Home transfusions are implemented using diverse approaches in Japan.

BACKGROUND AND OBJECTIVES: Japan's ageing society has increased the need for home healthcare, including home transfusions. We hence aimed to elucidate the purpose and utilization of home transfusions in Japan, which has not been clarified to date. MATERIALS AND METHODS: Clinics throughout Japan that provide home care and have experience in performing blood transfusions were surveyed. The study period was February to December 2019, and information of patients receiving home red blood cell transfusions, including patient background, pre-transfusion laboratory data and the purpose of the transfusions, was collected. RESULTS: Haematological malignancies and solid tumours accounted for 70% of the patients' underlying diseases, with the former being significantly more common in urban areas. Regarding the purpose of the home transfusions, haematologists focused on symptom improvement, whereas gastroenterology surgeons focused on life support. Furthermore, maintenance of life was more likely to be the aim in the group of patients with the lowest level of activities of daily living. The main items that were significantly associated with a low haemoglobin level before transfusion included age ≥90 years and a gastroenterologist being the physician in charge. CONCLUSION: Home transfusions were found to be performed in a restrictive and diverse manner in Japan. Life support is the second most common purpose of home transfusion in Japan, and optimizing effective home transfusion remains a challenge.

Management system of home transfusion in Japan: A nationwide survey in 2019.

BACKGROUND AND OBJECTIVES: In Japan, there are various opinions on the pros and cons of home transfusion because of safety concerns. We hence aimed to elucidate the safety and availability of home transfusion in Japan, which has not been clarified to date. MATERIALS AND METHODS: Clinics throughout Japan that provide home care and have experience in performing blood transfusions were surveyed. The analysis period was February to December 2019. Basic information about the clinics, their collaboration system with core hospitals, storage method of red blood cells (RBCs) and the system for the management of patient information regarding transfusion reactions were investigated. RESULTS: Detailed information was obtained regarding the implementation of home transfusions by 51 clinics. The proportion of home care clinics performing home transfusions was 17.6%, and they were more frequently performed in urban regions. Approximately half of the clinics collaborated with a core hospital for emergency responses to transfusion reactions. At 84% of the clinics, RBC units were stored in refrigerators that were not exclusively allocated to blood storage. Nurses and family members were involved as patient attendants in 83% and 77% of the home transfusions, respectively. No serious transfusion reactions were reported among the 150 patients in 2019, nor the 623 patients up to 2018. CONCLUSION: From data on its availability and safety, home transfusions are considered to be in the developing phase in Japan. Increased cooperation between hospitals and clinics is crucial towards improving the home transfusion system in Japan in the future.

Contribution of toxicological pathology to occupational health: lung carcinogenicity of fibrous and particulate substances in rats.

In this review, we focus on the rat pulmonary carcinogenicity of two solid substances, fibrous multi-walled carbon nanotube (MWCNT) and particulate indium tin oxide (ITO). Inhalation exposure to MWNT-7, a type of MWCNTs, and ITO induced lung carcinogenicity in both male and female rats. Toxicity to the alveolar epithelium is induced by macrophages undergoing frustrated phagocytosis or frustrated degradation of engulfed particles (referred to as frustrated macrophages). Melted macrophage contents contribute significantly to development of hyperplasia of the alveolar epithelium, which eventually results in the induction of lung carcinoma. MWNT-7 and ITO induce secondary genotoxicity; consequently, a no-observed-adverse-effect level can be applied to these materials rather than benchmark doses that are used for non-threshold carcinogens. Thus, establishing occupational exposure limit values for MWNT-7 and ITO based on the existence of a carcinogenic threshold is reasonable.

Lung carcinogenicity of inhaled multi-walled carbon nanotube in rats.

