Polyglycolic acid mesh for preventing post-thoracoscopic bullectomy recurrence.

PURPOSE: Thoracoscopic bullectomy is a common treatment modality for spontaneous pneumothorax but can result in a high frequency of postoperative recurrent pneumothorax in young patients. This retrospective study compared the recurrence rate of pneumothorax following conventional thoracoscopic bullectomy to that following bullectomy using a low-density polyglycolic acid mesh to cover the staple line. METHODS: Group A comprised 237 patients who experienced 294 episodes of pneumothorax and underwent thoracoscopic bullectomy alone, and Group B comprised 130 patients who experienced 155 episodes of pneumothorax and underwent bullectomy with polyglycolic acid mesh used to cover the visceral pleura. To compare the postoperative inflammatory response between the two groups, we measured three inflammatory parameters: highest body temperature after surgery, C-reactive protein level on postoperative day 3, and change in eosinophil count from the day before the surgery to postoperative day 3. RESULTS: The recurrence rate was significantly lower in Group B than in Group A (2.6% vs. 24.8%, P < 0.000001). All three inflammatory parameters were significantly higher in Group B than in Group A. CONCLUSIONS: Using a polyglycolic acid mesh covering after thoracoscopic bullectomy resulted in acceptable long-term results (recurrence rate: 2.6%). This method was associated with a slightly elevated inflammatory response.

Bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy in advanced nonsquamous non-small cell lung cancer (West Japan Oncology Group 5910L): An open-label, randomized, phase 2 trial.

BACKGROUND: Bevacizumab combined with platinum-based chemotherapy has been established as a standard treatment option in the first-line setting for advanced nonsquamous non-small cell lung cancer (NSCLC). However, there has been no evidence to support the use of bevacizumab beyond disease progression in such patients. METHODS: West Japan Oncology Group 5910L was designed as a multicenter, open-label, randomized, phase 2 trial of docetaxel versus docetaxel plus bevacizumab every 3 weeks for patients with recurrent or metastatic nonsquamous NSCLC whose disease had progressed after first-line treatment with bevacizumab plus a platinum-based doublet. The primary endpoint was progression-free survival (PFS). RESULTS: One hundred patients were randomly assigned to receive docetaxel (n = 50) or docetaxel plus bevacizumab (n = 50), and this yielded median PFS times of 3.4 and 4.4 months, respectively, with a hazard ratio (HR) of 0.71 and a stratified log-rank P value of .058, which met the predefined criterion for statistical significance (P < .2). The median overall survival also tended to be longer in the docetaxel plus bevacizumab group (13.1 months; 95% confidence interval [CI], 10.6-21.4 months) versus the docetaxel group (11.0 months; 95% CI, 7.6-16.1 months) with an HR of 0.74 (95% CI, 0.46-1.19; stratified log-rank P = .11). No unexpected or severe adverse events were recorded. CONCLUSIONS: Further evaluation of bevacizumab beyond disease progression is warranted for patients with advanced NSCLC whose disease has progressed after treatment with bevacizumab plus a platinum-based doublet.

[A case of pleomorphic malignant fibrous histiocytoma with multiple lung metastases with bilateral pneumothorax after chemotherapy].

A 70-year-old man diagnosed with pleomorphic malignant fibrous histiocytoma of the left thigh underwent tumor resection. After 10 months, he underwent extended resection due to local recurrence. However, because multiple lung metastases was detected at this time, chemotherapy with ifosfamide and doxorubicin was administered. After three courses of chemotherapy, the lung metastases enlarged and the patient received ifosfamide and etoposide as second line chemotherapy. Even after three courses of second line treatment, the disease progressed, for which docetaxel and gemcitabine were administered as third line chemotherapy. After three courses of third line treatment, multiple lung metastases reduced and were replaced with scar and cystic lesions (reduction ratio 85.9%). After four courses of treatment, the patient developed left pneumothorax. Partial resection of the left upper lobe was performed by thoracoscopic surgery. Histopathological examination revealed rupture of the visceral pleura in a scar lesion leading to air leakage. After 13 courses of treatment, he developed right pneumothorax. Partial resection of the right middle lobe was performed. Histopathological examination revealed a cystic lesion without tumor remnants. After 15 courses of third line treatment, lung metastasis could be controlled. Chemotherapy with docetaxel and gemcitabine resulted in few adverse effects that were within tolerance limits.

