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We report 3 cases of obstructive left-sided colon cancer that could be treated with laparoscopic resection.Case 1: A 25- year-old man was given a diagnosis of colonic obstruction due to transverse colon cancer.Twenty -four days after decompression by a nasointestinal tube, we performed a laparoscopic partial colectomy.Case 2: A 75-year-old woman was given a diagnosis of colonic obstruction due to sigmoid colon.Forty -nine days after decompression by a laparoscopic transverse colostomy, we performed a laparoscopic sigmoidectomy.Case 3: A 48-year-old man was given a diagnosis of colonic obstruction due to sigmoid colon cancer.Twenty -two days after decompression by colonic stent, we performed a laparoscopic sigmoidectomy.In these 3 cases, decompression was sufficient when resecting the primary lesions, and the operations could be completed laparoscopically.Elective radical surgery was possible by resolution of oncologic emergency state.

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.

Contains fulltext : 193579.pdf (Publisher’s version ) (Closed access) BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0.97 for colon tumour; r=0.97 for invasive margin; p

In surgery for elderly patients with colorectal cancer, it is unclear whether radical lymph node (LN) dissection safely offers a survival benefit. The aim of the study was to evaluate the impact of the LN yield in elderly patients undergoing surgery for colorectal cancer.The subjects were selected from a surgical database of 2065 patients aged ≥80 years old who underwent surgery for colorectal cancer at 41 hospitals in Japan between 2003 and 2007. The patients were divided into groups according to the number LN harvested:12 and ≥12. Propensity scores were subsequently matched to balance the baseline characteristics.Of the 954 patients initially selected, 331 were in the12 LN and 623 were in the ≥12 LN group. After cases were matched, 293 patients were allocated to each group, and all covariates were balanced. For short-term outcomes, the time for surgery was longer in the ≥12 LN group, but there was no significant difference in morbidity between the groups. Overall, relapse-free and cancer-specific survival rates were higher in the ≥12 LN group (P = 0.004, 0.001, and 0.02).In patients aged ≥80 years old with stage II-III colon cancer, harvesting ≥12 LN provides a survival benefit, and therefore, limited LN dissection is not recommended in these patients.

We investigated the relationship between axitinib pharmacogenetics and clinical efficacy/adverse events in advanced renal cell carcinoma (RCC) and established a model to predict clinical efficacy and adverse events using pharmacokinetic and gene polymorphisms related to drug metabolism and efflux in a phase II trial. We prospectively evaluated the area under the plasma concentration-time curve (AUC) of axitinib, objective response rate, and adverse events in 44 consecutive advanced RCC patients treated with axitinib. To establish a model for predicting clinical efficacy and adverse events, polymorphisms in genes including ABC transporters (ABCB1 and ABCG2), UGT1A, and OR2B11 were analyzed by whole-exome sequencing, Sanger sequencing, and DNA microarray. To validate this prediction model, calculated AUC by 6 gene polymorphisms was compared with actual AUC in 16 additional consecutive patients prospectively. Actual AUC significantly correlated with the objective response rate (P = 0.0002) and adverse events (hand-foot syndrome, P = 0.0055; and hypothyroidism, P = 0.0381). Calculated AUC significantly correlated with actual AUC (P < 0.0001), and correctly predicted objective response rate (P = 0.0044) as well as adverse events (P = 0.0191 and 0.0082, respectively). In the validation study, calculated AUC prior to axitinib treatment precisely predicted actual AUC after axitinib treatment (P = 0.0066). Our pharmacogenetics-based AUC prediction model may determine the optimal initial dose of axitinib, and thus facilitate better treatment of patients with advanced RCC.

The safety and immunological responsiveness of a peptide vaccine of ring finger protein 43 and 34-kDa translocase of the outer mitochondrial membrane combined with uracil-tegafur/leucovorin (UFT/LV) was previously demonstrated in metastatic colorectal cancer (CRC) in a phase I clinical trial. To clarify the survival benefit of a peptide vaccine combined with UFT/LV as adjuvant treatment, a phase II clinical trial was conducted involving patients with stage III CRC. All enrolled patients, whose human leukocyte antigen (HLA)-A status was double-blinded, were administered the same regime of a peptide vaccine and UFT/LV chemotherapy. The primary objective of the study was to compare relapse-free survival (RFS) in patients with HLA-A*2402 vs. those without HLA-A*2402. Secondary objectives included comparisons between the two groups regarding overall survival, safety, tolerability and peptide-specific activities of cytotoxic T lymphocytes (CTLs) as measured by the ELISPOT assay. Between December 2009 and December 2014, a total of 46 patients were enrolled to the present study. Three-year RFS was not significantly different between HLA-A*2402 matched and unmatched groups [67.8 vs. 73.6%, respectively; hazard ratio (HR)=1.254, 95% confidence interval (CI): 0.48-4.63; P=0.706]. Three-year RFS was significantly better in patients with positive CTL responses in the HLA-A*2402 matched group compared with those without (85.7 and 33.3%, respectively; HR=0.159, 95% CI: 0.023-0.697; P=0.011). In conclusion, vaccination-induced immune responses combined with UFT/LV were positively associated with survival benefit in patients with HLA-A*2402-positive stage III CRC. Further study is required to clarify whether vaccination-induced immune responses shortly following the initiation of therapy can predict the therapeutic effect and help develop a promising therapeutic strategy for patients with stage III CRC.

Breast cancer is the most frequent cancer threatening the lives of women between the ages of 30 and 64. The cancer antigen 15-3 assay (CA15-3) has been widely used for the detection of breast cancer recurrence; however, its sensitivity and specificity are inadequate. We previously found that the breast cancer cell line YMBS secretes mucin 1 possessing 3′-sulfated core1 (3Score1-MUC1) into the medium. Therefore, we here evaluated whether 3Score1-MUC1 is secreted into the blood streams of breast cancer patients, and whether it can serve as an improved breast cancer marker. We developed a lectin-sandwich immunoassay, called Gal4/MUC1, using a 3′-sulfated core1-specific galectin-4 and a MUC1 monoclonal antibody. Using the Gal4/MUC1 assay method, we found that 3Score1-MUC1 was profoundly expressed in the blood streams of patients with recurrent and/or metastatic breast cancer. The positive ratio of the Gal4/MUC1 assay was higher than that of the CA15-3 assay in both primary (n = 240) and relapsed (n = 43) patients, especially in the latter of which the positive ratio of Gal4/MUC1 was 86%. whereas that of CA15-3 was 47%. Furthermore, serum Gal4/MUC1 levels could more sensitively reflect the recurrence of primary breast cancer patients after surgery. Therefore, the Gal4/MUC1 assay should be an excellent alternative to the CA15-3 tumor marker for tracking the recurrence and metastasis of breast cancer.

