Cytotoxic T lymphocyte response to peptide vaccination predicts survival in stage III colorectal cancer.

We previously reported a phase I clinical trial of a peptide vaccine ring finger protein 43 (RNF43) and 34-kDa translocase of the outer mitochondrial membrane (TOMM34) combined with uracil-tegafur (UFT)/LV for patients with metastatic colorectal cancer (CRC), and demonstrated the safety and immunological responsiveness of this combination therapy. In this study, we evaluated vaccination-induced immune responses to clarify the survival benefit of the combination therapy as adjuvant treatment. We enrolled 44 patients initially in an HLA-masked fashion. After the disclosure of HLA, 28 patients were in the HLA-A*2402-matched and 16 were in the unmatched group. In the HLA-matched group, 14 patients had positive CTL responses specific for the RNF43 and/or TOMM34 peptides after 2 cycles of treatment and 9 had negative responses; in the HLA-unmatched group, 10 CTL responses were positive and 2 negative. In the HLA-matched group, 3-year relapse-free survival (RFS) was significantly better in the positive CTL subgroup than in the negative-response subgroup. Patients with negative vaccination-induced CTL responses showed a significant trend towards shorter RFS than those with positive responses. Moreover, in the HLA-unmatched group, the positive CTL response subgroup showed an equally good 3-year RFS as in the HLA-matched group. In conclusion, vaccination-induced CTL response to peptide vaccination could predict survival in the adjuvant setting for stage III CRC.

[Prognostic Implications of Programmed Cell Death Ligand-1(PD-L1)Expression on Tumor-Infiltrating Immune Cells and CD8+T Cells for Stage III Colorectal Cancer].

The purpose of this study was to evaluate the prognostic significance of programmed cell death-ligand 1(PD-L1)expression and CD8+T cells in the immune microenvironment. From January 2011 to December 2011, we retrospectively examined 31patients with Stage III colorectal cancer. PD-L1expression and CD8+T cell counts were evaluated by immunohistochemical study using whole-tumor slides. PD-L1expression in cancer cells(PDCC)and in tumor-infiltrating stromal cells(PDSC)was divided into high(H)and low(L)groups. CD8+T cells were counted in the core of the tumor(CDCT)and in the invasive margin of the tumor area(CDIM), and divided into high(H)and low(L)groups. Based on a median follow-up time of 69.3 months, the 5-year overall survival and disease-free survival of all patients were 74.2% and 64.5%, respectively. The overall survival was significantly longer for patients in the CDIM-H group(82.6%)than those in the CDIM-L group(50.0%; p= 0.034). Patients in the PDSC-H group also tended to have superior overall survival than those in the PDSC-L group(84.2% and 58.3%, respectively, p=0.094). In conclusion, both CD8+T cells and tumor-infiltrating immune cells with PD-L1may indicate antitumoral function in patients with Stage III colorectal cancer.

[A Case of Cecal Cancer Associated with Dermatomyositis].

We report a relatively rare case of cecal cancer with dermatomyositis. An 81-year-old man was diagnosed with dermatomyositis associated with the symptoms of eruption, limb muscle weakness, and difficulty swallowing. Colonoscopy revealed a type 2 tumor in the cecum. The patient underwent laparoscopic ileocecal resection. Although it was impossible for the patient to stand before the surgery, he could stand 10 days after the surgery and walk without assistance 14 days after the surgery. In addition, the eruption disappeared, and the preoperatively high creatine kinase(CK)value normalized. Dermatomyositis with malignant tumor has been reported to be associated with poor prognosis. Symptoms related to dermatomyositis may be improved by the resection of the associated tumor. Therefore, it is important to treat the malignant tumor when the patient's condition permits.

miR-125b-1 and miR-378a are predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer.