BACKGROUND: Multi-walled carbon nanotubes (MWCNTs) constitute one of the most promising types of nanomaterials in industry today. With their increasing use, the potential toxicity and carcinogenicity of MWCNT needs to be evaluated in bioassay studies using rodents. Since humans are mainly exposed to MWCNT by inhalation, we performed a 104-week carcinogenicity study using whole-body inhalation exposure chambers with a fibrous straight type of MWCNT at concentrations of 0, 0.02, 0.2, and 2 mg/m3 using male and female F344 rats. RESULTS: Lung carcinomas, mainly bronchiolo-alveolar carcinoma, and combined carcinomas and adenomas were significantly increased in males exposed to 0.2 and 2 mg/m3 MWNT-7 and in females exposed to 2 mg/m3 MWNT-7 compared to the clean air control group. However, no development of pleural mesothelioma was observed. Concentration-dependent toxic effects in the lung such as epithelial hyperplasia, granulomatous change, localized fibrosis, and alteration in BALF parameters were found in MWNT-7 treatment groups of both sexes. There were no MWNT-7-specific macroscopic findings in the other organs, including the pleura and peritoneum. Absolute and relative lung weights were significantly elevated in male rats exposed to 0.2 and 2 mg/m3 MWNT-7 and in all exposed female groups. The lung burdens of MWNT-7 were clearly increased in a concentration-dependent as well as a duration-dependent manner. CONCLUSION: There is clear evidence that MWNT-7 is carcinogenic to the lungs of male and female F344 rats, however no plural mesothelioma was observed.

Immunological evaluation of personalized peptide vaccination in refractory small cell lung cancer.

Since the prognosis of small cell lung cancer (SCLC) remains poor, development of new therapeutic approaches, including immunotherapies, would be desirable. In the current study, to evaluate immunological responses in refractory SCLC patients, we conducted a small scale phase II clinical trial of personalized peptide vaccination (PPV), in which vaccine antigens are selected based on pre-existing host immunity. Ten refractory SCLC patients, who had failed to respond to chemo- and/or chemoradiotherapies (median number of regimens, 2.5; median duration, 20.5 months), were enrolled. A maximum of four human leukocyte antigen (HLA)-matched peptides showing higher antigen-specific humoral responses were subcutaneously administered (weekly for six consecutive weeks and then bi-weekly thereafter). PPV was terminated before the 3rd administration in four patients because of rapid disease progression, whereas the remaining six patients completed at least one cycle (six times) of vaccinations. Peptide-specific immunological boosting was observed in all of the six patients at the end of the first cycle of vaccinations, with their survival time of 25, 24.5 (alive), 10 (alive), 9.5, 6.5, and 6 months. Number of previous chemotherapy regimens and frequency of CD3(+) CD26(+) cells in peripheral blood were potentially prognostic in the vaccinated patients (hazard ratio [HR] = 2.540, 95% confidence interval [CI] = 1.188-5.431, P = 0.016; HR = 0.941, 95% CI = 0.878-1.008, P = 0.084; respectively). Based on the feasible immune responses in refractory SCLC patients who received at least one cycle (six times) of vaccinations, PPV could be recommended for a next stage of larger-scale, prospective clinical trials.

Infrared Thermography with High Accuracy in a Neonatal Incubator.

As the accuracy of body temperature measurement is especially critical in premature infants on admission to the neonatal intensive care unit (NICU), noninvasive measurement using infrared thermography (IRT) has not been widely adopted in the NICU due to a lack of evidence regarding its accuracy. We have established a new calibration method for IRT in an incubator, and evaluated its accuracy and reliability at different incubator settings using a variable-temperature blackbody furnace. This method improved the accuracy and reliability of IRT with an increase in percentage of data with mean absolute error (MAE) < 0.3 °C to 93.1% compared to 4.2% using the standard method. Two of three IRTs had MAE < 0.1 °C under all conditions examined. This method provided high accuracy not only for measurements at specific times but also for continuous monitoring. It will also contribute to avoiding the risk of neonates' skin trouble caused by attaching a thermistor. This study will facilitate the development of novel means of administering neonatal body temperature.

[Current status and prospects of cancer vaccine therapy].