The aim of this study was to develop an accurate predictive system for prognosis of hepatocellular carcinoma (HCC) patients after hepatectomy. We pooled data of clinicopathological features of 234 HCC patients who underwent curative hepatectomy. On the basis of the pooled data, we established a simple predictive staging system (PS score) scored by the mathematical product of tumor number and size, and degree of liver function. We compared the prognostic abilities of the PS score (score 0–3) with those of six well-known clinical staging systems. Then, we found that there were significant differences (P

Cancer stem cells (CSCs) are thought to play important roles in cancer malignancy. Previously, we successfully induced sphere cancer stem-like cells (CSLCs) from several cell lines and observed the property of chemoresistance. In the present study, we examined the metastatic potential of these induced CSLCs. Sphere cancer stem-like cells were induced from a human hepatoma cell line (SK-HEP-1) in a unique medium containing neural survival factor-1. Splenic injection of cells into immune-deficient mice was used to assess hematogenous liver metastasis. Transcriptomic strand-specific RNA-sequencing analysis, quantitative real-time PCR, and flow cytometry were carried out to examine the expression of epithelial-mesenchymal transition (EMT)-related genes. Splenic injection of CSLCs resulted in a significantly increased frequency of liver metastasis compared to parental cancer cells (P

In this study, cytokine levels, outcome, and survival rates after esophagectomy for esophageal cancer were retrospectively investigated in a propensity score-matched comparison of operative approaches between the thoracoscopic esophagectomy (TE) in the prone position and open esophagectomy (OE). Between 2005 and 2014, TE was performed on a group of 85 patients, which was compared with a group of 104 OE cases. Eventually, 65 paired cases were matched using propensity score matching. Although the TE group underwent a significantly longer operation time than the OE group (P

Accumulating evidence shows an overabundance of Fusobacterium nucleatum in colorectal tumor tissues. However, the correlation between the absolute copy number of F. nucleatum in colorectal cancer tissues and colorectal cancer progression is unclear from previous reports. Therefore, we performed a study to compare the abundance of F. nucleatum in colorectal tissues with clinicopathologic and molecular features of colorectal cancer. We collected 100 colorectal cancer tissues and 72 matched normal-appearing mucosal tissues. Absolute copy numbers of F. nucleatum were measured by droplet digital PCR. The detection rates of F. nucleatum were 63.9% (46/72) in normal-appearing mucosal tissues and 75.0% (75/100) in CRC tissue samples. The median copy number of F. nucleatum was 0.4/ng DNA in the normal-appearing colorectal mucosa in patients with colorectal cancer and 1.9/ng DNA in the colorectal cancer tissues (P = 0.0031). F. nucleatum copy numbers in stage IV colorectal cancer tissues were significantly higher than those in the normal-appearing mucosa in patients with colorectal cancer (P = 0.0016). The abundance of F. nucleatum in colorectal cancer tissues correlated with tumor size and KRAS mutation and was significantly associated with shorter overall survival times; this trend was notable in the patients with stage IV colorectal cancer. Focusing on normal-appearing mucosa in the patients with colorectal cancer, the F. nucleatum copy number was significantly higher in the patients with stage IV rather than stages I–III. These results suggest that determining F. nucleatum levels may help predict clinical outcomes in colorectal cancer patients. Further confirmatory studies using independent datasets are required to confirm our findings.

Background The purpose of the present study was to explore novel biomarkers that can predict the clinical outcome of patients before treatment or during vaccination. These would be useful for the selection of appropriate patients who would be expected to exhibit better treatment outcomes from vaccination, and for facilitating the development of cancer vaccine treatments. Methods From a single-arm, non-randomized, human leukocyte antigen (HLA)-A-status-blind phase II trial of a vaccine treatment using three HLA-A*2402-restricted peptides for advanced pancreatic cancer (PC), we obtained peripheral blood samples from 36 patients of an HLA-A*2402-matched group and 27 patients of an HLA-A*2402-unmatched group. Results Multivariate analysis (HR = 2.546; 95% CI = 1.138 to 5.765; p = 0.0231) and log-rank test (p = 0.0036) showed that a high expression level of programmed death-1 (PD-1) on CD4+ T cells was a negative predictive biomarker of overall survival in the HLA-A*2402-matched group . Moreover, a high expression level of PD-1 on CD4+ T cells was a negative predictor for the induction of cytotoxic T lymphocytes (p = 0.0007). After treatment, we found that the upregulation of PD-1 and T cell immunoglobulin mucin-3 (Tim-3) expression on CD4+ and CD8+ T cells was significantly associated with a poor clinical outcome in the HLA-A*2402-matched group (p = 0.0330, 0.0282, 0.0046, and 0.0068, respectively). In contrast, there was no significant difference for these factors in the HLA-A*2402-unmatched group. Conclusions Our results indicate that the upregulation of PD-1 and Tim-3 expression on CD4+ and CD8+ T cells may restrict T cell responses in advanced PC patients; therefore, combination immunotherapy with blockade of PD-1 and Tim-3 to restore T cell responses may be a potential therapeutic approach for advanced PC patients. Trial registration Clinical-Trail-Registration: UMIN000008082. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0509-1) contains supplementary material, which is available to authorized users.

We report a case of borderline resectable(BR)pancreatic cancer, which was eligible for R0 resection following preoperative chemotherapy with GEM plus nab-PTX. A 77-year-old woman presented with brown urine and clay-colored stool. After further examination, she was diagnosed with obstructive jaundice due to pancreatic head cancer. Because the tumor was in contact with the region attached to the SMA nerve plexus, she was also diagnosed with BR-A pancreatic cancer. After 6 courses of preoperative GEM plus nab-PTX combination chemotherapy, she underwent subtotal stomach-preservingpancreaticoduodenectomy with SMV resection and right semicircular SMA nerve plexus dissection. In the histopathological diagnosis, malignant cells were observed at low levels in both the pancreatic parenchyma and duodenal mucosa. There were no findings of residual malignant cells in the wall of the SMV or in the nerve plexus around the SMA. Since the final diagnosis was pT3,(DU+), pN0, cM0, fStage III , we concluded that the R0 resection as complete. Histological therapeutic evaluation with the Evans classification concluded that the disease was Grade III . GEM plus nab-PTX combination chemotherapy could be considered for preoperative chemotherapy, which may allow R0 resection for BR pancreatic cancer.

We present a case of Fournier's gangrene secondary to rectal cancer that was managed with perineal reconstruction using a posterior thigh flap after debridement and tumor resection. A 67-year-old man was admitted with disturbed consciousness as well as hip and right thigh pain. His perineal and gluteal skin was necrotic. CT revealed subcutaneous emphysema that had spread from the rectum to the gluteal region and right thigh. We diagnosed him with Fournier's gangrene, and then removed the necrotic tissue and constructed a sigmoidostomy. A diagnosis of rectal cancer was later confirmed. Fifty-nine days after the initial operation, a laparoscopic abdominoperineal resection was performed. The perineal defect was repaired using a posterior thigh flap with the gluteus maximus. There were no postoperative complications, and the patient was discharged ahead of schedule. We concluded that the use of a posterior thigh flap is a good choice for perineal reconstruction, because it is simple to perform, can cover a large area, and has a low risk of infection.