Many clinical trials of peptide vaccines have been conducted. However, these vaccines have provided clinical benefits in only a small fraction of patients. The purpose of the present study was to explore microRNAs (miRNAs) as novel predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer. First, we carried out microarray analysis of pretreatment cancer tissues in a phase I study, in which peptide vaccines alone were given. Candidate miRNAs were selected by comparison of the better prognosis group with the poorer prognosis group. Next, we conducted microarray analysis of cancer tissues in a phase II study, in which peptide vaccines combined with chemotherapy were given. Candidate miRNAs were further selected by a similar comparison of prognosis. Subsequently, we carried out reverse-transcription PCR analysis of phase II cases, separating cancer tissues into cancer cells and stromal tissue using laser capture microdissection. Treatment effect in relation to overall survival (OS) and miRNA expression was analyzed. Three miRNA predictors were negatively associated with OS: miR-125b-1 in cancer cells (P = 0.040), and miR-378a in both cancer cells (P = 0.009) and stromal cells (P < 0.001). Multivariate analysis showed that expression of miR-378a in stromal cells was the best among the three predictors (HR, 2.730; 95% CI, 1.027-7.585; P = 0.044). In conclusion, miR-125b-1 and miR-378a expression might be considered as novel biomarkers to predict the efficacy of vaccine treatment against colorectal cancer.

[Survival Benefit by Combined Administration of Cyclophosphamide, Lentinula edodes Mycelia Extract(LEM), and Ganoderma lucidum Mycelia Extract(MAK)in S1018B10 Tumor-Bearing Mice].

Cyclophosphamide(CY)was intraperitoneally administered once a week to C57BL/10mice that had received Rous sarcoma virus(RSV)-induced S1018B10 syngeneic tumor transplantation and in whom tumor diameter exceeded 4.5 mm. Survival was prolonged in a group of mice that also received a mixture of LEM and MAK orally. When splenic cells were cultured under mitomycin C-treated S1018B10 stimulation and the S1018B10-directed cell killing ability was examined, the effector cells were found to be F4/80 - DC/Mф cells. Flow cytometric analysis showed that the proportion of F4/80- DC/Mф cells in the splenic cell culture of the CY+LEM+MAK treatment group was higher than that in the untreated group. The ratio of F4/80+ CD8a+ cells in the CY+LEM+MAK treatment group was lower than that in the untreated group.

[A Case of Local Resection for Rectal GIST Following Neoadjuvant Imatinib Mesylate Treatment].

A 67-year-old woman presented with bloody stools and constipation. A rectal digital examination revealed a smooth and elastic hard tumor in the posterior wall of the rectum. We diagnosed the tumor as rectal GIST measuring 5 cm in diameter. Because the patient desired anal preservation, neoadjuvant imatinib mesylate(IM)(400mg/day)treatment was administered. Although the diameter of the tumor reduced to 2 cm in the third week of administration, the patient experienced erythema-type drug eruption(Grade 3). We discontinued the IM treatment and initiated steroid therapy. After the eruption had disappeared, IM treatment was resumed, initially with half doses. Local transanal resection was performed 36days after the neoadjuvant IM treatment. Currently, the indication and the administration period of IM for preoperative treatment is not clear. It may be necessary to accumulate cases to evaluate neoadjuvant IM therapy.

Clinicopathological and genetic differences between low-grade and high-grade colorectal mucinous adenocarcinomas.

BACKGROUND: Although colorectal mucinous adenocarcinomas (MCs) are conventionally regarded as exhibiting high-grade differentiation, they can be divided by differentiation into 2 groups according to the glandular appearance: low-grade mucinous adenocarcinoma (low-MC) and high-grade mucinous adenocarcinoma (high-MC). METHODS: Patients with colorectal cancer (CRC) who underwent surgical resection between 2000 and 2012 were enrolled in this study. Among the cases with MC, the clinicopathological and genetic differences between low-MC and high-MC were investigated with next-generation sequencing. RESULTS: A total of 1373 patients with CRC were analyzed. Forty patients (2.9%) had MC, and 13 patients had high-MC. Patients with MC had significantly shorter disease-free survival (DFS) and overall survival (OS) periods than those with nonmucinous carcinoma. When low-MC patients and high-MC patients were compared, those with high-MC had significantly shorter DFS and OS periods than those with low-MC. Multivariate analyses revealed that high-MC was significantly associated with both shorter DFS and shorter OS, but low-MC was not. A genome analysis revealed that low-MC had a considerably larger number of mutations than high-MC, and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and adenomatous polyposis coli mutations were particularly frequently found in low-MC. In contrast, SMAD family member 4 (SMAD4) mutations were frequently found in high-MC. CONCLUSIONS: High-MC is an independent prognostic factor in CRC (but low-MC is not), and it is genetically different from other CRCs, including low-MC. Both the clinicopathological differences and the genetic differences suggest that low-MC and high-MC should be distinguished in clinical settings.

