinical and Clinical Studies.

The tumor microenvironment (TME) plays a pivotal role in the fate of cancer cells, and tumor-infiltrating immune cells have emerged as key players in shaping this complex milieu. Cancer is one of the leading causes of death in the world. The most common standard treatments for cancer are surgery, radiation therapy, and chemotherapeutic drugs. In the last decade, immunotherapy has had a potential effect on the treatment of cancer patients with poor prognoses. One of the immune therapeutic targeted approaches that shows anticancer efficacy is a type 2 diabetes medication, metformin. Beyond its glycemic control properties, studies have revealed intriguing immunomodulatory properties of metformin. Meanwhile, several studies focus on the impact of metformin on tumor-infiltrating immune cells in various tumor models. In several tumor models, metformin can modulate tumor-infiltrated effector immune cells, CD8+, CD4+ T cells, and natural killer (NK) cells, as well as suppressor immune cells, T regulatory cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). In this review, we discuss the role of metformin in modulating tumor-infiltrating immune cells in different preclinical models and clinical trials. Both preclinical and clinical studies suggest that metformin holds promise as adjunctive therapy in cancer treatment by modulating the immune response within the tumor microenvironment. Nonetheless, both the tumor type and the combined therapy have an impact on the specific targets of metformin in the TME. Further investigations are warranted to elucidate the precise mechanisms underlying the immunomodulatory effects of metformin and to optimize its clinical application in cancer patients.

Oncolytic herpes simplex virus HF10 (canerpaturev) promotes accumulation of CD8+ PD-1- tumor-infiltrating T cells in PD-L1-enriched tumor microenvironment.

Oncolytic viruses (OVs) remodel the tumor microenvironment by switching a "cold" tumor into a "hot" tumor with high CD8+ T-cell infiltration. CD8+ T-cell activity plays an essential role in the antitumor efficacy of OVs. However, the activity of T cells is impaired by the programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction. To date, it remains unclear why OVs alone have a significant antitumor activity even when PD-L1 expression persists on tumor or immune cells. In this study, we found that canerpaturev (C-REV) treatment significantly suppressed tumor growth, even though it induced a significant increase in PD-L1 expression in tumors in vivo as well as persistence of high PD-L1 expression on antigen-presenting cells (macrophage and dendritic cells [DCs]). Surprisingly, we observed that C-REV treatment increased the abundance of activated CD8+ PD-1- tumor-infiltrating lymphocytes (TILs) in the tumor on both the injected and contralateral sides, although infiltration of CD8+ PD-1high TILs into the tumor was observed in the control group. Moreover, the difference in PD-1 expression was observed only in tumors after treatment with C-REV, whereas most CD8+ T cells in the spleen, tumor-draining lymph nodes and blood were PD-1-negative, and this did not change after C-REV treatment. In addition, changes in expression of T-cell immunoglobulin and mucin-domain containing-3 and T-cell immune-receptor with Ig and ITIM domains were not observed on CD8+ TILs after C-REV treatment. Taken together, our findings may reveal mechanisms that allow OVs to trigger an antitumor immune response, irrespective of a PD-L1-enriched tumor microenvironment, by recruitment of CD8+ PD-1- TILs.

A Phase I clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer.