The patient was 66-year-old woman with anemia. A 6 cm GIST was diagnosed in the fourth portion of the duodenum using abdominal CT. Duodenal-jejunal segmental resection was performed for the GIST. Four years after surgery, multiple liver metastatic recurrences ofGIST were diagnosed using abdominal CT. The metastatic tumor was treated with imatinib, but the treatment caused adverse events such as leukocytopenia(Grade 2)and anemia(Grade 3). The treatment continued for 41 months while reduced or discontinued during the administration period. Sunitinib was administered, but the treatment caused a reduced platelet count(Grade 3), anemia(Grade 2), and melena(Grade 3). The treatment continued for 12 months while reduced or discontinued during the administration period. Regorafenib was administered and continued for 9 months. Thereafter, trancecatheter arterial embolization(TAE)was performed 5 times. The patient is alive 8 years and 3 months after recurrence.

Case 1: A 57-year-old woman with chronic hepatitis related to the hepatitis B virus was found to have a liver tumor on ultrasonography(US). Computed tomography(CT), magnetic resonance imaging(MRI), and angiography revealed 2 tumors in the liver. The patient underwent right anterior sectorectomy, and histopathologic analysis revealed mucosa-associated lymphoid tissue(MALT)lymphoma. Thirty months later, recurrence was confirmed using liver biopsy. CR was confirmed after radiation and chemotherapy, and the patient has survived. Case 2: A 71-year-old woman came to our hospital for rheumatism treatment. US, CT, and MRI revealed a tumor in the left lateral segment of the liver. The patient underwent laparoscopic partial liver resection and histopathologic analysis revealed MALT lymphoma. The patient has survived.

A 51-year-old woman was seen in our hospital because an ascending colon tumor with extensive abdominal wall abscess was detected on computed tomography(CT). On the same day, we performed open drainage and laparoscopic assisted ileocolostomy. Postoperative day 35, we performed right hemicolectomy with abdominal wall resection and closure of the colostomy as a radical surgery. After surgery, we started(negative pressure wound therapy: NPWT)to the surgical wound site; hence, the abdominal wall defect could be healed without a musculocutaneous flap. Laparoscopic assisted open drainage, a two-stage operation, and NPWT are useful in a case of colon cancer with abdominal wall abscess.

An asymptomatic 35-year-old man visited our hospital because of an esophageal abnormality identified on a medical check-up. Gastrointestinal endoscopic examination revealed a 4 cm diameter submucosal tumor(SMT)in the upper esophagus. endoscopic ultrasound fine-needle aspiration biopsy(EUS-FNAB)was performed. Histopathological examination showed that it was strongly positive for a-SMA and partially positive for c-kit. An esophageal leiomyoma was suspected but esophageal gastrointestinal stromal tumor(GIST)could not be completely ruled out. After considering the patient's age and the location of the tumor, we performed thoracic enucleation of the esophageal SMT. Immunostaining findings showed that it was a-SMA positive and S-100 negative. Mast cells, but not tumor cells were partially stained with c-kit. The final pathological diagnosis was leiomyoma. The postoperative course was uneventful. We report this case together with a review of the literature.

A 65-year-old woman who was diagnosed with unresectable Stage IV sigmoid colon cancer underwent transverse colostomy with double orifices. Although KRAS gene mutation was observed, we could not administer bevacizumab because of the risk of bleeding from the primary tumor and peritumoral abscess. We started bi-weekly XELOX therapy but bloody bowel discharge continued. We planned extended resection of the primary tumor in order to control the bleeding and perforation. Sigmoidectomy, partial resection of the left ureter and small intestine, partial hysterectomy, bilateral salpingo-oophorectomy, and umbilical tumor resection were performed and the patient was discharged on the 10th day after surgery. After surgery, bloody bowel discharge disappeared and bevacizumab was administered in the 55th day. Extended resection for a primary tumor may contribute to bleeding control and broaden treatment options.

Nanoparticle albumin-bound (nab)-paclitaxel is a solvent-free formulation of paclitaxel that is bound to albumin and has demonstrated improved progression free survival in previous studies of breast cancer. However, it is difficult to treat Japanese patients with metastatic or recurrent breast cancer with the recommended dose of 260 mg/m2 of (nab)-paclitaxel for more than six cycles due to the occurrence of adverse events. To evaluate the treatment continuity and safety of low-dose nab-paclitaxel, we conducted a phase II study of nab-paclitaxel in patients with metastatic or recurrent breast cancer who had received up to one prior chemotherapy. Treatment included low doses of 180 mg/m2 nab-paclitaxel that were administered on day 1 of each 3-week cycle to 35 patients. The primary endpoint was the completion rate of six cycles of treatment. A total of 35 eligible patients were enrolled and received a median of eight (range 2–24) cycles of low-dose nab-paclitaxel therapy. The completion rate of six cycles of treatment was 66%. ORR and clinical benefit rate was 23 and 71%, respectively. Median PFS was 6.5 months and median OS was 44 months. Adverse events were relatively mild. Commonly observed grade 3/4 adverse events were neutropenia (46%), leukopenia (9%), and hypertension (3%). No grade 3-4 peripheral sensory neuropathy occurred. Treatment with a low dose of nab-paclitaxel once every 3 weeks was tolerable and of acceptable safety and might be beneficial for patients with metastatic or recurrent breast cancer.

Six months of adjuvant chemotherapy is regarded as the standard of care for patients with stage III colon cancer. However, whether longer treatment can improve prognosis has not been fully investigated. We conducted a phase III study comparing 6 and 12 months of adjuvant capecitabine chemotherapy for stage III colon cancer, and report here the results of our preplanned safety analysis.Patients aged 20-79 years with curatively resected stage III colon cancer were randomly assigned to receive 8 cycles (6 months) or 16 cycles (12 months) of capecitabine (2500 mg/mA total of 1304 patients (642 and 636 in the 6-month and 12-month groups, respectively) were analyzed. The most common AE was hand-foot syndrome (HFS). HFS, leukocytopenia, neutropenia, and hyperbilirubinemia (any grade) occurred more frequently in the 12-month group than in the 6-month group. HFS was the only grade ≥3 AE to have a significantly higher incidence in the 12-month group (23 vs 17%, p = 0.011). The completion rate for 8 cycles was 72% in both groups, while that for 16 cycles was 46% in the 12-month group. HFS was the most common AE requiring dose reduction and treatment discontinuation.Twelve months of adjuvant capecitabine demonstrated a higher cumulative incidence of HFS compared to the standard 6-month treatment period, while toxicities after 12 months of capecitabine were clinically acceptable.UMIN-CTR, UMIN000001367.

