Effects of adoptive T-cell immunotherapy on immune cell profiles and prognosis of patients with unresectable or recurrent cholangiocarcinoma.

The identification of immune cell profiles (ICP) involved in anti-tumor immunity is crucial for immunotherapy. Therefore, we herein investigated cholangiocarcinoma patients (CCA) who received adoptive T-cell immunotherapy (ATI). Eighteen unresectable or recurrent CCA received ATI of αß T cells alone or combined with chemotherapy. ICP were evaluated by flow cytometry. There were 14 patients with intrahepatic cholangiocarcinoma (iCCA) and four with distal cholangiocarcinoma (dCCA). After one course of treatment, nine iCCA and four dCCA had progressive disease (PD), while five iCCA had stable disease (SD). Median overall survival (OS) was prolonged to 21.9 months. No significant differences were observed in OS between the PD and SD groups of iCCA. The frequency of helper T cells (HT) in iCCA decreased from 70.3% to 65.5% (P = .008), while that of killer T cells (KT) increased from 27.0% to 30.6% (P = .005). dCCA showed no significant changes of immune cells. OS was prolonged in iCCA with increased frequencies of CD3+ T cells (CD3) (P = .039) and αß T cells (αß) (P = .039). dCCA showed no immune cells associated with OS. The frequencies of CD3+ T cells and αß T cells in the PD group for iCCA decreased from 63.5% to 53% (P = .038) and from 61.6% to 52.2% (P = .028), respectively. In the SD group, the frequency of HT decreased from 65.8% to 56.9% (P = .043), whereas that of KT increased from 30.1% to 38.3% (P = .043). In conclusions, ATI affected ICP and prolonged OS. Immune cells involved in treatment effects differed according to the site of cholangiocarcinoma.

Evaluation of eligibility criteria in living donor liver transplantation for hepatocellular carcinoma by α-SMA-positive cancer-associated fibroblasts.

The eligibility criteria of liver transplantation (LT) for hepatocellular carcinoma (HCC) must clearly confirm the prognosis not only from pathological diagnosis but also from pre-operative imaging diagnosis. In the present study, we evaluated published eligibility criteria for LT based on both pre-operative imaging diagnosis and pathological diagnosis using living donor liver transplantation (LDLT) recipients at our hospital by α-smooth muscle actin (SMA)-positive cancer-associated fibroblasts (CAFs) in HCC. The Up-to-seven (Up-to-7), Asan and Tokyo criteria were evaluated, in both overall survival and HCC disease-free survival, to be statistically significantly beneficial criteria to define post-LDLT prognosis. Recipients only within Up-to-7 criteria based on both pre-operative imaging diagnosis and pathological diagnosis survived without HCC recurrence. Recipients with proliferation of α-SMA-positive CAFs in HCC had significantly poorer prognosis. All survival recipients without HCC recurrence, who were above the Up-to-7 criteria in pathological diagnosis, had no proliferation of α-SMA-positive CAFs. As a result of multivariate analysis, the significant independent factors defining prognosis of recipients after LDLT for HCC were Up-to-7 criteria and proliferation of α-SMA-positive CAFs. The ideal eligibility criteria for LDLT with HCC is Up-to-7 criteria and α-SMA-positive CAFs was considered to be an important factor in HCC recurrence. LDLT should be limited to recipients within Up-to-7 criteria or without proliferation of α-SMA-positive CAFs.

Duodenal adenocarcinoma with neuroendocrine features in a patient with acromegaly and thyroid papillary adenocarcinoma: a unique combination of endocrine neoplasia.

A 67-year-old woman with familial clustering of thyroid papillary adenocarcinoma was diagnosed with acromegaly due to pituitary macroadenoma. She had multiple skin vegetations, but had no parathyroid and pancreas diseases. Before transsphenoidal surgery, she was further diagnosed as having a duodenal tumor and multiple hypervascular liver nodules. Biopsy specimens from the duodenal tumor and liver nodules were diagnosed histologically as moderately differentiated adenocarcinoma. Immunohistochemically, the tumor cells were positive for chromogranin, synaptophysin and somatostatin receptor 2a, suggestive for neuroendocrine features. After surgery, the patient was not in biochemical remission, and octreotide treatment was initiated. The duodenal cancer was treated with chemotherapy (neoadjuvant cisplatin and S-1). After 24 months, the patient's insulin-like growth factor I level had been normalized, and her liver tumors had not progressed macroscopically. This is a rare case of acromegaly associated with multiple endocrine tumors, not being categorized as conventional multiple endocrine neoplasia. Octreotide treatment might have had beneficial effects on our patient's duodenal adenocarcinoma and liver metastases, both directly via SSTR2a and indirectly via GH suppression, thereby contributing to their slow progression.

Frequency of CD45RO+ subset in CD4+CD25(high) regulatory T cells associated with progression of hepatocellular carcinoma.

The purpose of this study was to assess the properties of CD4+CD25(high/low/negative) T cell subsets and analyze their relation with dendritic cells (DCs) in patients with hepatocellular carcinoma (HCC). In HCC patients, the prevalence of CD45RO+ cells in CD4+CD25(high) T cells was increased and associated with higher frequencies of plasmacytoid DCs. Larger proportions of this T cell subset were detected in the patients with larger tumor burdens. These results suggest that increased frequencies of the CD45RO+ subset in CD4+CD25(high) Tregs in HCC patients may establish the immunosuppressive environment cooperatively with tolerogenic plasmacytoid DCs to promote disease progression of liver cancer.