BACKGROUND: Prognosis of pancreatic cancer is poor with a 5-year survival rate of only 7%. Although several new chemotherapy treatments have shown promising results, all patients will eventually progress, and we need to develop newer chemotherapy treatments to improve response rates and overall survival (OS). HF10 is a spontaneously mutated oncolytic virus derived from a herpes simplex virus-1, and it has potential to show strong antitumor effect against malignancies without damaging normal tissue. We aimed to evaluate the safety and anti-tumor effectiveness in phase I dose-escalation trial of direct injection of HF10 into unresectable locally advanced pancreatic cancer under endoscopic ultrasound (EUS)-guidance in combination with erlotinib and gemcitabine administration. The mid-term results have been previously reported and here we report the final results of our study. METHODS: This was a single arm, open-label Phase I trial. HF10 was injected once every 2 weeks and continued up to four times in total unless dose-limiting toxicity (DLT) appears. A total of nine subjects in three Cohorts with dose-escalation were planned to be enrolled in this trial. The primary endpoint was the safety assessment and the secondary endpoint was the efficacy assessment. RESULTS: Twelve patients enrolled in this clinical trial, and ten subjects received this therapy. Five patients showed Grade III myelosuppression and two patients developed serious adverse events (AEs) (perforation of duodenum, hepatic dysfunction). However, all of these events were judged as AEs unrelated to HF10. Tumor responses were three partial responses (PR), four stable diseases (SD), and two progressive diseases (PD) out of nine subjects who completed the treatment. Target lesion responses were three PRs and six SDs. The median progression free survival (PFS) was 6.3 months, whereas the median OS was 15.5 months. Two subjects from Cohort 1 and 2 showed downstaging and finally achieved surgical complete response (CR). CONCLUSIONS: HF10 direct injection under EUS-guidance in combination with erlotinib and gemcitabine was a safe treatment for locally advanced pancreatic cancer. Combination therapy of HF10 and chemotherapy should be explored further in large prospective studies. TRIAL REGISTRATION: This study was prospectively registered in UMIN-CTR (UMIN000010150) on March 4th, 2013.

Combination therapy of oncolytic herpes simplex virus HF10 and bevacizumab against experimental model of human breast carcinoma xenograft.

Breast cancer is one of the most common and feared cancers faced by women. The prognosis of patients with advanced or recurrent breast cancer remains poor despite refinements in multimodality therapies involving chemotherapeutic and hormonal agents. Multimodal therapy with more specific and effective strategy is urgently needed. The oncolytic herpes simplex virus (HSV) has potential to become a new effective treatment option because of its broad host range and tumor selective viral distribution. Bevacizumab is a monoclonal antibody against VEGFA, which inhibits angiogenesis and therefore tumor growth. Our approach to enhance the antitumor effect of the oncolytic HSV is to combine oncolytic HSV HF10 and bevacizumab in the treatment of breast cancer. Our results showed that bevacizumab enhanced viral distribution as well as tumor hypoxia and expanded the population of apoptotic cells and therefore induced a synergistic antitumor effect. HF10 is expected to be a promising agent in combination with bevacizumab in the anticancer treatment.

Combination treatment of human pancreatic cancer xenograft models with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib and oncolytic herpes simplex virus HF10.

BACKGROUND: There is the potential to use replication-competent oncolytic viruses to treat cancer. We evaluated the efficacy of HF10, a herpes simplex virus type 1 (HSV-1) mutant, in combination with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in human pancreatic cancer xenograft models. METHODS: The viability of human pancreatic cancer cell lines (BxPC-3 and PANC-1) treated with HF10 and erlotinib, on their own or in combination, was determined. Effects of erlotinib on HF10 entry into tumor cells were also investigated. BxPC-3 subcutaneous tumor-bearing mice were treated with HF10 and erlotinib, on their own or in combination, with effects on tumor volume determined. Immunohistochemical examination of HSV-1 and CD31 was conducted to assess virus distribution and angiogenesis within tumors. A peritoneally disseminated BxPC-3 xenograft model was evaluated for survival. RESULTS: HF10 combined with erlotinib demonstrated the highest cytotoxicity against BxPC-3. A combination effect was not observed in PANC-1 cells, and erlotinib did not affect virus entry into tumor cells. In the peritoneally disseminated model, HF10 combined with erlotinib had no beneficial effect on survival. In the subcutaneous tumor model, combination therapy resulted in the inhibition of tumor growth to a greater extent than using each agent on its own. Immunohistochemistry revealed that virus distribution within the tumor persisted in the combination therapy group. CONCLUSIONS: Combination therapy with HF10 and erlotinib warrants further investigation to establish a new treatment strategy against human pancreatic cancers.

Phase I Dose-escalation Clinical Trial of HF10 Oncolytic Herpes Virus in 17 Japanese Patients with Advanced Cancer.