Cancer stem cells (CSCs) have been studied for their self-renewal capacity and pluripotency, as well as their resistance to anticancer therapy and their ability to metastasize to distant organs. CSCs are difficult to study because their population is quite low in tumor specimens. To overcome this problem, we established a culture method to induce a pancreatic cancer stem-like cell (P-CSLC)-enriched population from human pancreatic cancer cell lines. Human pancreatic cancer cell lines established at our department were cultured in CSC-inducing media containing epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), leukemia inhibitory factor (LIF), neural cell survivor factor-1 (NSF-1), and N-acetylcysteine. Sphere cells were obtained and then transferred to a laminin-coated dish and cultured for approximately two months. The surface markers, gene expression, aldehyde dehydrogenase (ALDH) activity, cell cycle, and tumorigenicity of these induced cells were examined for their stem cell-like characteristics. The population of these induced cells expanded within a few months. The ratio of CD24high, CD44high, epithelial specific antigen (ESA) high, and CD44variant (CD44v) high cells in the induced cells was greatly enriched. The induced cells stayed in the G0/G1 phase and demonstrated mesenchymal and stemness properties. The induced cells had high tumorigenic potential. Thus, we established a culture method to induce a P-CSLC-enriched population from human pancreatic cancer cell lines. The CSLC population was enriched approximately 100-fold with this method. Our culture method may contribute to the precise analysis of CSCs and thus support the establishment of CSC-targeting therapy.

To predict precisely severe toxicity of irinotecan, we evaluated the association of UGT1A variants, haplotypes and the combination of UGT1A genotypes to severe toxicity of irinotecan. UGT1A1*6 (211G>A), UGT1A1*28 (TA6>TA7), UGT1A1*60 (−3279T>G), UGT1A7 (387T>G), UGT1A7 (622T>C), and UGT1A9*1b (−118T9>T10, also named *22) were genotyped in 123 patients with metastatic colorectal cancer who had received irinotecan-based chemotherapy. Among the 123 patients, 73 were enrolled in either of two phase II studies of the FOLFIRI (leucovorin, 5-fluorouracil and irinotecan) regimen; these patients constituted the training population, which was used to construct the predicting system. The other 50 patients constituted the validation population; these 50 patients either had participated in a phase II study of irinotecan/5′-deoxy-5-fluorouridine or were among consecutive patients who received FOLFIRI therapy. This prediction system used sequential forward floating selection based on statistical pattern recognition using UGT1A genotypes, gender and age. Several UGT1A genotypes [UGT1A1*6, UGT1A7 (387T>G), UGT1A7 (622T>C) and UGT1A9*1b] were associated with the irinotecan toxicity. Among the haplotypes, haplotype-I (UGT1A1: −3279T, TA6, 211G; UGT1A7: 387T, 622T; UGT1A9: T10) and haplotype-II (UGT1A1: −3279T, TA6, 211A; UGT1A7: 387G, 622C; UGT1A9: T9) were also associated with irinotecan toxicity. Furthermore, our new system for predicting the risk of irinotecan toxicity was 83.9% accurate with the training population and 72.1% accurate with the validation population. Our novel prediction system using statistical pattern recognition depend on genotypes in UGT1A, age and gender; moreover, it showed high predictive performance even though the treatment regimens differed among the training and validation patients.

A therapeutic vaccine against minimal residual cancer cells is needed for the treatment of patients with colorectal cancer. Several gene therapy studies have revealed that the combination of a suicide gene and cytokine gene might induce effective antitumor immunity. In this study, we constructed an interleukin (IL)-18 and herpes simplex virus-thymidine kinase (HSV-TK) expression vector driven by the human telomerase reverse transcriptase (hTERT) promoter to study the efficacy of combination gene therapy with IL-18 and the HSV-TK suicide gene. Low immunogenic colon 26 cells were used for transfection and inoculation into syngeneic BALB/c mice. Large established tumors of colon 26 transfectants expressing IL-18 and HSV-TK driven by the hTERT promoter were completely eradicated after GCV administration in syngeneic BALB/c mice. Immunohistochemical analysis at the tumor rejection sites revealed enormous infiltrations of CD8+ T lymphocytes as well as CD4+ T lymphocytes and CD11b+ monocytes. Moreover, established distant tumors were completely eradicated by vaccination with the IL-18 and HSV-TK transfectants in combination with GCV. These data suggest that the IL-18 and suicide gene therapy can elicit antitumor specific immunity. In conclusion, gene therapy with IL-18 and HSV-TK plasmid vector driven by the hTERT promoter may be useful for cancer vaccination.

Cetuximab shows activity in KRAS (Kirsten rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer (mCRC). Recent studies have demonstrated that cetuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC) in mCRC. We investigated the associations of FcγR (fragment C γ receptor) and EGFR (epidermal growth factor receptor) polymorphisms with the outcome of mCRC patients treated with cetuximab and FOLFIRI (folic acid/5-fluorouracil/irinotecan) as second-line therapy in the FLIER (Cetuximab Plus Folinic Acid/5-Fluorouracil/Irinotecan in KRAS Wild-Type Metastatic Colorectal Cancer as a Second-Line Treatment) study. A total of 57 patients were evaluated in this study. The association of each polymorphism with the response rate, progression-free survival, and overall survival was analyzed. A tendency for longer overall survival was observed in patients with the EGFR CA repeat ≥36 genotype than in those with the ≤35 genotype (600 versus 483 days, P = 0.051). The haplotype containing the 131H and 158V alleles was associated with a lower response rate than the other haplotypes (P = 0.018). These results are contrary to previously published results. Our data suggest that FcγR and EGFR CA repeat polymorphisms may be associated with the outcome of mCRC patients treated with cetuximab and FOLFIRI, although further investigations will be needed to confirm the association of FcγR and EGFR polymorphisms with the efficacy of cetuximab.

Background We retrospectively evaluated the relationship between cytokine gene polymorphisms and development of postoperative pneumonia after esophagectomy. Methods In 120 patients who underwent esophagectomy, serum samples were obtained to measure levels of serum interleukin (IL)-6 and IL-10 at four time points (preoperatively, postoperative day (POD)0, POD1, and POD3). DNA extracted from peripheral blood in all patients was analyzed to determine polymorphisms of cytokines such as tumor necrosis factor-α -1031 T/C, IL-1β -511C/T, IL-6 -634C/G, and IL-10 -819 T/C. Results Postoperative pneumonia arose in 34 patients (28.3 %). Perioperative serum IL-10 levels were significantly higher for IL-10 -819 C/T + C/C genotypes than for T/T genotypes (POD0 16.7 ± 2.84 vs. 8.54 ± 0.87 pg/ml, p = 0.0002; POD1 14.0 ± 2.64 vs. 8.8 ± 0.87 pg/ml, p = 0.0143; POD3 8.9 ± 2.67 vs. 4.4 ± 0.52 pg/ml, p = 0.0076). The frequency of the IL-10 -819 T/T genotype was significantly higher in patients with postoperative pneumonia than in patients without pneumonia (p = 0.0323). Multivariate analysis of factors such as sex, smoking, length of operation, field of lymph node dissection, and IL-10 polymorphism identified IL-10 polymorphism as independent predictor of postoperative pneumonia. Conclusions Patients with IL-10 -819 T/T genotype may be at high risk for postoperative pneumonia after esophagectomy.