Cancer vaccine is proceeding to a promising therapy against cancer since 1990 when expression cloning method of tumor associated antigens was reported. Clinical trials showed immunological therapies contribute to prolonged survival in patients with cancers, such as prostate cancer and melanoma, so that FDA approved a dendritic cell vaccine in USA, and peptide vaccines are developing energetically in recent years in Japan. Peptide vaccines have advantages immunologically and economically as a cancer vaccine spreads all over the world, because CTL epitope peptides of tumor associate antigen has a highly antigen-specificity, and can be synthesized uniformly in large quantities for easy handing agents. However it has weak points, such as limited effectiveness in clinical responses due to cancer cells escaped from cancer immunity and possibility of unfavorable immune responses. For development of cancer peptide vaccines, biomarkers related with clinical effects and methods to measure favorable and unfavorable immune responses are necessary about vaccine alone and combination with multidisciplinary modalities in large scale phase III studies.

Immunological evaluation of personalized peptide vaccination monotherapy in patients with castration-resistant prostate cancer.

We previously reported that personalized peptide vaccine (PPV) therapy in combination with leutenizing hormone-releasing hormone (LH-RH) analog and estramustine phosphate in certain cases is safe and capable of inducing both immune responses and clinical responses for metastatic castration-resistant prostate cancer (CRPC) patients. In the present study, PPV monotherapy was given to CRPC patients. Twenty-three patients with metastatic CRPC were treated with PPV without any additional treatment modalities, including LH-RH analogs. Samples were analyzed for peptide-specific cytotoxic T-lymphocyte (CTL) precursor analysis and peptide-reactive IgG. Toxicity and immunological and clinical responses were assessed on a three-monthly basis. Seventeen patients were available for immunological and clinical evaluation. The vaccines were well tolerated, with grade 3 erythema at injection sites in only one patient. Augmentation of CTL or IgG responses to at least one of the peptides was observed in six of 17 (35%) and 15 of 17 (88%) patients tested, respectively. Among 57 peptides used, 9 and 36 peptides induced CTL and IgG responses, respectively. Delayed-type hypersensitivity reaction was observed in eight of 17 patients. More than 30% prostate-specific antigen (PSA) decline was observed in four of 17 patients. Of these, one patient achieved a complete PSA response and another patient showed a partial PSA response with profound shrinking of lymph node metastases and prostate. The overall median survival time was 24 months (range, 5-37 months). These results suggest that PPV monotherapy appears to be safe and capable of inducing peptide-specific immune responses and clinical responses in CRPC patients. This trial was registered with University Hospital Medical Information Network (UMIN) number R000003339.

Identification of biomarkers for personalized peptide vaccination in 2,588 cancer patients.

Peptide­based cancer vaccines have failed to provide sufficient clinical benefits in order to be approved in clinical trials since the 1990s. To understand the mechanisms underlying this failure, the present study investigated biomarkers associated with the lower overall survival (OS) among 2,588 patients receiving personalized peptide vaccination (PPV). Survival data were obtained from a database of 2,588 cancer patients including 399 patients with lung, 354 with prostate and 344 with colon cancer. They entered into phase II clinical trials of PPV in which 2 to 4 of 31 warehouse peptides were selected for vaccination on an individual patient basis based on human leukocyte antigen (HLA) class IA­types and pre­existing peptide­specific IgG levels. Higher pre­vaccination neutrophil, monocyte and platelet counts, and lower pre­vaccination lymphocyte and red blood cell counts were inversely associated with OS, with higher sensitivities in the proportions of neutrophils and lymphocytes, respectively. The most potent unfavorable and favorable factors for OS were the median percentage of neutrophils (≥64.8%) or percentage of lymphocytes (≥25.1%) with correlation coefficients (R2) of 0.98 and 0.92, respectively. Higher pre­vaccination levels of c­reactive protein and other inflammatory soluble factors were inversely associated with OS. Pre­vaccination peptide­specific immunity levels had no effect on OS, although lower immune boosting levels were inversely associated with OS. None of the 31 peptides was inversely associated with OS, although a few peptides were positively associated with it. On the whole, the findings of the present study suggested that pre­vaccination inflammatory signatures, but not those of post­vaccination immune induction, were associated with lower clinical benefits of PPV.