Oncolytic virus therapy is a promising new therapeutic method, one of an eagerly anticipated class of biological therapies against cancer. There are many different classes of oncolytic virus. One of these, herpes oncolytic virus, is strongly oncolytic and has a large DNA genome as 150k bp. HF10 is a spontaneous mutant of herpes simplex virus -1 (HSV-1) that replicates within tumors and destroys cancers without damaging normal tissue and organs. Clinical trials of HF10 are underway in Japan and the United States. The first pilot study of HF10 was initiated in Japan in 2003. This study examined the safety and efficacy of HF10 in the treatment of breast cancer and head and neck cancers; the trial also included careful dose escalation studies. In 2005, a clinical trial using HF10 to treat pancreatic cancer was initiated. screened In this Japanese study, 17 patients received HF10 in their tumor sites. A clinical trial in the United States is also ongoing to evaluate safety, tolerability and evidence of antitumor activity in patients with refractory superficial solid tumors. Here, we report the evaluation of the 17 patients treated in Japan. Among the patients, 6 had recurrent breast cancer, 3 had recurrent head and neck cancer, and 8 had non-resectable pancreatic cancer. No severe adverse side effects have been observed, and some therapeutic potential has been reported based on pathological findings, tumor markers, and diagnostic radiography. Those results should encourage further clinical trials of HF10 around the world.

STING activator 2'3'-cGAMP enhanced HSV-1-based oncolytic viral therapy.

Oncolytic viruses (OVs) can selectively replicate in tumor cells and remodel the microenvironment of immunologically cold tumors, making them a promising strategy to evoke antitumor immunity. Similarly, agonists of the stimulator of interferon genes (STING)-interferon (IFN) pathway, the main cellular antiviral system, provide antitumor benefits by inducing the activation of dendritic cells (DC). Considering how the activation of the STING-IFN pathway could potentially inhibit OV replication, the use of STING agonists alongside OV therapy remains largely unexplored. Here, we explored the antitumor efficacy of combining an HSV-1-based OV, C-REV, with a membrane-impermeable STING agonist, 2'3'-GAMP. Our results demonstrated that tumor cells harbor a largely defective STING-IFN pathway, thereby preventing significant antiviral IFN induction regardless of the permeability of the STING agonist. In vivo, the combination therapy induced more proliferative KLRG1-high PD1-low CD8+ T-cells and activated CD103+ DC in the tumor site and increased tumor-specific CD44+ CD8+ T-cells in the lymph node. Overall, the combination therapy of C-REV with 2'3'-cGAMP elicited antitumor immune memory responses and significantly enhanced systemic antitumor immunity in both treated and non-treated distal tumors.

Combination of the tumor angiogenesis inhibitor bevacizumab and intratumoral oncolytic herpes virus injections as a treatment strategy for human gastric cancers.

BACKGROUND/AIMS: Advanced gastric cancer is difficult to treat due to the frequency of liver metastases and peritoneal dissemination. A combination of two new strategies, including the anti-angiogenesis inhibitor bevacizumab and an oncolytic herpes virus is a promising treatment for advanced cancer. METHODOLOGY: The effects of bevacizumab on oncolytic herpes virus replication and viral cytotoxicity were examined at varying bevacizumab concentrations and viral titers. In addition, the ability of these two new promising anticancer agents to inhibit tumor growth was studied. Histological examinations of CD31 and LacZ were used to assess angiogenesis and virus distribution within the tumor, respectively. RESULTS: Bevacizumab did not affect viral replication or viral cytotoxicity in vitro. The combination of bevacizumab and the oncolytic herpes virus hrR3 significantly reduced tumor growth in vivo in an experimental gastric cancer model. Bevacizumab inhibited angiogenesis caused by local injection of hrR3 and induced virus spread. Bevacizumab increased the distribution of the intratumorally injected oncolytic herpes virus within the tumor. CONCLUSIONS: Combination therapy consisting of bevacizumab and an oncolytic herpes virus is a promising new treatment strategy for gastric cancer.

Social correlates of female infertility in Uzbekistan.