Inter- and intra-tumor profiling of multi-regional colon cancer and metastasis.

Intra- and inter-tumor heterogeneity may hinder personalized molecular-target treatment that depends on the somatic mutation profiles. We performed mutation profiling of formalin-fixed paraffin embedded tumors of multi-regional colon cancer and characterized the consequences of intra- and inter-tumor heterogeneity and metastasis using targeted re-sequencing. We performed targeted re-sequencing on multiple spatially separated samples obtained from multi-regional primary colon carcinoma and associated metastatic sites in two patients using next-generation sequencing. In Patient 1 with four primary tumors (P1-1, P1-2, P1-3, and P1-4) and one liver metastasis (H1), mutually exclusive pattern of mutations was observed in four primary tumors. Mutations in primary tumors were identified in three regions; KARS (G13D) and APC (R876*) in P1-2, TP53 (A161S) in P1-3, and KRAS (G12D), PIK3CA (Q546R), and ERBB4 (T272A) in P1-4. Similar combinatorial mutations were observed between P1-4 and H1. The ERBB4 (T272A) mutation observed in P1-4, however, disappeared in H1. In Patient 2 with two primary tumors (P2-1 and P2-2) and one liver metastasis (H2), mutually exclusive pattern of mutations were observed in two primary tumors. We identified mutations; KRAS (G12V), SMAD4 (N129K, R445*, and G508D), TP53 (R175H), and FGFR3 (R805W) in P2-1, and NRAS (Q61K) and FBXW7 (R425C) in P2-2. Similar combinatorial mutations were observed between P2-1 and H2. The SMAD4 (N129K and G508D) mutations observed in P2-1, however, were nor detected in H2. These results suggested that different clones existed in primary tumors and metastatic tumor in Patient 1 and 2 likely originated from P1-4 and P2-1, respectively. In conclusion, we detected the muti-clonalities between intra- and inter-tumors based on mutational profiling in multi-regional colon cancer using next-generation sequencing. Primary region from which metastasis originated could be speculated by mutation profile. Characterization of inter- and inter-tumor heterogeneity can lead to underestimation of the tumor genomics landscape and treatment strategy of personal medicine.

Towards the introduction of the 'Immunoscore' in the classification of malignant tumours.

The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named 'Immunoscore' has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).

The clinical risk score predicts the effectiveness of adjuvant chemotherapy for colorectal liver metastasis.

BACKGROUND: Hepatectomy is the most effective treatment for patients with colorectal liver metastasis (CRLM). However, the procedure is also associated with a high risk of recurrence, and adjuvant chemotherapy for postoperative recurrence remains controversial. We investigated the efficacy of adjuvant chemotherapy for CRLM with the clinical risk score (CRS) proposed by Fong et al. METHODS: Patients with CRLM who were treated, without preoperative chemotherapy, between 1992 and 2012 were classified as having low CRS (score of 0-1), intermediate CRS (2-3), or high CRS (4-5). The efficacy of adjuvant chemotherapy was retrospectively analyzed for each CRS subgroup. RESULTS: Of the 161 patients who underwent hepatectomy, 100 received adjuvant chemotherapy (group A) and 61 did not (group N). For intermediate CRS, 5-year disease free survival (DFS) was significant different between the groups (group A: n = 61; 33.9% vs. group N: n = 39; 23.2%, P = 0.008) and 5-year overall survival (OS) of group A was higher than group N (53.5 vs. 36.5%, P = 0.048), respectively. For both low CRS and high CRS, 5-year DFS and OS were similar between the groups. Multivariate analysis of DFS identified prognostic factors as major resection for low CRS (P = 0.02) and adjuvant chemotherapy for intermediate CRS (P = 0.015). Similarly, multivariate analysis of OS identified major resection for low CRS (P = 0.05) and adjuvant chemotherapy for intermediate CRS (P = 0.05). High CRS was not identified prognostic factor. CONCLUSIONS: Adjuvant chemotherapy for CRLM was effective in intermediate CRS patients. In low CRS patients, adjuvant chemotherapy may not be necessary, but adequate surgical resection is important.

