Distinct role of CD8 cells and CD4 cells in antitumor immunity triggered by cell apoptosis using a Herpes simplex virus thymidine kinase/ganciclovir system.

Immune cells can recognize tumor-associated antigens released from dead tumor cells, which elicit immune responses, potentially resulting in tumor regression. Tumor cell death induced by chemotherapy has also been reported to activate immunity. However, various studies have reported drug-induced immunosuppression or suppression of inflammation by apoptotic cells. Thus, this study aimed to investigate whether apoptotic tumor cells trigger antitumor immunity independent of anticancer treatment. Local immune responses were evaluated after direct induction of tumor cell apoptosis using a Herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system. The inflammatory response was significantly altered at the tumor site after apoptosis induction. The expression of cytokines and molecules that activate and suppress inflammation simultaneously increased. The HSV-tk/GCV-induced tumor cell apoptosis resulted in tumor growth suppression and promoted T lymphocyte infiltration into tumors. Therefore, the role of T cells after inducing tumor cell death was explored. CD8 T cell depletion abrogated the antitumor efficacy of apoptosis induction, indicating that tumor regression was mainly dependent on CD8 T cells. Furthermore, CD4 T cell depletion inhibited tumor growth, suggesting the potential role of CD4 T cells in suppressive tumor immunity. Tumor tissues were evaluated after tumor cell apoptosis and CD4 T cell depletion to elucidate this immunological mechanism. Foxp3 and CTLA4, regulatory T-cell markers, decreased. Furthermore, arginase 1, an immune-suppressive mediator induced by myeloid cells, was significantly downregulated. These findings indicate that tumors accelerate CD8 T cell-dependent antitumor immunity and CD4 T cell-mediated suppressive immunity. These findings could be a therapeutic target for immunotherapy in combination with cytotoxic chemotherapy.

Comprehensive genomic profiling of a unique liposarcoma arising in a patient with Li-Fraumeni syndrome and the novel detection of c-myc amplification: a case report.

BACKGROUND: Germline TP53 mutations have been frequently reported in patients with Li-Fraumeni syndrome (LFS), resulting in a predisposition to various malignancies. Mutations other than germline TP53 mutations can also cause LFS-associated malignancies, but their details remain unclear. We describe a novel c-myc amplification in a unique liposarcoma in a patient with LFS. CASE PRESENTATION: A female patient with LFS developed breast cancer twice at the age of thirty; both were invasive ductal carcinomas harboring HER2 amplifications. Computed tomography revealed an anterior mediastinal mass, which was surgically resected. Histological analysis revealed three different lesions corresponding to myxoid liposarcoma-, pleomorphic liposarcoma-, and well-differentiated liposarcoma-like lesions. Fluorescence in-situ hybridization (FISH) analysis did not detect MDM2 amplification, Rb1 deletion, break apart signals of EWS, FUS, DDIT3, or c-myc, or c-myc-IGH fusion signals, but it did detect more c-myc signals. Further FISH analysis and comprehensive genomic profiling revealed c-myc amplification. We considered two differential diagnoses, dedifferentiated liposarcoma lacking MDM2 amplification and myxoid pleomorphic liposarcoma (MPLPS), and determined that this case is most likely MPLPS. However, definite diagnosis could not be made because a clear-cut differentiation of the case from liposarcomas was not possible. CONCLUSIONS: A previous study demonstrated that c-myc amplification could not be detected in various liposarcomas, but the present unique liposarcoma showed c-myc amplification, so the c-myc amplification may indicate that the present liposarcoma is an LFS-related tumor. The present case further clarifies the pathological features of MPLPS and LFS-related liposarcomas by broadening their histopathological and genetic diversities.

Antibiotic Treatment Improves the Efficacy of Oxaliplatin-Based Therapy as First-Line Chemotherapy for Patients with Advanced Gastric Cancer: A Retrospective Study.

Purpose: One of the first-line treatment for gastric cancer patients is oxaliplatin, and the efficacy of this chemotherapeutic can be attenuated by the microbiome. In this study, we retrospectively evaluated whether treatment with antibiotics improved the efficacy of oxaliplatin-based chemotherapy in patients with advanced gastric cancer. Patients and Methods: Fifty-four patients were assigned to the antibiotic-treated group and 35 to the antibiotic-untreated group. Results: The response rate of oxaliplatin-based chemotherapy in the antibiotic-treated and antibiotic-untreated groups was 66.7% and 41.4%, respectively (p = 0.038). The median progression-free survival after oxaliplatin-based chemotherapy in the antibiotic-treated and antibiotic-untreated groups was 8.8 and 5.2 months, respectively (hazard ratio = 0.456, 95% confidence interval = 0.254-0.819; p = 0.007, Log rank test). Univariate and multivariate analyses revealed that antibiotic treatment was the only clinical parameter that correlated with the response to oxaliplatin. Conclusion: Antibiotic treatment could be used therapeutically to enhance the efficacy of oxaliplatin-based chemotherapy in patients with advanced gastric cancer.