The purpose of this matched case-control study was to investigate the social correlates of primary infertility among females aged 35 years or less. The study was conducted in the Clinics of Samarkand Medical Institute, Uzbekistan, among 120 infertile and 120 healthy women matched by age, residential area, and occupation from January to June 2009. Data were collected by face-to-face interviews using a structured questionnaire. Median duration of infertility was 10.0 months (interquartile range = 6.0-13.0). The rate of remarriage was 3.5 times higher among infertile women compared with healthy subjects. Insufficient family income, poor quality of life, life stress, and discontentment with daily routines as well as 'bad' relationships with family members (husband, mother- and father-in-law) were significant correlates of female infertility. Infertile women were more likely to underestimate the importance of sexual intimacy, and a negative attitude to sex. Female infertility is associated with various social correlates leading to higher remarriage rates and to further complicating the problem of infertility. Thus, a correction of women's basic attitudes and their relationships to their surrounding social habitat should be an essential component of any program of infertility management.

The impact of maternal obesity on mother and neonatal health: study in a tertiary hospital of Astana, Kazakhstan.

This study was aimed to investigate the impact of maternal obesity on mothers and their neonatal health. Our study population consisted of 157 women with completed singleton pregnancies, which included both obese (Body mass index, BMI > or =30) and non-obese women (BMI < 30). Data were collected from case histories, and ante- and postnatal records at the tertiary hospital in Astana, Kazakhstan between January and February of 2008. Associations between pregnancy and delivery-related complications, outcomes, and maternal obesity were estimated as odds ratios (ORs) and 95% confidence intervals (CIs) using a logistic regression model. Women aged 30 years or more were at higher risk of obesity (OR = 3.1, 95% CI = 0.8-11.6) than women less than 30 years old. Multiparous women were also at higher risk of obesity (OR = 4.1, 95% CI = 0.9-19.6) than primiparous ones. Obese women were also more likely to have longer hospital stays of more than 10 days (OR=2.2, 95% CI = 0.8-6.2), and were more prone to eclampsia/preeclampsia (OR = 24.7, 95% CI = 2.2-44.8), cesarean sections (OR = 2.1, 95% CI-0.7-6.2), and abnormal labor (OR = 8.1, 95% CI = 1.0-63.8) compared to non-obese women. Neonatal complications such as pneumonia (OR = 3.4, 95% CI = 0.6-20.2) and fetal macrosomia (OR = 2.2, 95% CI = 0.6-8.0) were also more common among babies born to obese mothers. Congenital baby birth defects were strongly associated with maternal obesity (P = 0.016). We concluded that maternal obesity is associated with increased risks of both maternal and neonatal complications, and that such risks increase with advanced age and parity of the mother. Hence, medical practices must take these complications into account by ensuring an adaptable and early management in order to improve mothers and their neonatal health.

Metformin enhances the antitumor activity of oncolytic herpes simplex virus HF10 (canerpaturev) in a pancreatic cell cancer subcutaneous model.

Oncolytic virus (OV) therapy is a promising cancer immunotherapy, especially for cold tumors by inducing the direct lysis of cancer cells and initiation of potent antitumor response. Canerpaturev (C-REV) is an attenuated oncolytic herpes simplex virus-1, which demonstrated a potent antitumor effect in various preclinical models when used either alone or combined. Metformin is a commonly prescribed antidiabetic drug that demonstrated a potent immune modulator effect and antitumor response. We combined C-REV with metformin in a low immunogenic bilateral murine tumor model to enhance C-REV's antitumor efficacy. In vitro, metformin does not enhance the C-REV cell cytotoxic effect. However, in in vivo model, intratumoral administration of C-REV with the systemic administration of metformin led to synergistic antitumor effect on both sides of tumor and prolonged survival. Moreover, combination therapy increased the effector CD44+ CD8+ PD1- subset and decreased the proportion of terminally-differentiated CD103+ KLRG-1+ T-regulatory cells on both sides of tumor. Interestingly, combination therapy efficiently modulates conventional dendritic cells type-1 (cDC1) on tumors, and tumor-drained lymph nodes. Our findings suggest that combination of C-REV and metformin enhances systemic antitumor immunity. This study may provide insights into the mechanism of action of OV therapy plus metformin combination against various tumor models.

Oncolytic herpes virus induces effective anti-cancer immunity against murine colon cancer.

