Gene expression profiles predicting the response to IFN-β and a combination of temozolomide and IFN-β in malignant gliomas

Temozolomide (TMZ) is an alkylating agent that has yielded significant benefits and is a current standard agent in the treatment of malignant gliomas. However, its survival benefit remains unsatisfactory. Recently, a synergistic antitumor effect between TMZ and interferon-β (IFN-β) was reported in malignant glioma cells. The Japan Clinical Oncology Group (JCOG) brain tumor study group has recently began a randomized phase II study to evaluate the clinical effectiveness of combination therapy with TMZ and IFN-β in glioblastomas. However, it is not sufficient just to evaluate the mechanisms and establish an experimental basis for rational clinical therapy with IFN-β and TMZ. The precise mechanisms governing the direct effects of IFN-β and a combination of IFN-β and TMZ in gliomas are not yet fully understood. To gain insight into the mechanisms of sensitivity/resistance involving IFN-β and combination therapy with IFN-β and TMZ, and further to identify new marker(s) that could be used clinically to predict the response to such therapy and new target gene(s) for therapies related to malignant glioma patho-genesis, we evaluated the gene expression profiles of human malignant glioma cell lines employing a high-density oligo-nucleotide DNA array, GeneChip. We present a list of the most highly upregulated and downregulated genes which may be involved in conferring a response to IFN-β and synergistic effect between IFN-β and TMZ in malignant gliomas. Although the present study has several limitations, our reported candidate genes could represent not only potential molecular markers but also chemotherapy targets for improving the treatment outcome by devising strategies that are able to circumvent primary drug resistance in malignant gliomas.     

Correlations of IFN-γ genetic polymorphisms with susceptibility to breast cancer: a meta-analysis

The meta-analysis was conducted to evaluate the correlations between common genetic polymorphisms in the IFN-γ gene and susceptibility to breast cancer. The following electronic databases were searched without language restrictions: MEDLINE (1966?~?2013), the Cochrane Library Database (issue 12, 2013), EMBASE (1980?~?2013), CINAHL (1982?~?2013), Web of Science (1945?~?2013), and the Chinese Biomedical Database (CBM) (1982?~?2013). Meta-analysis was performed with the use of the STATA statistical software. Odds ratios (OR) with their 95 % confidence intervals (95 % CIs) were calculated. Nine clinical case-control studies met all the inclusion criteria and were included in this meta-analysis. A total of 1,182 breast cancer patients and 1,525 healthy controls were involved in this meta-analysis. Three functional polymorphisms were assessed, including rs2069705 C>T, rs2430561 T>A, and CA repeats 2/X. Our meta-analysis results indicated that IFN-γ genetic polymorphisms might be significantly associated with an increased risk of breast cancer (allele model: OR?=?1.37, 95 % CI?=?1.03?~?1.83, P?=?0.031; dominant model: OR?=?1.55, 95 % CI?=?1.01?~?2.37, P?=?0.046; homozygous model: OR?=?2.23, 95 % CI?=?1.30?~?3.82, P?=?0.004; respectively), especially the rs2430561 T>A polymorphism. Subgroup analysis based on ethnicity suggested that genetic polymorphisms in the IFN-γ gene were closely correlated with increased breast cancer risk among Asians (allele model: OR?=?1.21, 95 % CI?=?1.02?~?1.58, P?=?0.017; dominant model: OR?=?3.44, 95 % CI?=?2.07?~?5.71, P?<?0.001; recessive model: OR?=?1.58, 95 % CI?=?1.06?~?2.37, P?=?0.025; homozygous model: OR?=?1.83, 95 % CI?=?1.19?~?2.80, P?=?0.006; respectively), but not among Caucasians (all P?>?0.05). Our meta-analysis supported the hypothesis that IFN-γ genetic polymorphisms may contribute to an increased risk of breast cancer, especially the rs2430561 T>A polymorphism among Asians.     