Contribution of Fcγ receptor IIB to creating a suppressive tumor microenvironment in a mouse model.

Various immune cells are recruited in the tumor microenvironment. It is well established that cellular immune responses, such as cytotoxic or suppressive activities, play an important role in regulating tumor growth and metastasis. However, the contribution of humoral immune responses against tumors is poorly understood. Fc receptors constitute critical elements for the up- or downregulation of immune responses through immune complexes. Here, we examined the potential role of the inhibitory Fc receptor, Fcγ receptor IIB (FcγRIIB), in tumor immunity using a mouse model. Our findings indicated that tumor-specific antibodies are induced in tumor-bearing mice and control tumor immunity. FcγRIIB deletion significantly improved both cellular and humoral immunity against tumors and delayed tumor growth. These findings indicated that spontaneous antibodies against tumors create a suppressive tumor microenvironment through FcγRIIB signaling, thus suggesting an attractive therapeutic target for cancer immunotherapy.

Predictive factors for the efficacy of the second taxane treatment in patients with advanced cancer.

PURPOSE: Research has revealed that some patients who develop resistance to the first taxane treatment exhibit a moderate response to the second taxane treatment (incomplete cross-resistance between paclitaxel and docetaxel). However, which patients are most likely to respond to the second treatment remains unclear. The aim of this study was to determine the predictive factors for the efficacy of the second taxane treatment in patients resistant to the first. PATIENTS AND METHODS: We enrolled patients treated with paclitaxel and docetaxel (n=31) in this study. Using univariate and multivariate analyses, we determined the predictive factors for the efficacy of the second taxane treatment. Then, we assigned patients to one of the three groups: 1) those with a partial response (PR) to the first taxane treatment who subsequently became refractory (PR group); 2) those whose response was stable disease (SD) and subsequently became refractory (SD group); and 3) those whose response was the progression of the disease with the first taxane treatment (progression disease [PD] group). Furthermore, the response rates were assessed for each group. All statistical analyses were performed using JMP 11. RESULTS: Responses to the first taxane treatment considerably correlated with the efficacy of the second treatment in patients with a PR to the first taxane treatment (P=0.0061, univariate analysis; P=0.0056, multivariate analysis). In addition, response rates to the second taxane treatment in the PR, SD, and PD groups were 33.3%, 0%, and 0%, respectively. CONCLUSION: The response to the first taxane treatment was a predictive factor for the efficacy of the second taxane treatment in patients with a PR to the first. Thus, the second treatment is highly recommended for patients who exhibit tumor shrinkage (a PR) by the first treatment.

Efficacy and Safety of Trastuzumab in Combination with S-1 and Cisplatin Therapy for Japanese Patients with HER2-Positive Advanced Gastric Cancer: Retrospective Analysis.

The combinations of oral fluoropyrimidines and cisplatin such as capecitabine and cisplatin (XP) or S-1 and cisplatin (SP) are regarded as a standard therapy against unresectable, recurrent, or advanced gastric cancer (AGC). Especially, SP is the most common regimen against AGC in Japan. For patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC, trastuzumab, a monoclonal antibody targeting HER2 antibody, is additionally used in combination. Although trastuzumab in combination with XP (trastuzumab-XP) have been widely accepted, the efficacy of trastuzumab in combination with SP (trastuzumab-SP) lacks sufficient verification. The aim of the present study is to validate the comparability of trastuzumab-SP to trastuzumab-XP. Patients with HER2-positive AGC were assigned to the trastuzumab-XP or trastuzumab-SP group. We then retrospectively compared the efficacy and safety between both groups. As a first-line chemotherapy, trastuzumab in combination with XP or SP was administered to 58 patients: 28 with trastuzumab-XP and 30 with trastuzumab-SP. In the trastuzumab-XP group, response rate (RR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) were 39.3%, 89.3%, 7.9 months, and 20.0 months, respectively. In the trastuzumab-SP group, RR, DCR, mPFS and mOS were 50.0%, 86.7%, 6.9 months, and 16.7 months, respectively. No significant difference in efficacy was observed between both groups. Severe hand-foot syndrome was observed more frequently in the trastuzumab-XP group than in the trastuzumab-SP group (14.3% vs. 0%, p = 0.05). Trastuzumab in combination with SP is a potential first-line therapeutic option for patients with HER2-positive AGC.