UNLABELLED: BACK GROUND/AIMS: Oncolytic virus therapy is becoming a promising anti-cancer therapy and oncolytic viruses have been shown to elicit anti-cancer immunity. We evaluated the anti-tumor immune responses elicited by the herpes oncolytic virus R3616 compared to a representative chemotherapy drug, 5-FU. METHODOLOGY: R3616 or 5-FU was directly injected into subcutaneous tumors of non-immunized mice. Additionally, complete adjuvant, R3616-infected MC26 cells or 5-FU plus MC26 cells were frozen, thawed and used to immunize mice. After 21 days of immunization, the adaptive immune response suppressed implanted tumor growth and prolonged survival rate. We monitored differences in the number of infiltrating CD8- and CD4-positive lymphocytes in implanted tumors by immunofluorescence. RESULTS: R3616 induced a statistically greater number of infiltrating T cells (Thy1.2), macrophages (CD68) and dendritic cells (CD83) in injected tumors than 5-FU. The group immunized with R3616-infected MC26 cells had greater tumor suppression and longer survival rate than non-immunized mice and mice treated with 5-FU plus MC26 cells with statistically significant differences between these groups. The mice immunized with R3616-infected MC26 cells had a statistically greater number of infiltrating T cells in the implanted tumor than non-immunized and mice treated with 5-FU plus MC26 cells. CONCLUSIONS: These results indicate that oncolytic herpes virus R3616 can elicit more effective host anti-tumor immune responses than 5-FU against murine colon cancer model.

S-1 facilitates canerpaturev (C-REV)-induced antitumor efficacy in a triple-negative breast cancer model.

Canerpaturev (C-REV) is a highly attenuated, replication-competent, mutant strain of oncolytic herpes simplex virus type 1 that may be an effective new cancer treatment option. S-1, an oral formulation containing the 5-fluorouracil (5-FU) prodrug tegafur and the two enzyme modulators gimeracil and oteracil, is used as a key chemotherapeutic agent for metastatic recurrent breast cancer. Although the antitumor effects of oncolytic viruses combined with 5-FU in vivo have been reported, the detailed mechanisms are unknown. Here, we investigated the antitumor mechanism of the combination of C-REV and S-1 in triple-negative breast cancer (TNBC) in the context of tumor immunity. The combined effect of C-REV and S-1 was evaluated in a bilateral tumor model of murine TNBC 4T1 in vivo. S-1 enhanced the TNBC growth inhibitory effects of C-REV, and decreased the number of tumor-infiltrating, myeloid-derived suppressor cells (MDSCs), which suppress both innate and adaptive immune responses. Moreover, C-REV alone and in combination with S-1 significantly increased the number of CD8+ T cells in the tumor and the production of interferon γ (IFNγ) from these cells. Our findings indicate that C-REV suppresses TNBC tumor growth by inducing the expansion of effector CD8+ T cell subsets in tumors in which S-1 can inhibit MDSC function. Our study suggests that MDSCs may be an important cellular target for breast cancer treatment. The combination of C-REV and S-1 is a new approach that might be directly translated into future clinical trials against TNBC.

Problem-Based Learning in Child and Adolescent Psychiatry: A Perspective from Japan.

PURPOSE: Japanese higher education institutions have long been striving for the globalization of medical education. Nagoya University (NU) adopted PBL as a means of enhancing intercultural awareness in globalizing medical education by working with the Norwegian University of Science and Technology (NTNU), Faculty of Medicine and Health Science, under the Trondheim NTNU-Nagoya (TroNa) partnership for mobility and internationalization of child and mental health studies. This study aims to assess students' attitudes towards PBL and to suggest future developments in this form of education by introducing common PBL scenarios experienced at NTNU and NU. METHODS: Two 90-minute PBL sessions were conducted at NU. Ten groups of medical students were formed, each consisting of up to 10 students, and students were asked to fill in a questionnaire developed to assess their understanding of, attitudes to and satisfaction with the classes. We investigated three different groups of questions on: NU medical students' general impressions of PBL; their impressions of PBL in child and adolescent psychiatry (CAP); and their impressions of PBL in specific case scenarios. Correlations between each of the questions from the three groups were evaluated using multivariate analysis. RESULTS: Overall, a majority of the NU medical students were satisfied with PBL, while a small number preferred traditional lecture-style learning (5%). More than half of the students agreed that PBL increased their understanding and interest in CAP (53%), although some male students felt that the amount of time spent was insufficient (20.3%). Correlations were seen for students who thought that PBL enhanced their understanding of and interest in CAP. Regarding case scenarios, most students (82.5%) agreed that PBL helped them to develop clinical problem-solving skills. CONCLUSION: The study found an overall positive attitude towards PBL, PBL in CAP and the specific PBL case scenario presented.

