[Efficacy of nivolumab in combination with chemotherapy after radiotherapy for meningeal carcinomatosis in patients with Epstein-Barr virus-associated gastric cancer:a case report].

A 62-year-old man presented with fever and anorexia since July X. Initial treatments were rendered ineffective, and due to altered consciousness and vomiting, he was referred to our hospital. On admission, he manifested delirium, drowsiness, and disorientation. While blood tests were normal, gastroscopy identified a type 3 tumor in his lower gastric body, later diagnosed as a poorly differentiated adenocarcinoma. Immunohistochemistry demonstrated negative human epidermal growth factor receptor 2 and positive programmed death-ligand 1 expression with a combined positive score ≥5. Furthermore, a positive Epstein-Barr virus-encoded small RNA in situ hybridization result was noted. Abdominal contrast-enhanced CT and PET-CT scans demonstrated multiple lymph node metastases around the stomach and liver, establishing the diagnosis of stage IVB gastric cancer (T4aN2M1). Brain magnetic resonance imaging (MRI) demonstrated enhanced lesions in the brainstem, cerebellar sulci, and right occipital lobe. Although cerebrospinal fluid cytology was negative for malignancy, the clinical symptoms and MRI findings confirmed leptomeningeal carcinomatosis (LMC). The patient underwent radiotherapy for LMC (total of 30Gy in 10 fractions), followed by combination therapy with a nivolumab and SOX regimen. Posttreatment, the LMC symptoms resolved;however, he experienced grade 3 immune-related adverse events related to liver dysfunction. Nivolumab was discontinued, and with steroid administration, the adverse events improved. Imaging evaluations posttreatment showed gastric tumor reduction and the absence of LMC. After 7 cycles, nivolumab was reintroduced, with no liver dysfunction recurrence noted through 15 cycles. Endoscopic examination 1 year postonset demonstrated that the gastric tumor had scarred, and MRI showed no signs of LMC recurrence. In 5-8% of solid tumors, LMC complications are present, resulting in limited treatment options and poor prognosis. Recent reports suggest the potential of immune checkpoint inhibitors in treating intracranial metastasis from solid tumors. In Japan, nivolumab was approved for gastric cancer treatment in 2017 and for first-line therapy in combination with chemotherapy since 2021. We report a case in which radiotherapy and chemotherapy combined with nivolumab provided durable control of LMC originating from gastric cancer for more than 1 year.

Immune Condition of Colorectal Cancer Patients Featured by Serum Chemokines and Gene Expressions of CD4+ Cells in Blood.

Background: Colorectal cancer (CRC), the most common malignancy worldwide, causes inflammation. We explored the inflammatory pathophysiology of CRC by assessing the peripheral blood parameters. Methods: The differences in gene expression profiles of whole blood cells and cell subpopulations between CRC patients and healthy controls were analyzed using DNA microarray. Serum cytokine/chemokine concentrations in CRC patients and healthy controls were measured via multiplex detection immunoassays. In addition, we explored correlations between the expression levels of certain genes of peripheral CD4+ cells and serum chemokine concentrations. Results: The gene expression profiles of peripheral CD4+ cells of CRC patients differed from those of healthy controls, but this was not true of CD8+ cells, CD14+ cells, CD15+ cells, or CD19+ cells. Serum IL-8 and eotaxin-1 levels were significantly elevated in CRC patients, and the levels substantially correlated with the expression levels of certain genes of CD4+ cells. Interestingly, the relationships between gene expression levels in peripheral CD4+ cells and serum IL-8 and eotaxin-1 levels resembled those of monocytes/macrophages, not T cells. Conclusions: Serum IL-8 and eotaxin-1 concentrations increased and were associated with changes in the gene expression of peripheral CD4+ cells in CRC patients.

Contralateral glissonian pedicle occlusion in a case of portal vein tumor thrombosis.

To dissect portal vein branches directly and encircle them separately is a common procedure that is performed to control back flow bleeding during operations for hepatocellular carcinoma with portal vein tumor thrombosis. However, this technique has an increased risk of injuring contralateral portal branches and disseminating thrombosis fragments to the remnant liver. We present an alternative technique using right-sided glissonian pedicle occlusion for hepatocellular carcinoma with left portal vein tumor thrombosis due to complex anatomical vasculatures of the hepatic pedicle. This technique would be very useful for liver resection of hepatocellular carcinoma with the major type of portal vein tumor thrombosis.

Possible involvement and the mechanisms of excess trans-fatty acid consumption in severe NAFLD in mice.

