[A Case of Abdominal Fullness Caused by a Retroperitoneal Bulky Tumor Treated with Epidural Analgesia].

We presented the case of a 63-year-old woman with severe abdominal distention due to recurrent retroperitoneal sarcoma. Further, the rapid progression of the tumor made it difficult to relieve the abdominal distention. Titrated intravenous morphine was administered. Although the dose of morphine was escalated and the patient was sedated, she continued to experience pain. The addition of a continuous epidural analgesic lidocaine to manage the abdominal distention was effective. This case report describes a stepwise approach with continuous epidural analgesia of lidocaine for a bulky tumor- related abdominal distention.

Phase I clinical trial of multiple-peptide vaccination for patients with advanced biliary tract cancer.

BACKGROUND: The prognosis of patients with advanced biliary tract cancer (BTC) is extremely poor and only a few standard treatments are available for this condition. We performed a phase I trial to investigate the safety, immune response and anti-tumor effect of vaccination with three peptides derived from cancer-testis antigens. METHODS: This study was conducted as a phase I trial. Nine patients with advanced BTC who had unresectable tumors and were refractory to standard chemotherapy were enrolled. Three HLA-A*2402 restricted epitope peptides-cell division cycle associated 1 (CDCA1), cadherin 3 (CDH3) and kinesin family member 20A (KIF20A)-were administered subcutaneously, and the adverse events and immune response were assessed. The clinical effects observed were the tumor response, progression-free survival (PFS) and overall survival (OS). RESULTS: The three-peptide vaccination was well-tolerated up to a dose of 3 mg per peptide (9 mg total). No grade 3 or 4 adverse events were observed after vaccination. Peptide-specific T cell immune responses were observed in all patients and stable disease was observed in 5 of 9 patients. The median PFS and OS were 3.4 and 9.7 months. The Grade 2 injection site reaction and continuous vaccination after PD judgment appeared to be prognostic of OS. CONCLUSIONS: Multiple-peptide vaccination was well tolerated and induced peptide-specific T-cell responses. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR000003229).

Forty-year experience with flow-diversion surgery for patients with congenital choledochal cysts with pancreaticobiliary maljunction at a single institution.

BACKGROUND: Congenital choledochal cyst with pancreaticobiliary maljunction (PBM) is known as a high-risk factor for various complications such as cholangitis, pancreatitis, and carcinogenesis of the biliary system by mutual refluxes of bile and pancreatic juice. Furthermore, it is not rare to suffer from postoperative complications if the wrong operative procedure is chosen. Therefore, we sought to review the relationship between operative procedure for types I and IV-A (Todani's classification) congenital choledochal cyst with PBM, and long-term treatment outcome. SUBJECTS AND METHODS: A retrospective review was carried out of 144 patients who underwent flow diversion surgery in our institution during the 40-year period from 1968 to 2008 and who did not have a coexisting malignant tumor at the time of surgery. RESULTS: Of these 144 patients, 137 underwent complete cyst excision and 7 underwent pancreas head resection as flow diversion surgery. The follow-up periods ranged from 1 to 345 months and from 1 to 271 months (average, 100.2 and 94.1) in patients with type I and type IV-A cysts, respectively. Regarding surgical treatment outcome, postoperative progress was good in 130 (90.3%) of the 144 patients. Fourteen patients required hospitalization for long-term postoperative complications such as cholangitis, pancreatitis, intrahepatic calculi, pancreatic calculus, and carcinogenesis during postoperative follow-up. Of these, 2 patients who underwent surgery for type IV-A cysts died because of secondary biliary cirrhosis with liver failure and advanced intrahepatic cholangiocarcinoma, respectively. CONCLUSIONS: The present study shows that flow diversion surgery for congenital choledochal cysts with PBM significantly reduces the risk of subsequent development of malignancy in the biliary tract, and it is vital to choose the appropriate operative procedure to prevent occurrence of these postoperative complications.

Hepatic resection in 485 R0 pT2 and pT3 cases of advanced carcinoma of the gallbladder: results of a Japanese Society of Biliary Surgery survey--a multicenter study.