[A case of cStage III B non-squamous non-small-cell lung cancer completely resected after downstaging with chemotherapy].

A 64-year-old man was diagnosed with a gastric ulcer, and a tumor shadow was observed in the right lower lung field on a chest radiograph. Chest computed tomography (CT) revealed the tumor shadow to be 33 × 25 mm in the right lower lobe; it also revealed a 7-mm nodule in the right S3, and lymph node swelling in the upper and lower mediastinum. Positron emission tomography (PET)-CT revealed an SUVmax of 12.8, 1.2, 7.6, and 10.0 for the right lower lobe tumor, right S3 nodule, and the No. 4 and No. 7 lymph nodes, respectively. The right lower lobe tumor was diagnosed as an adenocarcinoma via transbronchiall ung biopsy. The patient was diagnosed with cT4N2M0, cStage III B cancer. Four courses of carboplatin, pemetrexed, and bevacizumab were administered. After the fourth course, chest CT revealed that the right lower lobe tumor and the right S3 nodule significantly reduced to 14 × 7 mm and 5mm respectively, and the mediastinal lymph node swelling was nearly eliminated. Subsequent PET-CT examination revealed an SUVmax of 1.3 and 0.8 in the right lower lobe tumor and right S3 nodule, respectively. The patient was diagnosed with ycT4N0M0, ycStage III A cancer, and he underwent right lower lobe resection, right S3 partial resection, and lymph node. Postoperative pathological analysis was used to make a diagnosis of mixed type adenocarcinoma for the right lower lobe tumor, and a diagnosis of papillary adenocarcinoma for the right S3 nodule. Both tumors were diagnosed as primary lung cancers. There were no metastatic cancer cells in the dissected lymph nodes.

[A case of lung cancer in an elderly patient with malignant pleural effusion and pneumothorax treated with carboplatin, pemetrexed, and bevacizumab].

We report a case of an elderly patient with non-squamous non-small cell lung cancer who was successfully treated with chemotherapy using carboplatin(CBDCA), pemetrexed(PEM), and bevacizumab(Bev). The patient was an 84-year-old man who presented with a chief complaint of dyspnea. The right lung was completely collapsed due to malignant pleural effusion, and the mediastinum was shifted to the left. Right thoracic drainage was performed, but this was complicated by pneumothorax and a thoracotomy was performed. An absorbent tissue reinforcing agent was attached to the site of the air leakage and fibrin glue was applied. After discharge, the patient was administered 500mg/m / 2 PEM plus 15 mg/kg Bev for the first course of chemotherapy and experienced no serious side effects. CBDCA(area under the curve[AUC]4)was added from the second course. After the administration of seven courses, pleural effusion had almost disappeared and the primary tumor in the upper right lobe was observed to have shrunk. Administration of PEM+Bev was continued thereafter. The right pleural effusion was well controlled for up to 12 months(14 courses)from the start of the administration of chemotherapy, and shrinkage of the primary tumor was maintained. The side effects were mild and chemotherapy was administered safely. After the administration of 16 courses, a left malignant pleural effusion was observed, and the patient died 15 months after the initiation of chemotherapy.

[A case of advanced gastric cancer with recurrence-free long survival showing disappearance of distant lymph node metastases by S-1/docetaxel therapy followed by curative resection].

A screening CT of a 78-year-old man suffering from a laryngeal foreign body revealed multiple lymph nodes swelling at the left subclavicular, mediastinal, perigastric, and paraaortic space. He was diagnosed as advanced gastric cancer. After five courses of S-1/docetaxel therapy, the primary tumor became flat and lymph nodes became undetectable. After seven courses, he received operation(total gastrectomy and D2 lymph nodes dissection)because of tumor bleeding and severe adverse effects. The pathological chemotherapeutic effect was Grade 1b for the primary tumor and Grade 3 for lymph nodes. He received S-1 maintenance therapy for three years afterward, and is now still in good condition without recurrence 53 months after the first administration. S-1/docetaxel therapy was thought to be a useful optional regimen for highly advanced gastric cancer.