[A Case of Hypertrophic Pachymeningitis with Symptomatic Venous Congestion due to Sinus Stenosis].

We report a patient with hypertrophic pachymeningitis and symptomatic stenosis of the superior sagittal sinus. A 71-year-old man presented with right hemiparesis, sensory-dominant aphasia, and right hemispatial neglect that had been worsening over 2 weeks. Computed tomography showed isodense crescent-shaped lesions deforming the surface of the left cerebral hemisphere, mimicking a subdural hematoma with atypical perifocal edema in the left parietal lobe. Magnetic resonance imaging showed diffuse thickening of the dura mater with contrast enhancement of his left cerebral hemisphere. Histopathological examination of the dural specimen obtained by burr-hole surgery revealed mononuclear inflammatory cell infiltration, and he was diagnosed with hypertrophic pachymeningitis. Dynamic cerebral angiography showed superior sagittal sinus stenosis with reduced venous flow through the left parietal lobe. Administration of high-dose steroid therapy led to neurological improvement. In the case of a subdural mass with atypical parenchymal edema such as a chronic subdural hematoma, other etiology should be taken into consideration.

[A case of atherothrombotic embolization developing with slowly progressive symptoms and requiring differential diagnosis from metastatic tumor recurrence].

We report a case of atherothrombotic embolization that developed with slowly progressive symptoms and required differential diagnosis from metastatic tumor recurrence. A 64-year-old man with a history of lung cancer and metastatic brain tumor was carefully followed at our outpatient department for tumor recurrence. Five years after surgery for brain metastasis and whole brain radiation therapy, he had no recurrence and systemic disease was well controlled. At a routine follow up in October 2013, he complained of slight right arm dysesthesia. Follow up brain magnetic resonance (MR) imaging revealed no lesion. Two months later, he developed right hemiparesthesia and gait disturbance. Spinal MR imaging was unremarkable. However, at a routine follow up in January 2014, multiple enhancements were detected near the resection cavity and regions delineating the sulci. At first, this was diagnosed as tumor recurrence. However, 3 days later, additional MR imaging detected new multiple small infarctions after worsening right hemiparesis and dysarthria. With the diagnosis of embolic stroke, we searched for an embolic source. Cardiogenic embolization and carotid bifurcation stenosis studies were negative, but severe stenosis and thrombosis were detected near the left common carotid artery origin. This site was in the field of radiation the patient received as treatment for primary lung cancer.

Human bile contains microRNA-laden extracellular vesicles that can be used for cholangiocarcinoma diagnosis.

UNLABELLED: Cholangiocarcinoma (CCA) presents significant diagnostic challenges, resulting in late patient diagnosis and poor survival rates. Primary sclerosing cholangitis (PSC) patients pose a particularly difficult clinical dilemma because they harbor chronic biliary strictures that are difficult to distinguish from CCA. MicroRNAs (miRs) have recently emerged as a valuable class of diagnostic markers; however, thus far, neither extracellular vesicles (EVs) nor miRs within EVs have been investigated in human bile. We aimed to comprehensively characterize human biliary EVs, including their miR content. We have established the presence of extracellular vesicles in human bile. In addition, we have demonstrated that human biliary EVs contain abundant miR species, which are stable and therefore amenable to the development of disease marker panels. Furthermore, we have characterized the protein content, size, numbers, and size distribution of human biliary EVs. Utilizing multivariate organization of combinatorial alterations (MOCA), we defined a novel biliary vesicle miR-based panel for CCA diagnosis that demonstrated a sensitivity of 67% and specificity of 96%. Importantly, our control group contained 13 PSC patients, 16 with biliary obstruction of varying etiologies (including benign biliary stricture, papillary stenosis, choledocholithiasis, extrinsic compression from pancreatic cysts, and cholangitis), and 3 with bile leak syndromes. Clinically, these types of patients present with a biliary obstructive clinical picture that could be confused with CCA. CONCLUSION: These findings establish the importance of using extracellular vesicles, rather than whole bile, for developing miR-based disease markers in bile. Finally, we report on the development of a novel bile-based CCA diagnostic panel that is stable, reproducible, and has potential clinical utility.