The linkage between medical student readiness for interprofessional learning and interest in community medicine.

OBJECTIVES: The purpose of this study is to investigate the relationship between medical student readiness for interprofessional learning and interest in community medicine prior to incorporating community-oriented interprofessional education into the curriculum. METHODS: A questionnaire was administered to students at Nagasaki University School of Medicine in Japan during each of three consecutive years (N=2244). The Readiness for Interprofessional Learning Scale (RIPLS) was administered in addition to a questionnaire to evaluate interest in community medicine. The Kruskal-Wallis and Steel-Dwass tests were used to determine differences between school years. Correlation between the RIPLS score and interest in community medicine was evaluated with Spearman's rank correlation coefficient. Relationships between RIPLS score and demographic parameters, and interest in community medicine were evaluated with multiple linear regression analysis. RESULTS: Eighty-four percent (1891/2244) of students responded. The RIPLS score was highest in school year 1, followed by year 6, year 5, year 3, and years 4 and 2. Interest in community medicine correlated with the RIPLS score (rs = 0.332, p < 0.001), but less in year 1 (rs = 0.125, p = 0.002) than in other years. RIPLS score was significantly associated with gender, age, school year, interest in community medicine, but not the year that the survey was conducted. CONCLUSIONS: Community-oriented interprofessional education has the potential to improve attitudes towards interprofessional learning. When introducing this promising education into the curriculum from year 1, attracting students' interest in community medicine should be considered.

Immunological evaluation of personalized peptide vaccination in combination with UFT and UZEL for metastatic colorectal carcinoma patients.

To investigate the safety and immunological responses of personalized peptide vaccination in combination with oral administration of UFT and UZEL for metastatic colorectal carcinoma (mCRC), fourteen patients were enrolled in the present study. Peptides were determined based on the presence of peptide-specific cytotoxic T lymphocyte precursors and IgG in each patient. A maximum of four peptides were subcutaneously administered weekly with UFT (300 mg/m2 day(-1)) and UZEL (75 mg/day) for 4 weeks, followed by 1 week of rest. This therapy was well-tolerated although there was a grade-3 skin reaction at the vaccination site in one patient. An increase in peptide-specific interferon-gamma production or peptide-specific IgG after the tenth vaccination was observed in nine of ten or eight of ten patients tested, respectively. IgG responses were well correlated with overall survival (P = 0.0215). The safety and immunological responsiveness of the present therapy suggest that this combination would be of clinical benefit for mCRC patients, and further trials are merited.

Breast cancer cells expressing stem cell markers CD44+ CD24 lo are eliminated by Numb-1 peptide-activated T cells.

Cancer stem cells (CSC) are resistant to chemo- and radiotherapy. To eliminate cells with phenotypic markers of CSC-like we characterized: (1) expression of CD44, CD24, CD133 and MIC-A/B (NKG2 receptors) in breast (MCF7) and ovarian (SK-OV-3) cells resistant to gemcitabine (GEM), paclitaxel (PTX) and 5-fluorouracil (5-FU) and (2) their elimination by Numb- and Notch-peptide activated CTL. The number of cells in all populations with the luminal CSC phenotype [epithelial specific antigen(+) (ESA) CD44(hi) CD24(lo), CD44(hi) CD133(+), and CD133(+) CD24(lo)] increased in drug-resistant MCF7 and SK-OV-3 cells. Similarly, the number of cells with expressed MIC-A/B increased 4 times in drug-resistant tumor cells compared with drug-sensitive cells. GEM(Res) MCF7 cells had lower levels of the Notch-1-extracellular domain (NECD) and Notch trans-membrane intracellular domain (TMIC) than GEM(Sens) MCF7. The levels of Numb, and Numb-L-[P]-Ser(265) were similar in GEM(Res) and GEM(Sens) MCF7 cells. Only the levels of Numb-L (long)-Ser(295) decreased slightly. This finding suggests that Notch-1 cleavage to TMIC is inhibited in GEM(Res) MCF7 cells. PBMC activated by natural immunogenic peptides Notch-1 (2112-2120) and Numb-1 (87-95) eliminated NICD(positive), CD24(hi) CD24(lo) MCF7 cells. It is likely that the immunogenic Numb-1 peptide in MCF7 cells originated from Numb, [P]-lated by an unknown kinase, because staurosporine but not wortmannin and MAPK-inhibitors decreased peptide presentation. Numb and Notch are antagonistic proteins which degrade each other to stop and activate cell proliferation, respectively. Their peptides are presented alternatively. Targeting both antagonistic proteins should be useful to prevent metastases in patients whose tumors are resistant to conventional treatments.