Efficacy and safety of orally administered Lentinula edodes mycelia extract for patients undergoing cancer chemotherapy: a pilot study.

Lentinula edodes mycelia extract (L.E.M.) is extensively utilized as an herbal medicine. However, its safety and effectiveness have not yet been scientifically verified. In this study, we investigated its safety and its influence on quality of life (QOL) and the immune response in patients undergoing cancer chemotherapy. Seven patients were studied in total. The patients were undergoing postoperative adjuvant chemotherapy for breast cancer (n = 3) or gastrointestinal cancer (n = 2), or were receiving chemotherapy to prevent recurrence of gastrointestinal cancer (n = 2). The first course of treatment was chemotherapy alone and the second was chemotherapy plus concomitant administration of L.E.M. Adverse events and changes in the QOL score, lymphocyte subpopulations, lymphocyte activity and serum immune indices were evaluated during the study period. No adverse events attributable to L.E.M. were observed. Compared to the pre-chemotherapy state, no changes in QOL or immune parameters were noted after the first chemotherapy course. In contrast, following the second course of combined therapy, improvements were noted in QOL (p < 0.05), NK cell activity (p < 0.05) and immunosuppressive acidic protein (IAP) (p < 0.01) levels. Although a future large-scale investigation is necessary to confirm these results, these data suggest that the concomitant of L.E.M. with chemotherapy is safe and improves the QOL and immune function of patients undergoing chemotherapy.

[A patient with small intestinal cancer and extensive lymph node metastasis who responded to S-1].

The patient was an 89-year-old male who consulted our hospital with a complaint of black stools. He had undergone gastrectomy and Roux-en Y reconstruction. Upper digestive tract endoscopy revealed a flat plate-like ulcer in the jejunum on the anal side of the gastrojejunostomy site. Biopsy findings suggested undifferentiated adenocarcinoma. Computed tomography (CT) showed cervical, mediastinal, and intraperitoneal lymph node swelling, suggesting metastasis. Extensive lymph node metastasis made curative resection impossible, and symptoms such as perforation/stenosis were absent. Therefore, surgery was not performed, and systemic hemotherapy with S-1 (80 mg/body/day) was administered. We repeated 2-week administration and 1-week discontinuation per course. After the end of the second course, upper digestive tract endoscopy revealed cicatrization of the ulcer, and CT showed a marked decrease in the lymph node size; a complete response (CR) was achieved. During the 7-month follow-up after the initial consultation (7 courses of S-1 therapy in all), there has been no exacerbation, and the quality of life (QOL) has been maintained.

Docetaxel and S-1 as a first-line treatment in patients with advanced or recurrent gastric cancer.

BACKGROUND: The safety and efficacy of docetaxel plus S-1 combination chemotherapy as a first-line treatment in patients with advanced or recurrent gastric cancer was verified retrospectively. PATIENTS AND METHODS: Eighteen patients with advanced or recurrent gastric cancer were enrolled. The regimen used was intravenous docetaxel, 40 mg/m(2), on day 1 and oral S-1, 80 mg/m(2)/day, on days 1-14 every three weeks. RESULTS: In total 101 cycles were administered. One and 11 patients achieved complete and partial responses, while six and zero patients showed stable and progressive disease, respectively. The median time to progression (TTP) and median overall survival were 7.0 and 14.3 months, respectively. Neutropenia was the most common grade 3/4 hematological toxicity. Nausea and stomatitis were the most common grade 3 nonhematological toxicities. No treatment-related death was observed. CONCLUSION: Docetaxel plus S-1 combination is an active and tolerable regimen as a first-line treatment in patients with advanced or recurrent gastric cancer.

A feasibility study of postoperative adjuvant therapy of carboplatin and weekly paclitaxel for completely resected non-small cell lung cancer.