Background and Objectives Uridine-diphosphate glucuronosyltransferase 1A (UGT1A) is a key enzyme involved in irinotecan metabolism, and polymorphisms in the UGT1A gene are associated with irinotecan-induced toxicity. The aim of this study was to elucidate the allele frequencies of UGT1A polymorphisms in healthy Uzbek volunteers, and to compare them with those of the Japanese population. Method A total of 97 healthy volunteers from Uzbekistan were enrolled and blood samples were collected from each participant. Genotyping analysis was performed by fragment size analysis for UGT1A1*28, direct sequencing for UGT1A7*3 and UGT1A9*22, and TaqMan assays for UGT1A1*93, UGT1A1*6, UGT1A1*27, UGT1A1*60, and UGT1A7*12. The frequencies of polymorphisms were compared with the Japanese population by using the data previously reported from our study group. Results When the Uzbek and Japanese populations were compared, heterozygotes or homozygotes for UGT1A1*28, UGT1A1*60, and UGT1A1*93 were significantly more frequent in the Uzbek population (P

Triple-negative breast cancer (TNBC) cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2. Currently, apart from poly ADP-ribose polymerase inhibitors, there are few effective therapeutic options for this type of cancer. Here, we present comprehensive characterization of the genetic alterations in TNBC performed by high coverage whole genome sequencing together with transcriptome and whole exome sequencing. Silencing of the BRCA1 gene impaired the homologous recombination pathway in a subset of TNBCs, which exhibited similar phenotypes to tumors with BRCA1 mutations; they harbored many structural variations (SVs) with relative enrichment for tandem duplication. Clonal analysis suggested that TP53 mutations and methylation of CpG dinucleotides in the BRCA1 promoter were early events of carcinogenesis. SVs were associated with driver oncogenic events such as amplification of MYC, NOTCH2, or NOTCH3 and affected tumor suppressor genes including RB1, PTEN, and KMT2C. Furthermore, we identified putative TGFA enhancer regions. Recurrent SVs that affected the TGFA enhancer region led to enhanced expression of the TGFA oncogene that encodes one of the high affinity ligands for epidermal growth factor receptor. We also identified a variety of oncogenes that could transform 3T3 mouse fibroblasts, suggesting that individual TNBC tumors may undergo a unique driver event that can be targetable. Thus, we revealed several features of TNBC with clinically important implications., Author summary Cancer can result from genetic alterations, some of which can be good drug targets. To reveal genetic alterations that provide important information for the development of ideal therapeutic strategies for triple-negative breast cancer (TNBC), TNBC tumor samples were subjected to comprehensive genomic analyses. We identified novel recurrent structural variations associated with enhanced expression of the TGFA gene that encodes one of the high affinity ligands for epidermal growth factor receptor (EGFR). Although TGFA expression is known to be elevated in a subset of TNBC tumors, this is the first report of the mechanistic basis of this phenomenon. It is of particular importance considering that anti-EGFR agents are possible therapeutic options for TNBC patients. Our study also revealed several features associated with “BRCAness”, which is critical for identification of patients who may be responsive to platinum agents and/or poly ADP-ribose polymerase inhibitors. Thus, the data presented in this report may advance our understanding of the pathogenesis of TNBC.

Tumor microenvironment has been implicated in tumor development and progression. As a three-dimensional tumor microenvironment model, air liquid interface (ALI) organoid culture from oncogene transgenic mouse gastrointestinal tissues was recently produced. However, ALI organoid culture system from tissues of colorectal cancer patients has not been established. Here, we developed an ALI organoid model from normal and tumor colorectal tissues of human patients. Both organoids were successfully generated and showed cystic structures containing an epithelial layer and surrounding mesenchymal stromal cells. Structures of tumor organoids closely resembled primary tumor epithelium. Expression of an epithelial cell marker, E-cadherin, a goblet cell marker, MUC2, and a fibroblast marker, vimentin, but not a myofibroblast marker, α-smooth muscle actin (SMA), was observed in normal organoids. Expression of E-cadherin, MUC2, vimentin, and α-SMA was observed in tumor organoids. Expression of a cancer stem cell marker, LGR5 in tumor organoids, was higher than that in primary tumor tissues. Tumor organoids were more resistant to toxicity of 5-fluorouracil and Irinotecan than colorectal cancer cell lines, SW480, SW620, and HCT116. These findings indicate that ALI organoid culture from colorectal cancer patients may become a novel model that is useful for examining resistance to chemotherapy in tumor microenvironment.

O1 Combinatorial CD8+ and PD-L1+ cell densities correlate with response and improved survival in non-small cell lung cancer (NSCLC) patients treated with durvalumab #### Sonja Althammer1, Keith Steele2, Marlon Rebelatto2, Tze Heng Tan1, Tobias Wiestler1, Guenter Schmidt1, Brandon Higgs2, Xia

The purpose of this study was to evaluate the association between tumor necrosis factor (TNF)-α polymorphisms and oral mucositis (OM) from 5-fluorouracil (5-FU) plus cisplatin (CDDP) chemotherapy for esophageal cancer. The rs1799964 polymorphism of TNF-α was genotyped using the tetra-primer amplification refractory mutation system polymerase chain reaction. The experimental group comprised 64 patients who received chemotherapy for esophageal cancer between 1997 and 2004; a total of 106 patients between 2005 and 2013 were investigated as the validation group. Univariate analysis of the experimental group revealed that the TT genotype of TNF-α rs1799964 was significantly higher in patients with grade 1-4 OM compared with the TC/CC genotypes [univariate odds ratio (OR)=4.0; P=0.029]. Similarly, univariate analysis of the validation group revealed that the percentage of the TT genotype was significantly higher in patients with grade 1-4 OM compared with the TC/CC genotypes (OR=2.8; P=0.043). This difference in risk was replicated in the validation cohort. Thus, the TT genotype of TNF-α rs1799964 may be a predictor of chemotherapy-induced OM in patients with esophageal cancer.

Background Esophageal cancer is one of the most malignant gastrointestinal cancers and prognosis in recurrent cases remains extremely poor. However some studies show a relatively favorable prognosis among patients with solitary recurrence site who undergo locoregional therapy. It is important to clarify prognostic factors in postrecurrence cases. Methods This study included 156 patients who underwent curative resection for esophageal squamous cell carcinoma from January 2005 to December 2014. In this retrospective study we analysed relationship between clinicopathologic factors and prognosis after recurrence among these 156 patients. Results The average age was 65.2 years (± 8.2), 34 males, 11 females, The frequency of recurrence is pStage I: 2/36 cases (5.6%), pStage II: 7/48 cases (15%), pStage III: 21/43 cases (49%), pStage IVa: 8/11 cases (73%). Median survival time after recurrence was 377 (29 - 3266 days), and a 1 year/2 years/3 year survival rate after relapse was 50%/24%/11%. Patients with recurrent disease were offered treatment with chemotherapy + surgery (5 cases, 11%), chemotherapy + radiation (17 cases, 38%), chemotherapy (18 cases, 40%) and BSC (5 cases, 11%). MST was not reached in the chemotherapy + surgery group (741- 3266 days), 431 days (91–2324 days) in the chemotherapy + radiation group, 223 days (85–1079 days) in the chemotherapy group, and 52 days in the BSC group. There was a significant difference between each groups (P 65) single/multiple site recurrence, presence or absence of postoperative pneumonia, presence or absence of ARDS was selected as a prognostic factor after recurrence. In multivariate analysis, single/multiple site recurrence(HR 10.2, 95%CI 2.619–39.8, P = 0.0008), Postoperative pneumonia (HR 3.6, 95% CI 1.186 - 10.867, P = 0.024), postoperative ARDS (HR 5.6, 95% CI 1.209 - 26, 3, P = 0.0276) was selected. Conclusion Postoperative pulmonary complications might be related and aggressive local control for single site recurrence might improve the prognosis after recurrence of thoracic esophageal squamous cell carcinoma. Disclosure All authors have declared no conflicts of interest.