Recent advances in cancer vaccines: an overview.

The field of cancer vaccines is currently in an active state of clinical investigations. Human papilloma virus vaccine has been approved as a prophylactic cancer vaccine, while Oncophage (heat shock protein-peptide complex) was recently approved in Russia for a certain stage of kidney cancer, although to date none has been approved in Japan or the USA. We reviewed recent clinical trials of several different types of cancer vaccines, mainly by using PubMed from 2005 to 2008. There have been slow but substantial advances in peptide vaccines and dendritic cell-based vaccines with regard to both clinical responses and immunological markers. A personalized approach to boost immune responses, addition of chemotherapy to overcome robust cancers and changing of endpoints from tumor reduction to overall survival seem to be the three key elements for the development of therapeutic cancer vaccines.

Taxol increases the amount and T cell activating ability of self-immune stimulatory multimolecular complexes found in ovarian cancer cells.

It has been proposed that chemotherapy enhances tumor antigen (TA)-specific immunity. The molecular form of TA from ovarian tumor that activates cellular immunity is unknown. We report here identification of a novel molecular form of immunogenic TA for CD8(+) cells named self-immune stimulatory multimolecular complexes (ISMMC). ISMMC consist of a molecular complex of polyosome/ribosome-bound ubiquitinated nascent HER-2 polypeptides. This complex is chaperoned by heat shock protein Gp96, which mediates ISMMC uptake by antigen-presenting cells through the scavenger receptor CD91. RNAs in ISMMC stimulate immature dendritic cells to secrete interleukin 12 and induce IFN-gamma in peripheral blood mononuclear cells. ISMMC dissociate, retrotranslocate from the lysosome to cytoplasm, and are processed to peptides by the proteasome. At subpharmacologic doses, Taxol increased the amount of ISMMC by three to four times and modified their composition by inducing the attachment of cochaperones of HSP70, such as the mitotic-phase phosphoprotein 11J. On a total protein basis, Taxol induced ISMMC, expanded more CD8(+) cells, activated more CD56(+) NKG2D(+) cells to produce IFN-gamma, and were more potent inducers of high T-cell receptor density Perforin(+) cells than native ISMMC and peptide E75. Elucidation of the composition of ISMMC and identification of adducts formed by Taxol should be important for developing molecular cancer vaccines.

Kampo medicine, based on traditional medicine theory, in treating uncured glossodynia: efficacy in five clinical cases.