INTRODUCTION: Recent clinical trials have shown significant survival benefits from postoperative adjuvant therapy for respectable nonsmall cell lung cancer (NSCLC). However, evaluation of adjuvant chemotherapy with carboplatin combination is still uncertain. The purpose of the study was to test the feasibility of adjuvant chemotherapy with carboplatin and separate weekly paclitaxel after complete resection of pStage IB, II, IIIA NSCLC in a multicenter study. METHODS: The study was conducted from 2001 to 2006 in the outpatient setting. A total of 61 patients were enrolled. Patients received adjuvant chemotherapy with 4 cycles of carboplatin (AUC 5) on day 1 and paclitaxel (70 mg/m) on day 1, 8, and 15 every 4 weeks. Primary endpoints were toxicity and chemotherapy compliance. Secondary endpoints were disease-free survival and overall survival. RESULTS: More than 65% of eligible patients had pStage IIIA. The median number of chemotherapy cycles was 4 (range 1-4). Grade 3 or 4 toxicities of neutropenia were 34% (grade 4: 2%). Other hematologic adverse effects were extremely less frequent. Regarding the nonhematologic adverse effect, hair loss was frequent; however, peripheral neuralgia was less frequent. Treatment-related death was not registered. During median follow-up of 21 months, 24 patients developed recurrent disease. Estimated disease-free survival and overall survival at 2 years was 51.2% and 84.6%, respectively. CONCLUSIONS: Postoperative carboplatin and weekly paclitaxel showed favorable feasibility and acceptable toxicity in comparison with the cisplatin-containing regimen. Consequently, it is desirable that this regimen would be validated in a phase III clinical trial for NSCLC after curative resection.

[Combination of carboplatin and gemcitabine is a safe and feasible regimen in adjuvant therapy for stage II and IIIA NSCLC].

BACKGROUND: Recently, several randomized trials have shown that postoperative adjuvant treatment improves survival among patients with completely resected non-small cell lung cancer (NSCLC). Platinum-based chemotherapy has been reported to be effective for patients with postoperative stage II to IIIA. PATIENTS AND METHODS: In the present study, 5 patients with completely resected stage IIB and IIIA received carboplatin AUC 4 on day 1 and gemcitabine 1,000 mg/m(2) on days 1 and 8 every 3 weeks for six cycles as adjuvant chemotherapy. RESULTS: No early or toxic deaths were observed. All patients were administered 6 cycles completely and safely. Three patients had grade 3 neutropenia and three had grade 2 thrombocytopenia. One patient had grade 3 neutropenia on day 8 in the 2nd and 3rd cycle, and the medications were postponed for a week. Non-hematological toxicity including alopecia and neuropathy were not found. CONCLUSION: In the present study, the combination of carboplatin and gemcitabine has been a safe and feasible regimen in adjuvant therapy for stage II and IIIA NSCLC.

[Chemotherapy for patients with non-curative advanced or recurrent gastric cancer in our hospital].

In our hospital, beginning in April 2005, chemotherapy for non-curative advanced or recurrent gastric cancer was integrated, and 9 regimens including 6 combination therapies were prepared. First-line chemotherapy mainly focusing on TS-1 plus docetaxel combination therapy(S-1+DOC)was done. Second-line and subsequent chemotherapy treatments were chosen by the doctor in charge. 78.6% of second-line chemotherapy was monotherapy. Median survival time(MST)since first-line chemotherapy was 15.6 months, and 1-year survival rate since first-line chemotherapy was 65.0%. MST since the start of first-line S-1+DOC was over 16.4 months, and 1-year survival rate since this therapy start was 69.0%. The good results were ascribed to following: 1. good response rate(30.4%), prolonged time to progression(TTP)(6.1 months), and good control against adverse events at first-line chemotherapy; 2. good shift rate of second-line chemotherapy from the first-line one(82.4%); and 3. good disease control rate(78.6%), prolonged TTP(7.0 months), and good control against adverse events at second-line chemotherapy. In patients with peritoneal metastasis, however, despite the prolonged TTP of 8.7 months by first-line chemotherapy, MST since first-line chemotherapy was poor at 11.1 months. Thus, improvement of second-line or subsequent chemotherapy is warranted.

[Clinical administration of FOLFOX regimens for patients with unresectable advanced or recurrent colorectal cancer].