Cancer immunotherapy has emerged as a novel and effective treatment strategy for several types of cancer. Immune checkpoint inhibitors (ICIs) have recently demonstrated impressive clinical benefit in some advanced cancers. Nonetheless, in the majority of patients, the successful use of ICIs is limited by a low response rate, high treatment cost, and treatment-related toxicity. Therefore, it is necessary to identify predictive and prognostic biomarkers to select the patients who are most likely to benefit from, and respond well to, these therapies. In this review, we summarize the evidence for candidate biomarkers of response to cancer immunotherapy.

Tumor draining lymph nodes (TDLNs) are located in the routes of lymphatic drainage from a primary tumor and have the highest metastasis in various types of solid tumors. TDLNs are considered as a tissue to activate the antitumor immunity, where antigen-specific effector T cells are generated and released to the blood stream. These effector T cells then infiltrate into the tumor site and attack cancer cells. However, T cell receptor (TCR) repertoire in TDLNs has not been well characterized. We performed TCR sequencing of cancer tissues, corresponding normal mucosa tissues and a total of 203 regional lymph nodes, including 67 metastasis-positive lymph nodes from 23 colorectal cancer patients with lymph node metastasis. Metastasis-positive lymph nodes showed a significantly lower TCR diversity and shared TCR clones more frequently with primary tumor tissues compared to metastasis-negative TDLNs. Hierarchical clustering and principal component analyses also supported that TCR repertoires in metastasis-positive TDLNs were more similar to primary tumor tissues than metastasis-negative TDLNs. These finding suggest that cancer-reactive T cell clones might expand in the metastasis-positive TDLNs, although we have not tested their reactivity against cancer cells. We are now examining whether the T cells in TDLNs can recognized autologous cancer cells. Citation Format: Kazuma Kiyotani, Tatsuo Matsuda, Eisaku Miyauchi, Yu-Wen Hsu, Satoshi Nagayama, Makda Zewde, Jae-Hyun Park, Taigo Kato, Makiko Harada, Nobuaki Suzuki, Hiroaki Nagano, Shoichi Hazama, Yusuke Nakamura. Comparison of TCR repertoires between cancer tissues and lymph nodes in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1091.

e14306 Background: Even with curative resection, the recurrence rate of HCC is still high, and no effective adjuvant therapy is currently available. Our previous Phase I study with novel therapeutic peptides and immune adjuvants demonstrated the safety, antigen specific CTL induction in PBMC and a sign of efficacy (ASCO 2017 Abstract # 3086); thus, we started Phase I study of the same therapy as a perioperative immunotherapy setting in patients with resectable HCC (UMIN000029991). Methods: Two mg each of HLA-A*24:02, 02:01, or 02:06 restricted HSP70- and GPC3-derived peptides, in combination with hLAG-3Ig (1.0 mg) + Poly-IC:LC (1.4 mg) were injected intradermally at four sites of the inguinal and axillary regions every week for 6 weeks before surgery. Patients subsequently received 10 injections of adjuvant immunotherapy over 4 months. Surgical specimens and PBMCs were analyzed by mass cytometry (CyTOF), using 66 antibodies to monitor T cell exhaustion, T cell activation, Effector Treg induction, etc. Tumor specimens were also subjected to immunohistochemical staining of CD3, CD8, PD1, HSP70, and GPC3. The reason for early reporting is the interesting findings at the foci of HCC, and the interim analyses was approved by the Data and Safety Monitoring Committee. Results: Of the 11 screened patients, 5 completed the treatments and were analyzed. We found massive CD8+ T lymphocyte infiltration in the intratumor foci of HCC, which is usually accompanied by peritumoral lymphocytic infiltration. Moreover, the density of lymphocytes was markedly higher in areas of HSP70 or GPC3 antigen expression. One case out of five recurred 5 month after surgery and it showed low CD8+ and PD1+ cell infiltration and high effector Treg (CD4+/CD25+/CD45RA-/FoxP3 +) infiltration. This trend was not observed in PBMC, suggesting the importance of TIL analysis. The high PD1 expression was accompanied by massive intratumoral infiltration of CD8+ lymphocytes. Conclusions: The novel therapeutic peptide and immune adjuvant combination induced sustained immune cell infiltration into tumor microenvironments, especially those presenting target tumor-associated antigens. Our novel immunotherapy may convert cold tumors into hot tumors containing PD1+ lymphocytes. Thus, the combination of this novel strategy with PD (L) 1 antibody is warranted. Clinical trial information: 000029991.

565 Background: We have previously reported biweekly XELIRI + bevacizumab 10 mg/kg as second-line chemotherapy in metastatic colorectal cancer (mCRC). In this study, we investigated relationships between efficacy/toxicity and biomarkers (polymorphisms of UGT1A’s, somatic mutations of RAS, BRAF and PIK3CA). Methods: Patients with mCRC who had received prior chemotherapy including oxaliplatin based regimen were eligible for this study. Treatment protocol administrated capecitabine 1,000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan 150mg/m2 on day 1, and bevacizumab 10 mg/kg on day 1 every 2 weeks. Results: Between January 2013 and July 2015, 51 patients were enrolled in this study. The patients’ characteristics were as follows (N=51): median age, 66 years (range 41–82); male/female, 29/22; the median PFS was 5.47 months (95% CI, 4.23–7.40 months), the median OS was 13.5months (95%CI, 11.57– 20.23months), and the median TTF was 4.5 months (95%CI, 3.97–6.93 months). The response rate was 16% (95%CI, 7.2–29.1), and the disease control rate was 76% (95%CI, 61.8-86.9). Grade 3 or higher adverse events were mainly febrile neutropenia in two patients and hypertension in 14 patients (28.6%). The patients with UGT1A7 (387G