BACKGROUND & AIMS: Excessive trans-fatty acids (TFA) consumption has been thought to be a risk factor mainly for coronary artery diseases while less attention has been paid to liver disease. We aimed to clarify the impact of TFA-rich oil consumption on the hepatic pathophysiology compared to natural oil. METHODS: Mice were fed either a low-fat (LF) or high-fat (HF) diet made of either natural oil as control (LF-C or HF-C) or partially hydrogenated oil, TFA-rich oil (LF-T or HF-T) for 24 weeks. We evaluated the liver and body weight, serological features, liver lipid content and composition, liver histology and hepatic lipid metabolism-related gene expression profile. In addition, primary cultures of mice Kupffer cells (KCs) were evaluated for cytokine secretion and phagocytotic ability after incubation in cis- or trans-fatty acid-containing medium. RESULTS: The HF-T-fed mice showed significant increases of the liver and body weights, plasma alanine-aminotransferase, free fatty acid and hepatic triglyceride content compared to the HF-C group, whereas the LF-T group did not differ from the LF-C group. HF-T-fed mice developed severe steatosis, along with increased lipogenic gene expression and hepatic TFA accumulation. KCs showed increased tumor necrosis factor secretion and attenuated phagocytotic ability in the TFA-containing medium compared to its cis-isomer. CONCLUSIONS: Excessive consumption of the TFA-rich oil up-regulated the lipogenic gene expression along with marked hepatic lipid accumulation. TFA might be pathogenic through causing severe steatosis and modulating the function of KCs. The quantity and composition of dietary lipids could be responsible for the pathogenesis of non-alcoholic steatohepatitis.

SV40 infection associated with rituximab treatment after kidney transplantation in nonhuman primates.

BACKGROUND: A regimen consisting of polyclonal anti-T-cell antibody, sirolimus (SRL), and donor bone marrow (DBM) infusion induces robust transplantation tolerance to skin allografts in mice. We investigated the effect of a similar regimen in a nonhuman primate (NHP) model. METHODS: Cynomolgus macaques (Macaca fascicularis) were transplanted with mismatched kidney allografts. Recipients were treated with 7 doses of antithymocyte globulin (Thymoglobulin, day 1 to 9), sirolimus, and DBM infusion (day 14). Anti-CD20 antibody, rituximab, was given on days 0 and 5. RESULTS: A regimen of Thymoglobulin, 30 days of SRL, and DBM infusion induced significantly greater prolongation of graft survival with a mean survival time of 88 days compared with the control regimen (no DBM) with an mean survival time of 53 days (P=0.022). Unlike the murine skin allograft model, all grafts were rejected within 111 days. A combination of Thymoglobulin, continuous SRL, and rituximab caused graft and systemic SV40 infection and failed to achieve further extension of graft survival. C4d deposition was observed in 50% of recipients as early as 18 days, suggesting antidonor antibody production. A transient, low-to-moderate degrees of multilineage chimerism was observed after DBM infusion. Treatment with Thymoglobulin resulted in profound depletion of CD4+ and CD8+ T cells, whereas addition of rituximab achieved prolonged (up to 3 months) depletion of CD20+ B cells. CONCLUSION: The Thymoglobulin, SRL, and DBM protocol is simple and produces long-term kidney allograft survival in NHP although additional treatment modalities may be necessary for induction of long-term tolerance.

Cure of overt diabetes in NOD mice by transient treatment with anti-lymphocyte serum and exendin-4.

Treatment of overtly diabetic NOD mice with anti-lymphocyte serum (ALS), a polyclonal anti-T-cell antibody, abrogates autoimmunity and achieves partial clinical remission. Here we investigated whether the addition of exendin-4, a hormone that stimulates insulin secretion and beta-cell replication and differentiation, improves induction of remission by ALS. Transient treatment of overtly diabetic NOD mice with ALS and exendin-4 achieved complete remission in 23 of 26 mice (88%) within 75 days, accompanied by progressive normalization of glucose tolerance, improved islet histology, increased insulin content in the pancreas, and insulin release in response to a glucose challenge. Syngeneic islets transplanted into mice cured by treatment with ALS plus exendin-4 remained intact, and cotransfer of lymphocytes from cured mice delayed diabetes induction by adoptive transfer, suggesting the long-lasting presence of autoimmune regulatory cells. Although ALS alone also achieved reversal of diabetes, the frequency of remission was low (40%). No treatment or exendin-4 alone failed to produce remission. These results show that exendin-4 synergistically augments the remission-inducing effect of ALS. The addition of beta-cell growth factors, such as exendin-4, to immunotherapy protocols with anti-T-cell antibodies presents a potential novel approach to the cure of patients with new-onset type 1 diabetes.