FOLFOX regimens were administered to 14 patients with unresectable advanced or recurrent colorectal cancer from 1 to 9 cycles (median 5 cycles). In our patient characteristics, 10 patients had previous chemotherapies, 3 patients showed performance status 3. The response rate was 21%, and median time to progression was 5.0 months. Frequency of grade 3/4 adverse effect was 57% in neutropenia, 36% in leucopenia, 36% in thrombocytopenia, and 7% in allergic reaction. Only 64% patients could complete the treatment, for these adverse events brought treatment failure at 3-6 cycles. Median relative dose-intensity was 80-90% during 1-4 cycles, but about 50% after 5 cycles for these adverse events. No patient had grade 3 neurologic toxicity,because no one was administered over 10 cycles. FOLFOX regimens showed good anti-tumor effects but poor tolerability after 5-6 cycles in our patients.

Intrathecal administration of Y-27632, a specific rho-associated kinase inhibitor, for rat neoplastic meningitis.

The small GTP-binding protein Rho and its target Rho-associated kinase trigger an intracellular signaling cascade that controls actin cytoskeleton and plays an essential role in cell motility and adhesion. A specific Rho-associated kinase inhibitor, Y-27632, has been reported to inhibit cancer invasion. Clinically, disseminated tumor cells in the cerebrospinal fluid invade the intraparenchymal region, damaging the brain and nerves, resulting in fatal brain stem dysfunction, despite intrathecal chemotherapy. To expand therapeutic options for this devastating neoplastic meningitis, we evaluated the potential use of intrathecal Y-27632 administration by employing Walker 256 cells, a rat mammary cancer cell line. Y-27632 dose-dependently inhibited chemotactic and invasive activity of Walker 256 cells. Y-27632 also inhibited the phosphorylation level of regulatory myosin light chain in vitro, but the effect was temporary and was considerably diminished within 16 hours. Y-27632 induced striking morphologic changes in Walker 256 cells, as evidenced by decreased cell-matrix adhesion in culture dishes and three-dimensional collagen I gels, and slightly inhibited colony formation in soft agar. Nevertheless, this drug treatment did not affect Walker 256 cell growth rate. We were able to administer continuous delivery of this inhibitor using an osmotic pump and maintaining drug concentration of 10 mumol/L within the brain. Importantly, this concentration of Y-27632 showed minimal neurotoxicity both in vitro and in vivo. We found that an intrathecal therapy, combining 5-fluoro-2'-deoxyuridine with Y-27632, significantly increased the survival time of rats bearing meningeal carcinomatosis in comparison with animals treated with 5-fluoro-2'-deoxyuridine alone. Taken together, our findings indicate that continuous intrathecal administration of Y-27632 could be a promising therapeutic method when combined with chemotherapy for treating human neoplastic meningitis.

Continuous intrathecal administration of 5-fluoro-2'-deoxyuridine for the treatment of neoplastic meningitis.

OBJECTIVE: Previously, we reported a good clinical treatment effect of intrathecal chemotherapy by repeated bolus administration of 5-fluoro-2'-deoxyuridine (FdUrd) for neoplastic meningitis (NM). Moreover, we detected no side effects or neurotoxicity despite the long-term repetition of intrathecal administration. On the basis of these findings, continuous intrathecal chemotherapy (CIC) with FdUrd for patients with NM was attempted using a simple pump system. We evaluated the usefulness of CIC with FdUrd for the treatment of NM. METHODS: A total of 25 patients were enrolled in this study. FdUrd (1.0 mg/d) was administered using a balloon pump system. CIC was continued as long as possible. Eight patients received whole-brain irradiation (3 Gy x 10) simultaneously with CIC. The effects of the treatment were analyzed in terms of improvement in neurological signs and symptoms and the findings of ventricular and lumbar cerebrospinal fluid analysis 2 and 4 weeks after CIC was initiated and on magnetic resonance imaging scans 2 months after CIC began. RESULTS: No apparent toxicity has been observed to date. Evidence of a cerebrospinal fluid response was observed in 13 patients. Headache and nausea were improved in all patients, and cranial nerve impairment was improved in 12 patients. A magnetic resonance imaging response was observed in only 5 patients. Overall response was observed in 15 patients when cases of stable disease were excluded from the responding cases. Survival time from the commencement of CIC (mean +/- standard error of the mean) was 255 +/- 30 days in 25 patients. CONCLUSION: This therapy may be useful, especially as a maintenance therapy for NM.