Retrospective studies have suggested that UDP-glucuronosyltransferase (UGT)1A1, UGT1A7, and UGT1A9 predict severe toxicity and efficacy of irinotecan-containing regimens. We prospectively evaluated the impact of UGT1A genotypes and haplotypes on severe toxicity and efficacy in patients treated with fluorouracil, leucovorin, and irinotecan combination chemotherapy (FOLFIRI) for metastatic colorectal cancer (mCRC) from the two prospective multicenter phase II studies in Japan. The FLIGHT1 study was a first-line FOLFIRI trial, and FLIGHT2 was a FOLFOX-refractory, second-line FOLFIRI trial. A total of 73 patients agreed to additional analysis, and were genotyped for UGT1A polymorphisms, UGT1A1*28 (TA6>TA7), UGT1A1*6 (211G>A), UGT1A1*27 (686C>A), UGT1A1*60 (−3279T>G), UGT1A1*93 (−3156G>A), UGT1A7 (−57T>G), UGT1A7*3 (387T>G, 622T>C), and UGT1A9*22 (T9>T10). Of 73 patients, 34 developed G3/4 severe hematological toxicities. The toxicities were significantly more frequent in patients with UGT1A1*6 (211A), UGT1A7 (387G), and UGT1A9*22 reference alleles (T9). Haplotype I, which consists of all favorable alleles, was associated with a significant reduction in hematologic toxicity (P = 0.031). In contrast, haplotype II, which contains four high-risk alleles, showed significantly higher hematologic toxicity than the other haplotypes (P = 0.010). Six out of seven patients who were homozygous for UGT1A1*28 or *6 experienced severe hematological toxicity despite the fact that their response rate was not impaired (42.9%). We concluded that UGT1A polymorphisms, especially UGT1A1*6, are important for the prediction of severe toxicity of FOLFIRI in northeast Asian populations. In this regard, haplotype analyses should substantially impact the prediction of severe hematological toxicities of FOLFIRI. (Clinical Trial Registration: UMIN000002388 and UMIN000002476).

Various vaccine treatments against metastatic colorectal cancer have been developed and applied. However, to improve the efficacy of immunotherapy, biomarkers that can predict the effects are needed. It has been reported that various microRNAs (miRNAs) in peripheral blood may be useful as non-invasive biomarkers. In this study, miRNAs influencing the efficacy of vaccine treatment were screened for in a microarray analysis of 13 plasma samples that were obtained from patients prior to vaccine treatment. To validate the screening results, real-time RT-PCR was performed using 93 plasma samples obtained from patients prior to vaccine treatment. Four candidate miRNAs were selected according to the results of the comprehensive analysis of miRNA expression, which were ranked using the Fisher criterion and the absolute value of the log2 ratio in the screening analysis. The validation analysis showed that in the HLA-A*2402-matched patient group (vaccine-treated group), patients with a high expression of plasma miR-6826 had a poorer prognosis than those with a low expression (P=0.048). In contrast, in the HLA-A*2402-unmatched patient group (control group), there was no difference between the patients with high or low plasma miR-6826 expression (P=0.168). Similar results were obtained in the analysis of miR-6875 (P=0.029 and P=0.754, respectively). Moreover, multivariate analysis of the Cox regression model indicated that the expression of miR-6826 was the most significant predictor for overall survival (P=0.003, hazard ratio, 3.670). In conclusion, plasma miR-6826 and miR-6875 may be predictive biomarkers for a poor response to vaccine treatment. Although further clarification is needed regarding the functions of miR-6826 and miR-6875 and their relationship to immune-related molecules, plasma miR-6826 and miR-6875 may be useful negative biomarkers for predicting the efficacy of vaccine treatment.

MicroRNAs (miRNAs/miRs) regulate the levels of transcripts and serve a critical function in the regulation of tumor microenvironments. Therefore, miRNA levels in cancer tissues are thought to be potential biomarkers for immunotherapy. From a phase I trial of a vaccine treatment using 5 human leukocyte antigen (HLA)-A*2402-restricted peptides (registration no. UMIN000004948), colorectal cancer (CRC) tissues were obtained from 8 patients and normal colorectal tissues from 5 patients via surgery. From a phase II trial using the same peptides (registration no. UMIN000001791), CRC tissues were obtained from 16 patients from the HLA-A*2402-matched group and 10 patients from the HLA-A*2402-unmatched group. These tissues were used for miRNA microarray analysis. As the first step, cancer tissues from the phase I study were used and 10 candidate miRNAs were selected by comparing the miRNA expression between two groups; one with improved prognosis and the other with poor prognosis. The miRNAs were subsequently validated using the cases enrolled in the phase II study. Significantly improved prognoses were identified in 16 patients in the HLA-A*2402-matched group with high expression of miR-196b-5p and low expression of miR-378a-3p and miR-486-5p. There was no difference in prognosis in the 10 patients in the HLA-A*2402-unmatched group. Therefore, high miR-196b expression and low miR-378a-3p and miR-486-5p expression were indicated as useful biomarkers for prediction of the efficacy of vaccine treatment for patients with metastatic CRC. In a planned phase III study, expression levels of these 3 miRNAs (miR-196b-5p, miR-378a-3p and miR-486-5p) may be useful biomarkers for assessing patients who are likely to have an improved outcome following vaccination.

A 56-year-old man who underwent a radical operation and adjuvant chemotherapy for recurrent rectal cancer had been followed-up and had no recurrence for one and a half years. Thereafter, CT and upper endoscopy showed a submucosal tumor with a central recess developing in the stomach wall. It was suspected that the gastric tumor was either a metastasis of rectal cancer or a submucosal tumor-like gastric cancer. We performed a radical operation to remove the lesion. In the resected specimen, immunohistopathological findings including HER2 status suggested that the gastric tumor was a primary gastric cancer resembling a submucosal tumor.

In Japan, chemotherapeutic agents that have been approved for the treatment of esophageal cancer include cisplatin, nedaplatin, 5-fluorouracil, vindesine, and docetaxel. The aim of this study was to retrospectively investigate the efficacy and safety of docetaxel and nedaplatin combination chemotherapy for unresectable or recurrent esophageal cancer in an outpatient setting.In total, 33 patients with recurrent esophageal cancer after initial treatment (esophagectomy, chemotherapy, or chemoradiotherapy) were enrolled. Patients received docetaxel (30 mg/m(2)intravenously) and nedaplatin (30 mg/m(2)intravenously) on day 1 biweekly. The response rate (RR), time to treatment failure (TTF), overall survival time (OS), and toxicity were analyzed.The median number of cycles of combination therapy was five (range=2-25 cycles). The RR was 21.2%, and the disease control rate was 60.6%. The median TTF was 71 days, and median OS was 211 days. The most frequent toxicities were leukopenia and anemia; non-hematological toxicities were generally mild. There were no treatment-related deaths.This outpatient combination chemotherapy was useful as second-line chemotherapy for unresectable or recurrent esophageal cancer.

BACKGROUND Colorectal cancer (CRC) is the second most common malignancy in Japan. Treatment with inhibitors of the vascular endothelial growth factor (VEGF) signalling pathway has proven benefit in metastatic CRC. Cediranib is an oral highly potent VEGF signalling inhibitor that inhibits all three VEGF receptors. PATIENTS AND METHODS In this phase II, double-blind, placebo-controlled study, 172 patients with metastatic CRC were randomised to receive once-daily cediranib (20 or 30 mg) or placebo, each combined with modified FOLFOX6 (mFOLFOX6). The primary objective was comparison of progression-free survival (PFS). RESULTS The comparison of cediranib 20 mg versus placebo met the primary objective of PFS prolongation [hazard ratio = 0.70 (95% confidence interval 0.44-1.11), P = 0.167], which met the protocol-defined criterion of P < 0.2. Median PFS was 10.2 versus 8.3 months, respectively. The PFS comparison for cediranib 30 mg versus placebo did not meet the criterion. The most common adverse events (AEs) in the cediranib-containing groups were diarrhoea and hypertension. CONCLUSIONS Cediranib 20 mg plus mFOLFOX6 met the predefined criteria in terms of improved PFS compared with placebo plus mFOLFOX6. Cediranib 20 mg was generally well tolerated and the AE profile was consistent with previous studies.