PURPOSE: We conducted this study to evaluate the optimal hepatic resection for pT2 and pT3 advanced carcinoma of the gallbladder without invasion of the hepatoduodenal ligament. METHODS: We conducted a questionnaire survey regarding 4,243 cases of carcinoma of the gallbladder treated during the recent 10-year period at 112 institutions belonging to the Japanese Society of Biliary Surgery. The questionnaires included questions on preoperative-diagnosis, complications, treatment, and surgical treatment, procedures of resection, surgical result, path histological findings, mode, and site of recurrence, additional post-operative treatment. They included 293 pT2 and 192 pT3 R0 cases, which were negative for hepatoduodenal ligament invasion, and the cumulative survival rates and sites of postoperative recurrence in the form of liver metastasis, were retrospectively analyzed in these 485 cases. RESULT: There were no significant differences in survival rate or recurrence rates in the form of liver metastasis between the groups that underwent resection of the gallbladder bed, the group that underwent segmentectomy 4a+5, and the group that underwent hepatectomy in patients with of both pT2 or pT3 gallbladder cancers. Our results also did not show that liver metastasis to segment 4a5 alone was particularly common. CONCLUSION: For gallbladder cancer, neither with hepatoduodenal ligament invasion nor hepatic invasion, resection of the gallbladder bed is more preferable for surgical hepatic procedure. For gallbladder cancer that invades any hepatic sites, a hepatic surgical procedure that could eliminate surgical margins would be desirable.

Should the extrahepatic bile duct be resected or preserved in R0 radical surgery for advanced gallbladder carcinoma? Results of a Japanese Society of Biliary Surgery Survey: a multicenter study.

PURPOSE: We assessed the significance of an extra bile duct resection by comparing the survival of patients with advanced gallbladder carcinoma who had resected bile ducts with those who had preserved bile ducts. A radical cholecystectomy that includes extra bile duct resections has been performed without any clear evidence of whether an extra bile duct resection is preventive or curative. METHODS: We conducted a questionnaire survey among clinicians who belonged to the 114 member institutions of the Japanese Society of Biliary Surgery. The questionnaires included questions on the preoperative diagnosis, complications, treatment, and surgical treatment, resection procedures, surgical results, pathological and histological findings, mode and site of recurrence, and the need for additional postoperative treatment. A total of 4243 patients who had gallbladder carcinoma and were treated from January 1, 1994 to December 31, 2003 were identified. The 838 R0 patients with pT2, pT3, and pT4 advanced carcinoma of the gallbladder for which there was no cancer invasion to the hepatoduodenal ligament or cystic duct in the final analysis. RESULTS: The 5-year cumulative survival, postoperative complications, postoperative lymph node metastasis, and local recurrence along the hepatoduodenal ligament were not substantially different between the resected bile duct and the preserved bile duct groups. CONCLUSIONS: Our retrospective questionnaire survey showed that an extrahepatic bile duct resection had no preventive value in some patients with advanced gallbladder carcinoma in comparison to similar patients who had no such bile duct resection. An extrahepatic bile duct resection may therefore be unnecessary in advanced gallbladder carcinoma without a direct infiltration of the hepatoduodenal ligament and the cystic duct.

[The case of tumor escape mechanism by changing their tumor-associated antigens].

A 53-year-old woman presented with a diagnosis of advanced gallbladder cancer at our hospital. She was evaluated with CT scan and given a diagnosis of Stage IVb due to the multiple lymph nodes metastases and significant invasion to the artery. However, we underwent simple cholecystectomy followed by immunotherapy that was the hope of herself and her family. The serum level of DUPAN-2 was gradually elevated to 6,800 U/mL, and the metastases to the liver were detected. After we started the dendritic cell vaccine pulsed with autologous tumor-lysate with S-1, DUPAN-2 decreased to 980 U/ mL. The CT scan showed complete response (CR) in the liver metastases and partial response (PR) in the lymph node metastases. However, the serum level of CEA elevated since the MUC-1 peptide was used instead of autologous tumor- lysate, even DUPAN-2 did not. The liver metastases were in control, but the lymph nodes metastases had progressed. She died of the progressed lesion later in approximately one year from the operation. This case demonstrated a possibility of the tumor escape mechanism by changing their tumor-associated antigens.

[Combined cell therapy by using dendritic cells, T-cells and NK cells to human polymorphic cancer].