Guidance for peptide vaccines for the treatment of cancer.

Recent progress in fundamental understanding of tumor immunology has opened a new avenue of cancer vaccines. Currently, the development of new cancer vaccines is a global topic and has attracted attention as one of the most important issues in Japan. There is an urgent need for the development of guidance for cancer vaccine clinical studies in order to lead to drug development. Peptide vaccines characteristically have the effect of indirectly acting against cancer through the immune system - a mechanism of action that clearly differs from anticancer drugs that exert a direct effect. Thus, the clinical development of cancer peptide vaccines should be planned and implemented based on the mechanism of action, which differs significantly from conventional anticancer drug research. The Japanese Society for Biological Therapy has created and published Guidance for peptide vaccines for the treatment of cancer as part of its mission and responsibilities towards cancer peptide vaccine development, which is now pursued globally. We welcome comments from regulators and business people as well as researchers in this area.

A phase ΙI study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study).

BACKGROUND: We previously conducted a phase I trial for advanced colorectal cancer (CRC) using five HLA-A*2402-restricted peptides, three derived from oncoantigens and two from vascular endothelial growth factor (VEGF) receptors, and confirmed safety and immunological responses. To evaluate clinical benefits of cancer vaccination treatment, we conducted a phase II trial using the same peptides in combination with oxaliplatin-based chemotherapy as a first-line therapy. METHODS: The primary objective of the study was the response rates (RR). Progression free survival (PFS), overall survival (OS), and immunological parameters were evaluated as secondary objective. The planned sample size was more than 40 patients for both HLA2402-matched and -unmatched groups. All patients received a cocktail of five peptides (3 mg each) mixed with 1.5 ml of IFA which was subcutaneously administered weekly for the first 12 weeks followed by biweekly administration. Presence or absence of the HLA-A*2402 genotype were used for classification of patients into two groups. RESULTS: Between February 2009 and November 2012, ninety-six chemotherapy naïve CRC patients were enrolled under the masking of their HLA-A status. Ninety-three patients received mFOLFOX6 and three received XELOX. Bevacizumab was added in five patients. RR was 62.0% and 60.9% in the HLA-A*2402-matched and -unmatched groups, respectively (p=0.910). The median OS was 20.7 months in the HLA-A*2402-matched group and 24.0 months in the unmatched group (log-rank, p=0.489). In subgroup with a neutrophil/lymphocyte ratio (NLR) of <3.0, patients in the HLA-matched group did not survive significantly longer than those in the unmatched group (log-rank, p=0.289) but showed a delayed response. CONCLUSIONS: Although no significance was observed for planned statistical efficacy endpoints, a delayed response was observed in subgroup with a NLR of <3.0. Biomarkers such as NLR might be useful for selecting patients with a better treatment outcome by the vaccination. TRIAL REGISTRATION: Trial registration: UMIN000001791.

Treatment strategies for gastric cancer patients with peritoneal metastasis.

Although the treatment of gastric cancer improves the clinical outcomes, the survival of gastric cancer patients with peritoneal metastasis is still very poor. Effective drugs against peritoneal metastasis, coupled with new therapeutic modalities, are needed to improve the prognoses of these patients. Paclitaxel and TS-1 are candidate drugs for peritoneal metastasis, and intraperitoneal chemotherapy and targeted therapy are potential new therapeutic modalities. Two phase II studies using TS-1 and intraperitoneal and systemic paclitaxel for gastric cancer patients with peritoneal metastasis showed respectable survival results. In addition, peritoneal metastatic lesions showed high levels of epithelial cellular adhesion molecule (ECAM) and very low levels of human epidermal growth factor receptor 2 (HER2), thus indicating that an anti-ECAM monoclonal antibody, catumaxomab, would be effective against gastric cancer-derived peritoneal metastasis. Although catumaxomab and intraperitoneally administered paclitaxel are not generally used in Japan at present, these treatment strategies might therefore be effectively used in Japan in the near future.

Distal dissection in total mesorectal excision, and preoperative chemoradiotherapy and lateral lymph node dissection for rectal cancer.