C-REV Retains High Infectivity Regardless of the Expression Levels of cGAS and STING in Cultured Pancreatic Cancer Cells.

Oncolytic virus (OV) therapy is widely considered as a major breakthrough in anti-cancer treatments. In our previous study, the efficacy and safety of using C-REV for anti-cancer therapy in patients during stage I clinical trial was reported. The stimulator of interferon genes (STING)-TBK1-IRF3-IFN pathway is known to act as the central cellular host defense against viral infection. Recent reports have linked low expression levels of cGAS and STING in cancer cells to poor prognosis among patients. Moreover, downregulation of cGAS and STING has been linked to higher susceptibility to OV infection among several cancer cell lines. In this paper, we show that there is little correlation between levels of cGAS/STING expression and susceptibility to C-REV among human pancreatic cancer cell lines. Despite having a responsive STING pathway, BxPC-3 cells are highly susceptible to C-REV infection. Upon pre-activation of the STING pathway, BxPc-3 cells exhibited resistance to C-REV infection. However, without pre-activation, C-REV completely suppressed the STING pathway in BxPC-3 cells. Additionally, despite harboring defects in the STING pathway, other high-grade cancer cell lines, such as Capan-2, PANC-1 and MiaPaCa-2, still exhibited low susceptibility to C-REV infection. Furthermore, overexpression of STING in MiaPaCa-2 cells altered susceptibility to a limited extent. Taken together, our data suggest that the cGAS-STING pathway plays a minor role in the susceptibility of pancreatic cancer cell lines to C-REV infection.

Continuing medical education during pandemic waves of COVID-19: Consensus from medical faculties in Asia, Australia and Europe.

This article was migrated. The article was marked as recommended. Medical faculties have the responsibility to train tomorrow's doctors and in a crisis face the challenge of delivering students into the workforce promptly and safely. Worldwide, medical faculties have faced unprecedented disruptions from viral outbreaks and pandemics including SARS, Ebola, H1N1 and COVID-19 which bring unique challenges. Currently there is worldwide disruption to medical faculties and medical education due to COVID-19. Despite close links with clinical medicine and the known risks of pandemics, many medical faculties have been caught off guard without pandemic planning in place, to deal with an exponential rise in infections and deaths, overwhelmed health services and widespread community risk of transmission. Assessing transmission risk of COVID-19 in teaching, clinical and community attachments and continuing medical education is paramount as medical faculties face subsequent pandemics waves. Consensus statements based on best available evidence and international expertise from medical faculties in Asia, Australia and Europe were developed to help guide the protection of staff and students, priorities on teaching activities and further educational development. Infection prevention, infection control, contact tracing and medical surveillance are detailed to minimise transmission and to enhance safety. Recommendations on teaching activities planning can enhance responsiveness of medical faculties to tackle subsequent waves of COVID-19 infection. A global approach and dialogue are encouraged.

The tumor suppressor NPRL2 in hepatocellular carcinoma plays an important role in progression and can be served as an independent prognostic factor.

BACKGROUND/AIMS: Hepatocarcinogenesis is a multifactorial, multistep process that involves the activation of oncogenes or the inactivation of tumor suppressor genes throughout the different stages of hepatocellular carcinoma (HCC) progression. NPRL2 is one of the candidate tumor suppressor genes identified on chromosome 3p21.3, a region which frequently contains genetic abnormalities found in the early stages of the development of various human cancers. In the current study, we aimed to evaluate NPRL2 expression in HCC and to explore the prognostic significance of NPRL2. METHOD: We investigated NPRL2 mRNA expression in 70 HCC specimens, using quantitative real-time reverse transcription polymerase chain reaction analysis, and the correlation between NPRL2 expression and clinicopathologic parameters. RESULTS: NPRL2 mRNA was found to be expressed equally in both HCC tissues and corresponding non-cancerous liver tissues. However, higher NPRL2 expression correlated significantly with tumor size (P = 0.0062) and serum PIVKA-II levels (P = 0.0002). Univariate and multivariate analyses revealed that higher NPRL2 mRNA expression was an independent prognostic factor for overall survival (risk ratio 0.39; P < 0.0001). CONCLUSION: Our results suggest that NPRL2 mRNA expression has prognostic significance for the survival of patients with HCC.