Glossodynia, or tongue pain, is resistant to conventional therapies. Kampo medicines were evaluated in patients suffering from incurable glossodynia. Patients were diagnosed by traditional Chinese medicine (TCM) theory in order to determine the appropriate herbal prescriptions. Five Japanese females (50-76 years old) with glossodynia refractory to conventional therapy were enrolled in this study. Small portions of rikkunshito, jiinkokato, hachimijiogan and ryutanshakanto worked for a female diagnosed with "Spleen" and "Heart" Yin deficiency, "Kidney" Yang deficiency and "Liver" Qi stagnation producing heat syndrome. Seishoekkito and bakumondoto were effective for a patient diagnosed with "Spleen Qi" deficiency and "Stomach" Yin deficiency producing heat syndrome. Rikkunshito, kamikihito and chikujountanto worked for a patient diagnosed with "Spleen Qi" and "Heart Yin" deficiency, stagnation of "Liver" Qi producing fire and "Gallbladder" Qi deficiency. Rokumijiogan, kamishoyosan and kambakutaisoto were effective for a patient with Yang rise based on Yin deficiency of "Kidney" and "Liver," and restless organ disorder based on Yin deficiency of 5 viscera. A patient diagnosed with "Spleen" Yang deficiency responded to a combination of anchusan and hangeshashinto. These patients with glossodynia had resolution of pain within 1 month of treatment. Herbal mixtures containing Ganoderam lucidum, not prescribed based on TCM theory, but effective for herpes virus infection, worked for a female suffering from glossodynia for 1 year after artificial teeth were placed, but required about 5 months to note improvement. Kampo medicines, properly prescribed based on TCM theory, quickly resolved the pain of refractory glossodynia.

Combination therapy of personalized peptide vaccination and low-dose estramustine phosphate for metastatic hormone refractory prostate cancer patients: an analysis of prognostic factors in the treatment.

The aim of this study was to investigate prognostic factors of patients with metastatic hormone refractory prostate cancer (HRPC) under combined administration of personalized peptide vaccination and low-dose estramustine phosphate (EMP). From February 2001 to July 2004, 58 men with metastatic HRPC received the combination therapy of personalized peptide vaccination and low-dose EMP. Conducted immune monitorings for those patients were peptide-specific cytotoxic T lymphocyte (CTL) precursor analysis by interferon-gamma production and peptide-reactive immunoglobulin G (IgG) by an enzyme-linked immunosorbent assay. Clinical responses and survival times were also evaluated. The combination therapy was well tolerated with no major adverse effects. Increased levels of CTL precursors and IgG responses to the vaccinated peptides were observed in 29 of 37 (78%) patients and in 36 of 41 (88%) patients tested, respectively. A prostate-specific antigen decline of at least 50% occurred in 24% of patients. The median survival time was 17 months (95% confidence interval, 12-25 months). Cox proportional hazards analysis showed that a low number of lymphocytes (p = 0.0075, odds ratio 2.700), a negative immunological activity response after the vaccination (p = 0.0185, odds ratio 2.658), and poor performance status (p = 0.0347, odds ratio 2.569) were independent predictors of disease death. These encouraging results show the need for further evaluation of the combination of personalized peptide vaccination and low dose of EMP for metastatic HRPC patients.

Increased levels of IgG antibodies against peptides of the prostate stem cell antigen in the plasma of pancreatic cancer patients.

One of the longstanding challenges in the treatment of pancreatic cancer, the fifth most common cancer worldwide, is to establish a simple and reliable diagnostic marker for the disease. This study examined whether or not the plasma levels of IgG antibodies (IgGs) reactive to peptides derived from the prostate stem cell antigen (PSCA), which is highly expressed in pancreatic cancer cells, were elevated in patients with pancreatic cancer. Fifty-seven kinds of peptides encoded by PSCA were tested for their reactivity to plasma IgGs of pancreatic cancer patients. The results showed that the levels of IgGs specific to each of the 10 different peptides in the plasma of pancreatic cancer patients were significantly higher than those of non-cancer subjects. Eighty percent of subjects with and 18% of subjects without pancreatic cancer were diagnosed as having pancreatic cancer, respectively, when those cases showing significantly elevated levels of IgGs against at least one of the three peptides of PSCA at positions 2-11, 85-95, and 109-118 were judged as positive for pancreatic cancer. These results indicate that the measurement of IgGs reactive to these PSCA-derived peptides can provide novel information on the host-tumor interaction in pancreatic cancer, and could potentially be used as a new diagnostic tool to screen for pancreatic cancer.

Antitumor effects of systemic and local immunization with a CTL-directed peptide in combination with a local injection of OK-432.