Intratumoral administration of mRNA encoding a fusokine consisting of IFN-β and the ectodomain of the TGF-β receptor II potentiates antitumor immunity

It is generally accepted that the success of immunotherapy depends on the presence of tumor-specific CD8⁺ cytotoxic T cells and the modulation of the tumor environment. In this study, we validated mRNA encoding soluble factors as a tool to modulate the tumor microenvironment to potentiate infiltration of tumor-specific T cells. Intratumoral delivery of mRNA encoding a fusion protein consisting of interferon-β and the ectodomain of the transforming growth factor-β receptor II, referred to as Fβ², showed therapeutic potential. The treatment efficacy was dependent on CD8⁺ T cells and could be improved through blockade of PD-1/PD-L1 interactions. In vitro studies revealed that administration of Fβ² to tumor cells resulted in a reduced proliferation and increased expression of MHC I but also PD-L1. Importantly, Fβ² enhanced the antigen presenting capacity of dendritic cells, whilst reducing the suppressive activity of myeloid-derived suppressor cells. In conclusion, these data suggest that intratumoral delivery of mRNA encoding soluble proteins, such as Fβ², can modulate the tumor microenvironment, leading to effective antitumor T cell responses, which can be further potentiated through combination therapy.     

Clinical Research of a Modified Midfacial Degloving in a Maxillectomy （with a Report of a Typical Case）

OBJECTIVE To investigate the feasibility of employing a modified midfacial degloving in maxillectomy. METHODS Eight patients with carcinoma of the maxillary sinus underwent a modified midfacial degloving operation.The tumors were classified according to the 2002 AJCC system.The TNM staging of the cases was as follows:1 T4aN0M0,2 T3N0M0 and 5 T2N0M0.Of the 8 cases,1 patient underwent extended maxillectomy;exenteration of the orbit;tumorectomy of the sphenomaxillary and infratemporal fossae.Two patients received a total maxillectomy,and 5 a partial resection of the maxilla. Postoperative pathological report:4 well-di?erentiated squamous carcinoma,2 moderately-differentiated squamous carcinoma,1 mucoepidermoid carcinoma and 1 adenoid cystic carcinoma. RESULTS A modified midfacial degloving operation can sufficiently expose a field of operation,resect the tumor within a safe margin,and leave no facial cicatricles.One patient died of intracranial metastasis 8 months a er operation.We observed no recurrences or metastasis in other patients during the period of follow-up. CONCLUSION The major advantages of employing the modified midfacial degloving in maxillectomy is that a facial incision can be avoided.It has an advantage of minimal invasive surgery.     

Occurrence of a germinoma 22 years after resection of a mature cerebral teratoma

We present the rare case of a 31-year-old man who developed a germinoma 22 years after resection of a mature teratoma of the pineal region. The initial stereotactic biopsy showed a granulomatous inflammation, but no malignant cells. The correct diagnosis could only be confirmed in a second cerebral biopsy, allowing for proper treatment with radiation therapy. The need to consider metachronous germinoma in this setting is discussed. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Determination of a CD4+CD25−FoxP3+ T cells subset in tumor-draining lymph nodes of colorectal cancer secreting IL-2 and IFN-γ

CD4⁺CD25⁻FoxP3⁺ cells are a newly recognized subset of T cells which was first reported in autoimmune diseases. In our previous study, this subset was detected in tumor-draining lymph nodes (TDLNs) of patients with breast cancer. As little is known about their function in TDLNs of cancer patients, in this study, their frequency as well as their ability to produce interleukin (IL)-2, IL-10, or interferon (IFN)-γ were investigated in TDLNs of colorectal cancer (CRC) patients. Mononuclear cells were isolated from lymph nodes of 13 patients with CRC using Ficoll-Hypaque gradient centrifugation. Cells were stimulated in vitro and stained with CD25, CD4, FoxP3, IFN-γ, IL-10, and IL-2 or isotype matched antibodies and subjected to flow cytometry. The frequency of CD4⁺CD25⁻FoxP3⁺CD127^dim/− cells was significantly lower than CD4⁺CD25⁺FoxP3⁺CD127^dim/− population in TDLNs of CRC patients. The percentage of CD127^dim/− cells and also the MFI of FoxP3 expression was significantly lower in CD4⁺CD25⁻FoxP3⁺ in comparison with CD4⁺CD25⁺FoxP3⁺ population. Moreover, CD4⁺CD25⁻FoxP3⁺ cells contained higher percentages of IL-2- and IFN-γ-producing cells than CD4⁺CD25⁺FoxP3⁺ subpopulation. But, no difference was seen between two subsets in terms of IL-10 production. CD4⁺CD25⁻FoxP3⁺ cells in TDLNs of CRC patients had lower suppressive and higher effector properties in comparison with CD4⁺CD25⁺FoxP3⁺ conventional regulatory T cells.