Locoregional immunotherapy of malignant ascites from gastric cancer using DTH-oriented doses of the streptococcal preparation OK-432: Treatment of Th1 dysfunction in the ascites microenvironment.

Locoregional administration of the streptococcal preparation OK-432 is effective in treating malignant ascites from gastric cancer. In order to enhance the efficacy, we conducted a pilot study of locoregional immunotherapy for malignant ascites using host-oriented doses of OK-432. Moreover, action mechanisms of OK-432 were further explored in view of the T-helper type 1 (Th1)-Th2 concept. Gastric cancer patients with cytologically determined malignant ascites were locoregionally administered with OK-432. The dose of OK-432 was selected according to the delayed-type hypersensitivity (DTH) reaction levels to OK-432. Cytokine production profiles of ascites cells were determined using whole ascites assay by stimulation with OK-432. IL-10 mRNA expression was analyzed using RT-PCR. It was found that a positive clinical response was observed in 37 of the 51 (73%) patients with the DTH-oriented approach, showing a significantly higher efficacy than traditional dosage methods using empirical doses (31/58, 53%) (p=0.0487). The DTH-oriented administration of OK-432 produced adverse effects such as fever elevation (p<0.0001) and abdominal pain (p=0.0013) to a significantly lesser extent compared with the traditional treatment. Analysis of the action mechanism of OK-432 revealed that the DTH reaction in responders (19+/-6 mm) was stronger than that in non-responders (6+/-4 mm) (p<0.0001). Tumor necrosis factor (TNF)-alpha production of ascites cells was also higher in responders (3943+/-1247 pg/ml) than in non-responders (1217+/-939 pg/ml) (p=0.0002). There was a significant positive correlation (p=0.0085) between the levels of DTH reaction and TNF-alpha production of ascites cells, but not of blood cells. Responders appeared to polarize on the Th1 axis when clinical responses were plotted on Th1-Th2 dimensions according to the cytokine production profiles of TNF-alpha, IFN-gamma, IL-4 and IL-6 of ascites cells. In vitro culture with IL-2 of ascites cells after OK-432 administration demonstrated an almost clonal expansion of CD4+ lymphocytes, which produced TNF-alpha and IFN-gamma, but did not produce IL-4 or IL-6. IL-10 mRNA expression was detectable in ascites cells from non-responders before treatment. These results suggest that the DTH-oriented locoregional administration of OK-432 may be both effective and less toxic in treating malignant ascites from gastric cancer, showing a possibility of the tailored immunotherapy for malignant ascites. Th1 dysfunction exists in the microenvironment of malignant ascites from gastric cancer, in which IL-10 may, in part, play a role. The up-regulation of Th1 responses by OK-432 may result in positive clinical responses. The DTH reaction to OK-432 may be a useful tool not only for predicting clinical response but also for selecting the optimal dose of OK-432.

[Generation of TRiDAK (tumor RNA-introduced dendritic cell-activated killer) cells].

Tumor-reactive effector lymphocytes were generated using tumor-derived amplified RNA and cultured dendritic cells (DC). Tumor RNAs were extracted from gastric cancer cell line MKN45 or cancer cells of malignant effusions, and were processed with T7 amplification. DCs were induced from an adherent cell population of peripheral blood mononuclear cells (PBMCs) with GM-CSF and IL-4. Tumor-RNA was introduced into DCs using electroporation. Effector cells were generated by stimulating a non-adherent fraction of PBMCs with tumor RNA-introduced DCs. It was observed that milligram RNA could efficiently be amplified from microgram RNA. The effector cells, designated as tumor-RNA-introduced DC-activated killer (TRiDAK) cells, showed IFN-gamma spots in a tumor-specific manner when examined using ELISPOT analysis, and demonstrated cytotoxic activities against tumor cells from which RNA was extracted. TRiDAK cells produced more tumor-specific IFN-gamma spots when stimulated repeatedly. These results suggest that TRiDAK cells are practical and may be effective lymphocytes for adoptive cancer immunotherapy.