The local recurrence rate after total mesorectal excision (TME) appears to be markedly lower than that after conventional operations. We reviewed all relevant articles identified from the MEDLINE databases and clarified the rationale for TME. It is clear that distal intramural spread is rare. Even when present, such spread is not likely to extend beyond 2 cm. Data with attention to mesorectal cancer deposits suggest that mesorectal clearance of at least 4-5 cm distal to the tumor should be sufficient. TME should be performed for most tumors of the mid- and lower rectum. This does not mean that the gut tube needs to be divided at the same level in every case. Dissection of the distal mesorectum off the gut tube can be performed, so the distal line of division of the bowel wall can be made at a minimum of 2 cm below the tumor if such a maneuver would ensure that the sphincters are preserved. In cases with cancer in the upper third of the rectum, the mesorectum and gut tube can safely be divided 5 cm below the tumor without jeopardizing the recurrence rates. Our findings indicate that TME is an essential treatment approach for rectal cancer, and lateral lymph node dissection and preoperative chemoradiotherapy are additional therapies that should be considered for advanced rectal cancer.

[Clinical trial of a seven-peptide vaccine and tegafur-uracil/leucovorin as combination therapy for advanced colorectal cancer].

We conducted a clinical trial of a seven-peptide vaccine in combination with tegafur-uracil/Leucovorin for advanced colorectal cancer. These antigenic peptides were derived from 5 proteins identified as cancer-testis antigens(ring finger protein 43 [RNF43], translocase of outer mitochondrial membrane 34[TOMM34], maternal embryonic leucine zipper kinase[MELK], forkhead box M1[FOXM1], and holliday junction recognition protein[HJURP])and 2 vascular endothelial growth factor receptors(VEGFR1 and VEGFR2). Thirty patients with advanced colorectal cancer were enrolled. We found that 25 patients had Grade 1 injection-site redness/induration and 1 patient had Grade 3 anaphylaxis. Tumor imaging revealed that 3 patients had a partial response (PR), 15 had stable disease(SD)and 12 had progressive disease(PD). This trial showed that treatment with the seven-peptide vaccine and UFT/LV was well tolerated and feasible for advanced colorectal cancer.

Unresectable colorectal liver metastases: the safety and efficacy of conversion therapy using hepatic arterial infusion immunochemotherapy with 5-fluorouracil and polyethylene glycol-interferon α-2a.

BACKGROUND: Hepatic arterial infusion (HAI) or systemic chemotherapy has been used to treat unresectable colorectal liver metastases. The prognosis of the disease in recent years has been improved because chemotherapy is performed before hepatectomy to reduce tumor size (conversion therapy). The purpose of this study was to investigate the safety and efficacy of conversion therapy following HAI immunochemotherapy. METHODS: Hepatic arterial infusion of 5-fluorouracil (5-FU)/polyethylene glycol (PEG)-IFNα-2a was performed in 21 patients. The primary endpoint was the safety of HAI and hepatectomy. The secondary endpoints were response rate, rate of conversion to hepatectomy, survival rate, and prognostic factors. RESULTS: With regard to side effects, drugs were discontinued temporarily in one patient because of a decrease in white blood cell count; however, other patients continued chemotherapy. The response rate with HAI was 61.9 %, and the conversion rate was 38.1 %. Hepatectomy was completed successfully without mortality. Median progression-free survival (PFS) was 11.5 months (with and without conversion, 16.7 and 4.8 months, respectively; p = 0.021). Median overall survival was 34.6 months (with and without conversion, 48.4 and 26.6 months, respectively; p = 0.003). Prognosis was poor when the number of metastatic tumors was ≥10 [PFS: hazard ratio (HR) 32.21, p = 0.003; overall survival (OS): HR 9.13, p = 0.07], but prognosis improved after hepatectomy (OS: HR 0.08, p = 0.09). CONCLUSIONS: Hepatic arterial infusion immunochemotherapy with 5-FU/PEG-IFNα-2a was performed safely without major side effects. Prognosis is expected to improve after successful conversion to hepatectomy.

Analysis of the clinical factors associated with anal function after intersphincteric resection for very low rectal cancer.