     

TNF-α is a novel target of miR-19a

Many studies have demonstrated the overexpression and amplification of the miR-17-92 cluster in malignant human cancers, including B-cell lymphomas and lung cancers. The purpose of this study was to investigate for the first time, the expression of the miR-17-92 cluster in esophageal squamous cell carcinoma (ESCC). The miR-17-92 cluster was found to be overexpressed in 21 out of 28 (75%) esophageal cancer samples. It was also found that overexpression of the miR-17-92 cluster could promote cellular growth in vivo and in vitro. Furthermore, inhibition of miR-19a by antisense oligonucleotides (ONs) induced apoptosis, while antisense ONs against miR-17-5p, miR-18a, miR-20a and miR-92-1 did not exhibit such an effect. In addition, it was found that antagomir-19a treatment could impair tumor growth in vivo. Using Human Apoptosis RT2 Profiler PCR Array 384HT, we found that tumor necrosis factor-α (TNF-α) was up-regulated 12-fold in cells transfected with miR-19a antisense ONs compared to the cells treated with the control scramble ONs. MiR-19a was predicted to target the 3' untranslated region of TNF-α mRNA, and this was confirmed by luciferase reporter assay. Taken together, we conclude that the miR-17-92 cluster is overexpressed in ESCC and that TNF-α is a novel target of miR-19a.     

IFN-γ combined with targeting of XIAP leads to increased apoptosis-sensitisation of TRAIL resistant pancreatic carcinoma cells

The tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a specific and potent inducer of apoptosis in cancer cells, but the resistance of many tumour cells to TRAIL still represents a major hurdle for the clinical treatment of tumours with TRAIL. As apoptosis is regulated by the balance of activities of several anti-apoptotic factors and pro-apoptotic factors, we analysed the relative contribution of the two sides and found that down-regulation of Bcl-x_L and in particular XIAP, but not c-Flip, sensitised the TRAIL resistant pancreatic cancer cell line Panc-1. A combination of both XIAP and Bcl-x_L knock-downs showed no substantial added benefit indicating that both act in the same pathway. Notably, the degree of sensitisation by silencing of anti-apoptotic genes was further elevated by concomitantly increasing the pro-apoptotic potential in Panc-1 cells through over-expression of TRAIL-R1 or IFN-γ-mediated increases in caspase-8 levels. Similar sensitisation effects were obtained for another TRAIL-resistant pancreatic tumour cell line, AsPC-1. Our findings demonstrate that modulation of the balance between anti- and pro-apoptotic pathways from both sides by inhibition of apoptosis-antagonists and stimulation of pro-apoptotic factors provides the best way to enhance the anti-tumourigenic effect of TRAIL.     

The patients’ experience of a bladder cancer diagnosis: a systematic review of the qualitative evidence

Purpose

Bladder cancer (BC) is a common disease with disparate treatment options and variable outcomes. Despite the disease’s high prevalence, little is known of the lived experience of affected patients. National patient experience surveys suggest that those with BC have poorer experiences than those with other common cancers. The aim of this review is to identify first-hand accounts of the lived experiences of diagnosis through to survivorship.

Method

This is a systematic review of the qualitative evidence reporting first-hand accounts of the experiences of being diagnosed with, treated for and surviving bladder cancer. A thematic analysis and ‘best-fit’ framework synthesis was undertaken to classify these experiences.