Although an expression of MHC molecules and tumor associated antigens of the cancer are not uniform, we consider that the cancer immunotherapy for some specific tumor antigens cannot correspond to molecular biological varieties of the cancer. Consequently, we tried to develop a method to separate dendritic cells (DC), T-cells and natural killer (NK) cells from peripheral blood mononuclear cells (PBMC) obtained from healthy volunteers. PBMC were separated by centrifugation on Ficoll-Hypaque gradients from peripheral blood obtained from healthy volunteers. After separating these cells, the cells were put into a plastic flask, and we isolated monocyte fraction (dendritic cells), NK cell fraction and T-cell fraction one after another by the difference in its ability to adhere to a plastic flask. We analyzed surface markers and activation states of these groups. We could induce dendritic cells from the monocyte fraction, CD3-activated T-cells (CAT) from the T-cell fraction, and adherent lymphokine activated-killer cells (A-LAK) from the NK cell fraction. Therefore, we indicate the possibility of the combined cell therapy with three immune cell fractions in which we can induce from the same blood at once.

Postoperative dendritic cell vaccine plus activated T-cell transfer improves the survival of patients with invasive hepatocellular carcinoma.

The recurrence rate after surgery in patients with hepatocellular carcinoma (HCC) is very high, while prognosis is quite poor. However, there is no standard treatment to prevent recurrence of HCC after a curative operation. In this study, we investigated the clinical utilization of an autologous tumor lysate-pulsed dendritic cell vaccine plus ex vivo activated T cell transfer (ATVAC) in an adjuvant setting for postoperative HCC as a non-randomized controlled trial. Ninety-four patients with invasive HCC received informed consent information regarding the study, and 42 opted to have the ATVAC after surgery. Their recurrence-free survival (RFS) and overall survival (OS) were measured after 5 years and compared with those of 52 patients who selected to have the curative operation alone. The median RFS and OS were 24.5 months and 97.7 months in the patients receiving adjuvant ATVAC and 12.6 months and 41.0 months in the group receiving surgery alone (P = 0.011 and 0.029). In the treated group, patients with positive delayed-type hypersensitivity (DTH) had a better prognosis (RFS P = 0.019, OS P = 0.025). No adverse events of grade 3 or more were observed. A postoperative dendritic cell vaccine plus activated T cell transfer would be a feasible and effective treatment for preventing recurrence in HCC patients and achieving long-term survival especially in DTH positive patients.

Long-term Vaccination with Multiple Peptides Derived from Cancer-Testis Antigens Can Maintain a Specific T-cell Response and Achieve Disease Stability in Advanced Biliary Tract Cancer.

PURPOSE: The prognosis of patients with advanced biliary tract cancer (BTC) is extremely poor and there are only a few standard treatments. We conducted a phase I trial to investigate the safety, immune response, and antitumor effect of vaccination with four peptides derived from cancer-testis antigens, with a focus on their fluctuations during long-term vaccination until the disease had progressed. EXPERIMENTAL DESIGN: Nine patients with advanced BTC who had unresectable tumors and were refractory to standard chemotherapy were enrolled. HLA-A*2402-restricted epitope peptides, lymphocyte antigen 6 complex locus K, TTK protein kinase, insulin-like growth factor-II mRNA-binding protein 3, and DEP domain containing 1 were vaccinated subcutaneously once a week at doses of 0.5, 1, or 2 mg and continued until disease progression. The adverse events were assessed by Common Terminology Criteria for Adverse Events and the immune response was monitored by an enzyme-linked immunospot assay or by flow cytometry. The clinical effects observed were tumor response, progression-free survival (PFS), and overall survival (OS). RESULTS: Four-peptide vaccination was well tolerated. No grade 3 or 4 adverse events were observed. Peptide-specific T-cell immune responses were observed in seven of nine patients and clinical responses were observed in six of nine patients. The median PFS and OS were 156 and 380 days. The injection site reaction and CTL induction seemed to be prognostic factors of both PFS and OS. CONCLUSIONS: Four-peptide vaccination was well tolerated and seemed to provide some clinical benefit to some patients. These immunologic and clinical responses were maintained over the long term through continuous vaccinations.

Clinical utilization of postoperative dendritic cell vaccine plus activated T-cell transfer in patients with intrahepatic cholangiocarcinoma.