Immune system modulation in patients with malignant and benign breast disorders: tryptophan degradation and serum neopterin.

Tryptophan degradation metabolites are known to suppress T-cell function, which is a mechanism of resistance of tumor cells against immune surveillance. The aim of this study was to evaluate tryptophan degradation along with serum neopterin levels in benign and malignant breast disease. Serum tryptophan and kynurenine levels and neopterin concentrations of 30 patients with malignant and 27 patients with benign breast disease were determined by HPLC and ELISA, respectively. The slight increase in tryptophan degradation in a subgroup of cancer patients with higher grade tumors was not statistically significant, but the increased degradation was correlated with higher neopterin concentrations. Neopterin levels in patients with malignant breast disease were significantly higher than in the benign group (p<0.05). Tryptophan degradation positively correlates with the aggressiveness of the tumor because it changes with tumor grade rather than disease stage.

Nonfunctioning neuroendocrine pancreatic tumors: our experience and management.

BACKGROUND AND PURPOSE: We present our experience in the treatment of nonfunctioning neuroendocrine pancreatic tumors (NFNPTs) to define the clinical and pathological characteristics and to suggest proper management. METHODS: The records of 17 patients with NFNPTs operated on between 1998 and 2008 were retrospectively reviewed, and all tumors were classified clinicopathologically as benign, uncertain, and malignant, based on the World Health Organization (WHO) classification of neuroendocrine tumors. RESULTS: There were four benign, six uncertain, and seven malignant NFNPTs. The most frequent symptoms were abdominal pain (five patients) and obstructive jaundice (one patient). Most of these symptomatic patients had malignant tumors. Mean tumor size of benign, uncertain, and malignant tumors were 1.0 +/- 0.3, 3.2 +/- 1.6, and 5.3 +/- 2.4 cm, respectively. Metastatic lesions of malignant tumors were lymph node (six patients), liver (four patients), and adrenal gland (one patient). Six of seven patients with malignant tumors underwent curative rejection. There were recurrences in four of six patients with curatively rejected malignant tumors. Two patients underwent more rejection, three patients received systemic chemotherapy, and two patients underwent radiofrequency ablation and transcatheter arterial chemoembolization for liver metastases. Survival of patients with malignant tumors was significantly shorter than that of patients with benign and uncertain tumors. However, three patients with malignant tumors had long survival of more than 3 years, even with metastases or recurrences. CONCLUSIONS: Aggressive surgical resection should be performed in patients with resectable NFNPTs, even with metastases. Even when a tumor was unresectable or there were recurrences, long-time palliation could be achieved by a multidisciplinary approach.

Pancreatic cancer with distant metastases: a contraindication for radical surgery?

BACKGROUND/AIMS: The purpose of this study was to analyze cases of resected pancreatic cancer with distant metastasis (M1) and to review the surgical indication for these patients. METHODOLOGY: Between July 1981 and December 2007, 542 patients with pancreatic cancer underwent surgery at the Department of Surgery II, Nagoya University. These patients included 48 cases of paraaortic lymph node metastases, 11 cases of hepatic metastases and 6 cases of peritoneal metastases. The overall survival rates were evaluated using the Kaplan-Meier method. RESULTS: Overall survival in patients stratified by M0 and M1 showed significant differences between M0 and M1 cases. As for hepatic metastases and peritoneal metastases, no significant difference in survival was observed between resected and unresected cases. However, survival in cases of paraaortic lymph node metastases was better than that in unresected cases, although this observation was not statistically significant. CONCLUSIONS: Hepatic or peritoneal metastases are contraindications for radical surgery for pancreatic cancer. On the other hand, patients with paraaortic lymph node metastases are relatively promising targets for radical surgery, and radical resection with extended lymphadenectomy remain an option for these patients.