Results

The inconsistent nature of symptoms contributes to delays in diagnosis. Post-diagnosis, many patients are not actively engaged in the treatment decision-making process and rely on their doctor’s expertise. This can result in patients not adequately exploring the consequences of these decisions. Learning how to cope with a ‘post-surgery body’, changing sexuality and incontinence are distressing. Much less is known about the quality of life of patients receiving conservative treatments such as Bacillus Calmette-Guerin (BCG).

Conclusions

The review contributes to a greater understanding of the lived experience of bladder cancer. Findings reflect a paucity of relevant literature and a need to develop more sensitive patient-reported outcome measures (PROMs) and incorporate patient-reported outcomes in BC care pathways.

Implications for cancer survivors

Collective knowledge of the patients’ self-reported experience of the cancer care pathway will facilitate understanding of the outcomes following treatment.

     

Tumor dormancy resulting from subcutaneous injection to SCID mice with cultured nasopharyngeal carcinoma cells is mediated via IFN-γ induction of a highly differentiated phenotype

The mechanisms underlying tumor dormancy in human primary lesions and bone marrow metastases of nasopharyngeal carcinoma (NPC) are still not completely understood. The aim of this study was to determine differences in the fates of cultured primary NPC (P-NPC) cells, interferon-γ-transduced primary NPC (IFN-γ-P-NPC) cells, bone marrow metastatic NPC (BM-NPC), and IFN-γ-transduced BM-NPC (IFN-γ-BM-NPC) cells following xenotransplantation into these four groups of SCID mice through subcutaneous injection of 5×10(6) cells/site/animal (4 animals/group). The injected mice were monitored for tumor development at the sites of injection. In only the group injected with IFN-γ-P-NPC cells, the resulting nodules remained small throughout the 60-day observation period after injection, but gradually became palpably prickly. Histopathological examination revealed that these lesions invariably consisted of mostly structures of horny pearls and keratin bridges with occasional apoptotic and degenerative cells. In contrast, animals injected with nontransduced-P-NPC cells developed tumors progressively with occasional central necroses. In the two groups injected with IFN-γ-NPC-BM and NPC-BM cells, progressive growths of tumors were noted, with the latter being at slightly faster rates, whereas the xenografts of both groups showed a poorly differentiated phenotype with abundant vascularity. The study results highlight the high susceptibility of P-NPC but not BM-NPC following IFN-γ gene transfer to the induction of tumor dormancy, which is mediated via induced cell differentiation. Thus, induced cell differentiation could provide a new mechanism by which tumor dormancy is induced.     

The Influence of IFN-α on Blood Plasmacytoid Dendritic Cell in Chronic Myeloid Leukaemia

OBJECTIVE To study the mechanism of IFN on CML.METHODS Samples of 15 CML patients and 10 healthy controls were studied. The flow cytometry was performed to identify circulating pDCs. The concentration of IFN-α in serum and that in the supematant of peripheral blood mononuclear cells (PBMCs)cultured after stimulation with CpG ODN2216 were examined both in CML patients and in the healthy controls RESULTS There was significant reduction in the number of circulating pDCs, serum concentration of IFN-α and the capacity of IFN-α producing PBMCs in CML patients compared with those in healthy control individuals (P < 0.001). After the active treatment with IFN-α and hydroxyurea, the quantity and function of pDCs were increased in stabilized patients, especially the function of pDCs in 2 patients achieving major cytogenetic.response (MCR). The proportion and function of pDCs and the serum levels of IFN were inversely correlated with both WBC and age of the patients with CML, and positively correlated with the state of the illness.dysfunction of circulating pDCs. The active treatment with IFN in CML patients may be related to the restoration of pDCs.     