PURPOSE: The accumulation of T cells into the tumor site is crucial for the elicitation of in vivo antitumor effects after cancer vaccination. In this study, we investigated the antitumor effects and associated mechanisms of action that were induced by systemic and local immunization with a CTL-directed peptide in combination with a peritumoral injection of a streptococcal preparation, OK-432. EXPERIMENTAL DESIGN AND RESULTS: The human SART3(315-323) peptide, which has the potential to induce human leukocyte antigen-A24-restricted CTLs, not only has the same amino acid sequence as the mouse SART3, but also has the capacity for binding to H-2K(d) molecules. Therefore, the SART3(315-323) peptide could be used as a tumor antigen-derived peptide in H-2(d) mice. Systemic immunization with the SART3(315-323) peptide and the subsequent peritumoral injection of both the SART3(315-323) peptide and OK-432 effectively induced peptide-specific and colon26 carcinoma-reactive CTLs in BALB/c mice. The combination therapy suppressed the growth of s.c. established colon26 carcinoma. The accumulation of both CD8(+) and CD4(+) T cells into the tumor site was more apparent in mice treated with the combination therapy than in those treated with other protocols. In addition, the level of IgG reactive to the administered SART3(315-323) peptide increased in mice that were treated with the combination therapy. CONCLUSION: These results indicate that antitumor effects could be efficiently induced by a combination therapy that included systemic and local immunization with a CTL-directed peptide together with a local injection of OK-432.

Immunologic evaluation of personalized peptide vaccination for patients with advanced malignant glioma.

PURPOSE: The primary goal of this phase I study was to assess the safety and immunologic responses of personalized peptide vaccination for patients with advanced malignant glioma. EXPERIMENTAL DESIGN: Twenty-five patients with advanced malignant glioma (8 grade 3 and 17 grade 4 gliomas) were evaluated in a phase I clinical study of a personalized peptide vaccination. For personalized peptide vaccination, prevaccination peripheral blood mononuclear cells and plasma were provided to examine cellular and humoral responses to 25 or 23 peptides in HLA-A24+ or HLA-A2+ patients, respectively; then, only the reactive peptides (maximum of four) were used for in vivo administration. RESULTS: The protocols were well tolerated with local redness and swelling at the injection site in most cases. Twenty-one patients received more than six vaccinations and were evaluated for both immunologic and clinical responses. Increases in cellular or humoral responses specific to at least one of the vaccinated peptides were observed in the postvaccination (sixth) samples from 14 or 11 of 21 patients, respectively. More importantly, significant levels of peptide-specific IgG were detected in the postvaccination tumor cavity or spinal fluid of all of the tested patients who showed favorable clinical responses. Clinical responses were 5 partial responses, 8 cases of stable disease, and 8 cases of progressive disease. The median overall survival for patients with recurrent glioblastoma multiforme in this study (n = 17) was 622 days. CONCLUSIONS: Personalized peptide vaccinations were recommended for the further clinical study to malignant glioma patients.

[A phase I study of combination-therapy using personalized peptide vaccine and UFT/UZEL for advanced or recurrent colorectal cancer].

We herein administered combination-therapy using a personalized vaccination and the oral administration of UFT/UZEL for the treatment of either advanced or recurrent colorectal cancer. Safety and the efficacy of this new treatment modality were evaluated. Eight patients were enrolled in this clinical trial from July 2005 to May 2006. Up to 4 kinds of peptide vaccines which were selected according to the immune response of each patient were injected hypodermically every week. At the same time, UFT (300 mg/m2/day) and UZEL (75 mg/day) were also administered orally for 28 days followed by a 7-day rest period. Regarding the adverse events, callosity, a type of leukopenia, and liver-dysfunction, such as hyperbilirubinemia, an increase in the aminotransferase were observed. During the clinical evaluation after the end of the 2 courses, 3 cases showed progressive disease (PD) while 5 cases showed stable disease (SD). Our findings indicate that additional peptide vaccine therapy with UFT/UZEL, can be administered without compromising the patient's safety. Moreover, the use of UFT/UZEL does not normally interfere with the normal course of immune-therapy.