BACKGROUND: Intersphincteric resection (ISR) has been used to avoid permanent colostomy in very low rectal cancer patients. This study aimed to assess the surgical safety and oncologic and functional outcomes of ISR. METHODS: The records of 30 consecutive very low rectal cancer patients who underwent ISR without neoadjuvant therapy were retrospectively analyzed; survival and locoregional recurrence rates were calculated by the Kaplan-Meier method. Incontinence was assessed by a functionality questionnaire and the Wexner score. RESULTS: The median distance between the distal margin of the dentate line was 10 mm. A total of 12, 4, and 14 patients underwent partial ISR, subtotal ISR, and total ISR, respectively. The mean distal resection margin was negative in all cases, and circumferential resection margin was positive in two cases. Morbidity was 33.3%: anastomotic stricture in seven patients, colonic J-pouch prolapse in two patients, and an anovaginal fistula in one patient. During the median, 56.2-month follow-up period, local, distant, and combined recurrences occurred in four, three, and two patients, respectively. The 5-year overall and disease-free survival rates were 76.5% and 68.4%, respectively. Local recurrence rates were 5.2% for the patients with Tis-T2 tumors as compared with 45.5% for those with T3 tumors (P = 0.008). The mean Wexner scores and stool frequencies, 12 months after stoma closure in 19 patients, were 11.5 and 6.6 per 24 h, respectively. Significant differences were not seen in the Wexner scores between partial ISR and subtotal/total ISR (11.8 ± 2.6 and 9.1 ± 5.6). Stool frequency (P = 0.02), urgency (P = 0.04), and fragmentation (P = 0.015) were worse in patients with anastomotic stricture than in those without; there was no symptom improvement in patients with anastomotic stricture. CONCLUSIONS: The anastomotic strictures in patients undergoing ISR may have negatively affected anal function. For total ISR patients, at least, informed consent stating the possibility of a permanent colostomy is necessary.

High ligation of the inferior mesenteric artery in rectal cancer surgery.

In rectal cancer surgery, it is unclear whether the inferior mesenteric artery (IMA) should be ligated as high as possible, at its origin, or low, below the origin of the left colic artery. We reviewed all relevant articles identified from MEDLINE databases and found that despite a trend of improved survival among patients who underwent high ligation, there is no conclusive evidence to support this. High ligation of the IMA is beneficial in that it allows for en bloc dissection of the node metastases at and around the origin of the IMA, while enabling anastomosis to be performed in the pelvis, without tension, at the time of low anterior resection. High ligation of the IMA does not represent a source of increased anastomotic leak in rectal cancer surgery and postoperative quality of life is improved by preserving the hypogastric nerve without compromising the radicality of the operation. More importantly, high ligation of the IMA improves node harvest, enabling accurate tumor staging. Although the prognosis of patients with node metastases at and around the origin of the IMA is poor, the survival rate of patients with rectal cancer may be improved by performing high ligation of the IMA combined with neoadjuvant and adjuvant therapy.

[Treatment outcome of peptide vaccination for advanced colorectal cancer].

Complementary DNA( cDNA) microarray technology coupled with laser microdissection has been used to identify human leukocyte antigen (HLA)-A24-restricted epitope peptides as potential targets for cancer vaccination in colorectal cancer patients. These antigenic peptides were derived from 2 different cancer-testis antigens, ring finger protein 43 (RNF43) and translocase of outer mitochondrial membrane 34( TOMM34). We conducted a clinical trial of colorectal cancer-specific peptide( RNF43, TOMM34) vaccines with uracil/tegafur( UFT)+Leucovorin( LV) for the treatment of advanced or recurrent colorectal cancer. The vaccinations were well tolerated without any serious adverse events. There were long-term survivors in the group showing cytotoxic T lymphocyte (CTL) responses against both RNF43 and TOMM34, as well as in the group showing CTL responses against either RNF43 or TOMM34. A new study has been planned to obtain more immunological responses. We started a clinical trial of vaccines against multiple peptides (RNF43, TOMM34, forkhead box protein M1 [FOXM1], maternal embryonic leucine zipper kinase [MELK], holliday junction recognition protein[HJURP], vascular endothelial growth factor receptor 1[VEGFR1], and VEGFR2) for the treatment of advanced or recurrent colorectal cancer.

Cancer classification using the Immunoscore: a worldwide task force.

Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy. Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune-classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification. It is therefore imperative to begin to incorporate the 'Immunoscore' into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization. In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).