The influence of IFN-α on blood plasmacytoid dendritic cell in chronic myeloid leukaemia

OBJECTIVE To study the mechanism of IFN on CML.
METHODS Samples of 15 CML patients and 10 healthy controls were studied. The flow cytometry was performed to identify circulating pDCs. The concentration of IFN-α in serum and that in the supernatant of peripheral blood mononuclear cells （PBMCs） cultured after stimulation with CpG ODN2216 were examined both in CML patients and in the healthy controls
RESULTS There was significant reduction in the number of circulating pDCs, serum concentration of IFN-α and the capacity of IFN-α producing PBMCs in CML patients compared with those in healthy control individuals （P 〈 0.001）. After the active treatment with IFN-α and hydroxyurea, the quantity and function of pDCs were increased in stabilized patients, especially the function of pDCs in 2 patients achieving major cytogenetic response （MCR）. The proportion and function of pDCs and the serum levels of IFN were inversely correlated with both WBC and age of the patients with CML, and positively correlated with the state of the illness.
CONCLUSION CML patients had a reduced number and dysfunction of circulating pDCs. The active treatment with IFN in CML patients may be related to the restoration of pDCs.     

Successful management of a non-Hodgkin’s lymphoma of the gallbladder by chemotherapy: a case report

Introduction

Non-Hodgkin’s lymphoma of the gallbladder is a rare location of lymphoma.

Case presentation

We report a case of T cell non-Hodgkin’s lymphoma (NHL) of the gallbladder in a 39-year-old man in whom cholecystectomy made the diagnosis. Abdominal ultrasound did not reveal gallbladder stones. At this time, our patient had no lymph nodes. Histopathology of gastric and pulmonary biopsy and cholecystectomy made a definite diagnosis of non-Hodgkin’s T cell lymphoma. Our patient had eight cycles of chemotherapy CHOP 21 (cyclophosphamide 750 mg/m² intravenously (IV) on day 1, doxorubicine 50 mg IV on day 1, vincristine 1.4 mg/m² IV on day 1, and prednisone 40 mg/m² per day from day 1 to day 5 per os) with good response. He was free of disease 12 months after completion of chemotherapy. Gallbladder location of NHL is rare and has to be suspected every time when lymph nodes are associated, and we postulate that delays in making the diagnosis may lead to underdiagnosis of lymphoma of the gallbladder.

Conclusion

Review of the literature shows the existence of non-Hodgkin’s lymphoma of the gallbladder, its rarity, and its general dismal prognosis. Our case illustrated that the prognosis could be improved by correct chemotherapy.     

IFN-γ与肿瘤免疫

恶性肿瘤（以下简称肿瘤）是世界范围内人类致死的重要因素之一，其易转移与高复发的特性，导致每年数千万人因此失去生命。近年来研究发现，机体的免疫系统对肿瘤的产生、转移和复发等方面存在着制约作用，而肿瘤微环境中的免疫因子、各种免疫细胞分泌的细胞因子等在抗肿瘤以及免疫调节方面发挥着关键性作用。IFN-γ作为其中之一，在免疫反应中不可或缺，已成为当下研究的主要对象。以下对近几年来基于IFN-γ的肿瘤免疫研究进展进行综述。     

IFN-β临床应用研究进展

利用脂质体包被IL-2理论上能达到IL-2用量小、副作用少、疗效提高等效果.们前期应用脂质体IL-2联合CD3AK细胞治疗鼠肝黑色素转移瘤,取得了满意的实验结果.在此基础上,再探讨脂质体IL-2联合TIL、CY抗鼠肝癌的作用,旨在证明脂质体IL-2的优越性.1 材料与方法制备鼠H22肝癌皮下荷瘤模型,然后采用机械、酶消化和不连续密度梯度离心分离获得TIL,体外掺入rIL-2(1000U/ml)后培养、扩增.参照Konno及我所建立的制备脂质体方法制备复层大囊泡rIL-2脂质体(MLV-rIL-2).取昆明鼠40只随机分4组(即对照组、TIL CY组、TIL CY rIL-2组、TIL CY MLV-rIL-2组),每组10只进行体内治疗.后3组治疗开始前3天均用环磷酰胺(CY)腹腔注射,每日1次CY50mg/kg,然后尾静脉注射TIL,每次每只     

Rhinosporidiosis — a report of two cases

Rhinosporidiosis is primarily an infection of the nose. Though occasional involvement of other areas in the human body has been reported, it rarely presents as a disseminated disease. We describe two cases of recurrent nasopharyngeal rhinosporidiosis, one of them with cutaneous and pulmonary involvement. The clinical manifestations and the management of both the cases are discussed.