Prevention of intrahepatic metastasis of liver cancer by suicide gene therapy and chemokine ligand 2/monocyte chemoattractant protein-1 delivery in mice.

BACKGROUND: The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, largely as a result of intrahepatic metastasis. Using a mouse model of intrahepatic metastasis, we investigated whether chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) could potentiate the antitumor effects of the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system. METHODS: Mouse hepatoma cells infected with recombinant adenovirus vectors expressing HSV-tk, CCL2/MCP-1 and LacZ at multiplicities of infection of Ad-tk/Ad-MCP1 = 3/0.03 (T/M(Low)), 3/3 (T/M(High)) and Ad-tk/Ad-LacZ = 3/3 (T/L) were injected into BALB/c mice. RESULTS: Intrahepatic tumor growth was significantly lower in T/M(Low) mice. By contrast, no tumor suppression was observed in T/M(High) mice. The tumor-specific cytolytic activities of splenocytes from T/M(Low) and T/M(High) mice were comparable. Immunohistochemical analysis of liver tissues showed similar infiltration by Mac-1(+) and T cells in these animals, whereas the proportions of classical activated (M1) monocytes/macrophages were significantly higher in T/M(Low) mice. In addition, interleukin-12 production was elevated in these tissues. Vascular endothelial growth factor-A expression and CD31(+) microvessels were increased in T/M(High) mice. CONCLUSIONS: Collectively, these results demonstrate that an adequate amount of CCL2/MCP-1, together with the HSV-tk/GCV system, may induce T helper 1-polarized antitumor effects without inducing tumor angiogenesis in the microenvironment of intrahepatic HCC progression.

Tumor cell apoptosis induces tumor-specific immunity in a CC chemokine receptor 1- and 5-dependent manner in mice.

The first step in the generation of tumor immunity is the migration of dendritic cells (DCs) to the apoptotic tumor, which is presumed to be mediated by various chemokines. To clarify the roles of chemokines, we induced apoptosis using suicide gene therapy and investigated the immune responses following tumor apoptosis. We injected mice with a murine hepatoma cell line, BNL 1ME A.7R.1 (BNL), transfected with HSV-thymidine kinase (tk) gene and then treated the animals with ganciclovir (GCV). GCV treatment induced massive tumor cell apoptosis accompanied with intratumoral DC infiltration. Tumor-infiltrating DCs expressed chemokine receptors CCR1 and CCR5, and T cells and macrophages expressed CCL3, a ligand for CCR1 and CCR5. Moreover, tumor apoptosis increased the numbers of DCs migrating into the draining lymph nodes and eventually generated a specific cytotoxic cell population against BNL cells. Although GCV completely eradicated HSV-tk-transfected BNL cells in CCR1-, CCR5-, or CCL3-deficient mice, intratumoral and intranodal DC infiltration and the subsequent cytotoxicity generation were attenuated in these mice. When parental cells were injected again after complete eradication of primary tumors by GCV treatment, the wild-type mice completely rejected the rechallenged cells, but the deficient mice exhibited impairment in rejection. Thus, we provide definitive evidence indicating that CCR1 and CCR5 and their ligand CCL3 play a crucial role in the regulation of intratumoral DC accumulation and the subsequent establishment of tumor immunity following induction of tumor apoptosis by suicide genes.

[Unresectable pancreatic cancer in the Hokuriku area].

To clarify the diagnosis and treatment for unresectable pancreatic cancer from April 2001 when gemcitabine was released, we conduct a retrospective survey in the Hokuriku area. We analyzed clinical data of 254 patients. Seventy-two percent of the patients was treated by any method, and 90.7% of those were treated with a protocol including gemcitabine. Gemcitabine was administered a standard protocol (1000 mg/m(2) for 3 consecutive weeks with one week rest) in 62.2% patients, and dose of gemcitabine was reduced or schedule was changed in others. The median survival time was 8.2 months in the therapy group, and were is no differences between gemcitabine monotherapy, multi-drug therapy including gemcitabine and radiation combining gemcitabine in survival time. Multivariable analysis clarify patient's age, performance status, ascites, pleural effusion, and any therapy were prognostic factors. This investigation revealed chemotherapy for unresectable pancreatic cancer with gemcitabine have been spread around the Hokuriku area, in addition various ways have been tried.

Intestinal obstruction in autosomal dominant polycystic kidney disease.

A 42-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) was admitted to our hospital on April 29, 1999, with complaints of abdominal pain. A diagnosis of intestinal obstruction was reached on the basis of clinical findings and X-ray evidence. A computed tomography scan of the abdomen showed massively enlarged kidneys, especially the right kidney, which seemed to compress the small intestine. The patient underwent percutaneous aspiration of the largest cysts on the surface of the right kidney. The symptoms, in this rare case of intestinal obstruction by an enlarged kidney in ADPKD, were alleviated the day after the aspiration procedure.