BACKGROUND: The prognosis of patients with intrahepatic cholangiocarcinoma (ICC) is extremely poor and the recurrence rate after curative operation is very high. There is no standard treatment to prevent recurrence of ICC. In this study, we investigated the clinical utilization of a dendritic cell vaccine plus activated T-cell transfer in an adjuvant setting for postoperative ICC. METHODS: 36 patients with ICC were vaccinated at least 3 times with autologous tumor lysate pulsed dendritic cells plus ex-vivo activated T-cell transfer. The 5-year progression-free survival (PFS) and overall survival (OS) were measured and compared with those of 26 patients who received the curative operation alone as a concurrent control. The registration number was UMIN000005820. RESULTS: The median PFS and OS were 18.3 and 31.9 months in the patients receiving adjuvant immunotherapy and 7.7 and 17.4 months in the group receiving surgery alone (p = 0.005 and 0.022, respectively). In the treated group, patients whose skin reactions were 3 cm or more at the vaccine site showed dramatically better prognosis (PFS p < 0.001, OS p = 0.001). CONCLUSIONS: A postoperative dendritic cell vaccine plus activated T-cell transfer would be a feasible and effective treatment for preventing recurrence and achieving long-term survival in ICC patients.

Tumor-induced immune suppression of in vivo effector T-cell priming is mediated by the B7-H1/PD-1 axis and transforming growth factor beta.

We have generated effector T cells from tumor-draining lymph nodes (TDLN) that are efficacious in adoptive immunotherapy. We now examine the effect of concomitant tumors on the generation of effector T cells. We inoculated methylcholanthrene (MCA) 205 in the flanks of normal mice and mice bearing MCA 205 lung metastases. TDLN cells from these mice were activated and expanded in vitro, and adoptively transferred to mice bearing lung metastases. Effector T cells generated from TDLN in mice with only flank tumor mediated potent antitumor activity. However, antitumor efficacy of the effector T cells generated from TDLN in mice with pre-existent lung tumor (cTDLN) was reduced. Phenotyping studies showed that dendritic cells in cTDLN expressed higher levels of B7-H1, whereas cTDLN T cells expressed higher levels of PD-1. The levels of IFNgamma were reduced, and the levels of CD4(+)Foxp3(+) regulatory T cells were increased in cTDLN versus TDLN. The in vitro activation of cTDLN was increased by blocking B7-H1 or transforming growth factor (TGF)-beta. Importantly, we found a synergistic up-regulation of IFNgamma with simultaneous blockade of B7-H1 and TGF-beta that was much greater than observed with TDLN. In vitro activation of cTDLN with anti-B7-H1 and anti-TGF-beta and in vivo administration of these antibodies after adoptive transfer resulted in the abrogation of the suppression associated with cTDLN. These results show a major role for the B7-H1/PD-1 axis and TGF-beta as synergistic suppressive mechanisms in cTDLN. Our data have clinical relevance in the generation of effector T cells in the tumor-bearing host.

Simultaneous targeting of CD3 on T cells and CD40 on B or dendritic cells augments the antitumor reactivity of tumor-primed lymph node cells.

To date, molecular targets chosen for Ab activation to generate antitumor effector cells have been confined on T cells, such as TCR/CD3, CD28, CD137 (4-1BB), CD134 (OX40), and inducible costimulator. In this report we investigated the immune function of murine tumor-draining lymph node (TDLN) cells after simultaneous Ab targeting of CD3 on T cells and CD40 on APCs. Anti-CD3 plus anti-CD40-activated TDLN cells secreted significantly higher amounts of IFN-gamma, but less IL-10, compared with anti-CD3-activated cells. In adoptive immunotherapy, ligation of CD3 and CD40 resulted in the generation of more potent effector cells in mediating tumor regression. Freshly harvested TDLN cells were composed of approximately 60% CD3+ T cells, 30-35% CD19+ B cells, 5% CD11c+ dendritic cells (DC), and few CD14+ or NK cells (each <3%). CD40 was distributed predominantly on B cells and DCs. Cell depletion indicated that simultaneous targeting was toward CD3 on T cells and CD40 on APCs, respectively. Elimination of APCs completely abrogated the augmented antitumor responses induced by anti-CD40. Either B cell or DC removal partially, but significantly, reduced the therapeutic efficacy conferred by CD40 engagement. Furthermore, the immunomodulation function of anti-CD40 was associated with its capability to increase IL-12 secretion while inhibiting IL-4 production. Our study establishes a role for CD40 expressed on B cells or DCs in the costimulation of TDLN cells. Eliciting antitumor activity via simultaneous targeting of CD3 on T cells and CD40 on APCs is relevant for the design of effective T cell-based cancer immunotherapy.