CT enteroclysis（CTE）とは，水や等張性緩下剤等（Niflec®，Elental®等）の陰性造影剤を小腸チューブから注入し，全小腸を十分に拡張させた後Dynamic CTを撮影して小腸病変の診断を行う検査法である．海外ではクローン病に対する報告が多数なされており，腸管の炎症，狭窄や瘻孔に対して高い確率での検出が可能とされている．症例は30歳代男性．2006年に小腸大腸型クローン病と診断され，5－アミノサリチルサン（5-ASA）製剤内服と成分栄養剤で加療されていた．2008年，臀部痛が出現し，近医の造影CTで仙骨前面に膿瘍を認めたが保存的加療にて症状は軽快し，以後の受診歴はない．2009年4月，鮮血便を頻回に認め，上部・下部消化管内視鏡検査では出血源が同定されなかったことから小腸出血が疑われた．出血は絶食のみで自然止血したが，出血源の同定目的で当院へ転院となった．陰性造影剤としてNiflec®を用いてCTEを施行したところ，回腸の壁肥厚，狭窄および直腸との内瘻の形成が疑われ手術適応と判断し，当院外科で手術が行われた．術中所見でCTEにて検出された回腸直腸瘻が実際に確認された．従来クローン病における内瘻の診断には小腸X線造影検査が用いられてきたが，瘻孔を明確に描出するのは難しく，術中所見ではじめて瘻孔形成部位が確定することも少なくなかった．本症例では内瘻の存在および局在の同定にCTEが安全に実施でき，手術適応を判断する上で有用であったことから，文献的考察を加えて報告する．

Objective We evaluated DNA amplificability to achieve a 100% success rate in KRAS mutation testing with dideoxy sequencing using formalin-fixed and paraffin-embedded colorectal cancer tissue samples obtained from a recent clinical trial. Methods We evaluated the effects of deparaffinization, formalin fixation or storage time, and amplicon size on the amplificability of DNAs extracted from 19 formalin-fixed and paraffin-embedded colorectal cancer tissue samples. We subjected to KRAS mutation analysis 112 samples from metastatic colorectal cancer patients in 31 hospitals enrolled in a Phase II trial of a second-line FOLFIRI (5-fluorouracil+ leucovorin + irinotecan) + cetuximab regimen. Results Deparaffinization, formalin fixation and storage times did not appear to affect the recovery and amplificability of DNAs. However, amplicon size had a remarkable effect on the amplificability of DNAs. The smaller fragments with a size of ≤278 bp (96-278 bp) were successfully amplified with polymerase chain reaction in all samples tested, whereas the larger fragments with a size of ≥298 bp (298-565 bp) were not amplified. All samples from our clinical trial were successfully analyzed using three sets of primers with the amplicon sizes of 201, 221 and 240 bp, and KRAS mutations in exons 2 and 3 were detected in 49 of the 112 cases (43.8%). Conclusions These data suggest that the evaluation of DNA amplificability and amplicon size is important for the success of mutation detection tests such as the KRAS test with dideoxy sequencing using formalin-fixed and paraffin-embedded tissue samples in the clinical setting.

Background Prognosis of patients with esophageal squamous cell carcinoma (ESCC) can be significantly improved by neoadjuvant chemotherapy (NAC). The current best clinical method to predict pathologic response of chemotherapy is the maximum standardized uptake value (SUVmax) in 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET). However, most of the FDG-PET evaluation has been focused on the primary tumors, but not on other metastatic lesions. The aim of this study was to determine the predictive value of FDG-uptake measured prior and after NAC both in the primary tumors and in the metastatic lymph modes (mLN) in ESCC. Methods Forty-five consecutive potentially resectable ESCC patients treated with NAC, which consisted of 2 courses of continuous infusion of 5-FU for days 1–5 and CDDP on day 1, between 2009 and 2016 were evaluated. FDG-uptake was measured at baseline and after chemotherapy in the primary tumors and in the mLN, and all patients underwent esophagectomy with R0 resection. The predictive values of FDG-PET and clinicopathological characteristics were determined with univariate and multivariate analyses. Results The median age was 66 years, with 35 males and 9 females. Pretreatment clinical classification of tumor depth was T1 in 9, T2 in 10, T3 in 26, respectively, and that of lymph modes metastases was N0 in 9, N1 in 12, N2 in 18, N3 in 6, respectively. The average SUVmax before and after NAC in the primary tumors was 13.9 and 7.9, respectively, and the average SUVmax reduction was 39.8% after chemotherapy. Pathological response was found to correlate well with the SUVmax reduction in the primary tumors, however, relative change in FDG uptake after chemotherapy was not associated with overall survival (OS). The average SUVmax before and after NAC in the mLN was 6.9 and 3.3, respectively, and the average SUVmax reduction was 46.2% after chemotherapy. Univariate and multivariate analyses revealed that both of the SUVmax and relative change in FDG uptake after chemotherapy in the mLN were well correlated with OS. Conclusion Post-NAC SUVmax and relative change in FDG uptake after chemotherapy in the mLN are valuable independent preoperative predictor of prognosis for patients with ESCC who received chemotherapy before surgery. Disclosure All authors have declared no conflicts of interest.

Background Malnutrition is frequent in esophageal cancer patients and aggravated by operation, increasing postoperative complications and mortality. Although a preoperative immunonutrition pharmaceutics diet significantly reduced the incidence of postoperative infectious complications, the effect of perioperative immunonutrition of esophagectomy for esophageal cancer still remains unclear. Methods This study design was a prospective randomized study. 40 patients with thoracic esophageal carcinoma who underwent esophagectomy were divided into two groups. Continiously 7 days before and after surgery, they enrolled and received either immunomodulating enteral nutrition (IMPACT® Group: IG) or standard enteral nutrition (Ensure® Group: EG). The nutrition statement, postoperative ICU stay, postoperative hospital stay, morbidity and mortality were investigated prospectively. Results There was no difference of patient demographics between two groups. Retinol-binding protein as rapid turnover protein was significantly higher on postoperative day (POD) -1, POD 7 and POD 14 in the IG than in the EG (P = 0.009, P = 0.004 and P = 0.024, respectively). The incidence of postoperative infectious complications and changes to therapeutic antibiotics was significantly lower in the IG than in the EG (P = 0.048 and P = 0.012, respectively). No difference was observed in postoperative ICU stay and postoperative hospital stay between two groups. The 5-year PFS in the IG and EG groups were 75% and 64% (P = 0.188), respectively, and OS were 68% and 55% (P = 0.187), respectively. Conclusion This study showed that immunonutrition would be effective to improve the early nutritional status and reduce postoperative infectious complications. Disclosure All authors have declared no conflicts of interest.