[Tumor RNA introduction into dendritic cells and Epstein-Barr virus transformed B cells].

In induction of autologous tumor-reactive antigen (TRA) specific cytotoxic T lymphocytes (CTLs) using antigenic peptides and cultured dendritic cells (DCs), identification of the adequate tumor antigens and HLA typing of individuals are required. These restrictions have promoted the use of tumor cells themselves, including tumor cell lysates and tumor cell-DC fusion cells. However, it is very difficult to obtain enough tumor cells for treatment in the clinical setting. We have studied the use of RNA derived from tiny tumor cells. RNA was reverse-transcribed into cDNA, after which T7-amplification and in vitro transcription were carried out. The amplified RNA was successfully electroporated into DCs, and polyclonal polyspecific CTLs could be generated. EBV transformed B cells were also good candidates to be electroporated with the RNA. This suggests that tumor RNA amplification followed by introduction into DCs or EBV transformed B cells is a feasible and practical method to prepare potent APCs.

Screening of gastrointestinal hormone release in patients with lung cancer.

The aim of this study was the screening of gastrointestinal (GI) hormones release as possible sensitive tumor markers. The subjects were eight patients with carcinoma of the lung compared with nine healthy controls. Six kinds of GI hormones were measured by the specific radioimmunoassay. It was evaluated by fasting level (F), increased integrated responses (IIR60, IIR180 pmol/l/min) and total integrated responses (TIR60, TIR180 pmol/l/min) after a meal. The data were analyzed by the Student's t-test. The F of pancreatic polypeptide (PP) was significantly higher in patients than that in healthy controls (24.4 vs. 12.3 pmol/l, p = 0.002). Consequently, the sensitivity was 75% (6 out of 8) and specificity was 100% (9 out of 9). Almost all parameters of IIR60, IIR180, TIR60 and TIR180 in PP and peptide YY were significantly higher in patients than in healthy controls (p value: 0.00020-0.021). The other four kinds of hormones showed similar results to the healthy controls. These results seem to indicate that PP and PYY would be useful tumor markers for lung cancer in clinical management.

Adoptive immunotherapy of cancer using activated autologous lymphocytes--current status and new strategies.

After the discovery of interleukin-2 (IL-2), lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocytes (TILs), and cytotoxic T lymphocytes (CTLs) sensitized with the mixed lymphocyte-tumor culture (MLTC) system have been conducted in adoptive immunotherapy (AIT) trials during past 15 years. Although the overall response rate of tumor shrinkage was marginal (9%), locoregional administration of TILs for malignant effusions was effective (77%) for a decrease or disappearance of the effusions even in terminally-ill patients, resulting in an improvement of QOL. Recent advances for molecular understanding of antigen presentation and recognition have promoted us to enhance the efficacy of AIT by using cultured dendritic cells (DCs) for generating antigen-specific CTLs in vitro. The peptide-pulsed DC-activated killer (PDAK) cells showed tumor recognition against antigen-expressing cells, and were efficiently propagated with the IL2 plus immobilized anti-CD3 antibody (IL-2/CD3) culture system. Clinical trials using PDAK cells against patients with lung metastases are now progressed, in which peptides suitable for generating CTLs were chosen in individual patients using the method designated as host-oriented peptide evaluation (HPOE) approach. Moreover, DCs were introduced with tumor-derived RNA, which was amplified with the T7 promoter system, and then were used for stimulating lymphocytes. The tumor RNA-introduced DC-activated killer (TRiDAK) cells showed tumor-specific interferon-gamma spots even in a patient in whom we failed to generate PDAK cells using DCs and peptides, suggesting that the clinical trial of AIT using TRiDAK cells is warranted for the treatment of patients with metastatic cancer. Thus, more understanding of antigen-presentation and -recognition mechanisms and immune regulation systems may promote clinical applications of AIT to establish a novel modality of cancer treatment.