Mutated genes on ctDNA detecting postoperative recurrence presented reduced neoantigens in primary tumors in colorectal cancer cases.

The detection and sequencing of the mutated ctDNA is one of the irreplaceable clinical measures in the postoperative management of colorectal cancer (CRC) cases. However, we are curious to comprehend the essential traits of mutated genes comprising metastatic sites out of whole mutated genes in primary sites. In the current retrospective study, we conducted target resequencing of ctDNA using 47 plasma samples and established a cancer panel carrying the commonly mutated genes between primary and recurrent tumors. We found that mutated genes in ctDNA indicated immune-resistance traits with respect to the impaired ability to present neoantigens by loss of expression or binding affinity to HLA in the primary tumor. Compared with the estimated neoantigens from all mutated genes in primary tumors, the neoantigen peptides from commonly mutated genes on the panel showed abundant expression but no binding affinity to HLA. Therefore, ctDNA mutations can be frequently and postoperatively detected to identify recurrence; however, these mutated genes were derived from immune-tolerated clones owing to the loss of neoantigen presentation in primary CRC tumors.

[A Case of Advanced Gastric Cancer of an Elderly Patient Responding Effectively to Pembrolizumab].

A 96-year-old man was admitted to our hospital because of dysphagia. After examination, he was diagnosed with type 3 advanced gastric cancer in the antrum with duodenal invasion. A gastrojejunostomy was performed because of dissemination in the pelvic floor. He was put on pembrolizumab after surgery because the microsatellite instability test showed positive results. The therapeutic response was PR. Pembrolizumab can improve the outcomes in elderly patients with unresectable advanced gastric cancer.

[Case of Hyperammonemia Induced by High-Dose Fluorouracil].

A case of hyperammonemia induced by chemotherapy, including high-dose fluorouracil(5-FU), for advanced unresectable large intestinal cancer has been reported. This case involved an 81-year-old female who was diagnosed with pT4bcN2M1 (multiple hepatic metastases; stage Ⅳ; KRAS: mutant)after emergency surgery for sigmoid colon cancer and diffuse peritonitis. Post-operation, the 4 courses of mFOLFOX6 plus Bmab therapy was started for advanced unresectable recurrent large intestinal cancer; 48 hours later, she developed consciousness disorder(JCS Ⅲ-300). The disorder promptly disappeared after discontinuation of high-dose 5-FU. Because high-dose 5-FU was inferred to be the main cause of hyperammonemia, XELOX plus Bmab therapy was started as a post-treatment. She did not develop hyperammonemia; therefore, 8 courses were administered. The patient is being followed-up now.

Genomic Landscape of Esophageal Squamous Cell Carcinoma in a Japanese Population.

BACKGROUND & AIMS: Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer in Japan. Smoking and drinking alcohol are environmental risk factors for ESCC, whereas single nucleotide polymorphisms in ADH1B and ALDH2, which increase harmful intermediates produced by drinking alcohol, are genetic risk factors. We conducted a large-scale genomic analysis of ESCCs from patients in Japan to determine the mutational landscape of this cancer. METHODS: We performed whole-exome sequence analysis of tumor and nontumor esophageal tissues collected from 144 patients with ESCC who underwent surgery at 5 hospitals in Japan. We also performed single-nucleotide polymorphism array-based copy number profile and germline genotype analyses of polymorphisms in ADH1B and ALDH2. Polymorphisms in CYP2A6, which increase harmful effects of smoking, were analyzed. Functions of TET2 mutants were evaluated in KYSE410 and HEK293FT cells. RESULTS: A high proportion of mutations in the 144 tumor samples were C to T substitution in CpG dinucleotides (called the CpG signature) and C to G/T substitutions with a flanking 5' thymine (called the APOBEC signature). Based on mutational signatures, patients were assigned to 3 groups, which associated with environmental (drinking and smoking) and genetic (polymorphisms in ALDH2 and CYP2A6) factors. Many tumors contained mutations in genes that regulate the cell cycle (TP53, CCND1, CDKN2A, FBXW7); epigenetic processes (MLL2, EP300, CREBBP, TET2); and the NOTCH (NOTCH1, NOTCH3), WNT (FAT1, YAP1, AJUBA) and receptor-tyrosine kinase-phosphoinositide 3-kinase signaling pathways (PIK3CA, EGFR, ERBB2). Mutations in EP300 and TET2 correlated with shorter survival times, and mutations in ZNF750 associated with an increased number of mutations of the APOBEC signature. Expression of mutant forms of TET2 did not increase cellular levels of 5-hydroxymethylcytosine in HEK293FT cells, whereas knockdown of TET2 increased the invasive activity of KYSE410 ESCC cells. Computational analyses associated the mutations in NFE2L2 we identified with transcriptional activation of its target genes. CONCLUSIONS: We associated environmental and genetic factors with base substitution patterns of somatic mutations and provide a registry of genes and pathways that are disrupted in ESCCs. These findings might be used to design specific treatments for patients with esophageal squamous cancers.

Complete Surgical Resection of a Leiomyosarcoma Arising from the Inferior Vena Cava.

A 76-year-old Japanese man was referred to our hospital with chief complaint of right hypochondoralgia. Abdominal ultrasound showed a retroperitoneal tumor in the suprarenal region of the right kidney. Computed tomography revealed an enhanced lobular tumor with irregular, circumscribed, and indistinct border. Ultrasound-guided biopsy was performed. The tumor consisted of spindle-shaped cells with a giant nucleus and multinuclear cells. The diagnosis was leiomyosarcoma by immunohistochemical staining. The patient underwent surgery accessed by a right eighth intercostal thoracoabdominal incision. The tumor was completely resected, accompanied by removal of the posterosuperior segment of the right hepatic lobe, right adrenal gland, and a portion of the inferior vena cava (IVC). The histopathologic diagnosis was leiomyosarcoma arising from the IVC. We present a rare case of a successfully managed leiomyosarcoma of the IVC. This case suggests the importance of curative surgical resection of the tumor due to low efficacy of adjuvant chemotherapy for leiomyosarcoma.

Giant polypoid tumor expressing on the pyloric ring.

A 66-year-old Japanese man was referred to our hospital because of suspected duodenal cancer. Upper gastric endoscopy revealed a giant polypoid-type tumor that extended from the duodenum bulb to the pyloric ring. A computed tomography scan revealed a slightly enhanced lobular tumor protruding into the duodenum bulb. Positron emission tomography showed an accumulation of (18)F-fluorodeoxyglucose in the area extending from the antrum of the stomach to the duodenum bulb. Since an endoscopic ultrasound test suggested that the tumor might invade the muscular tunic, indications of endoscopic mucosal resection were not favored, and the tumor was curatively removed via distal gastrectomy. The histopathologic diagnosis was papillary adenocarcinoma, and the invasion depth was the mucosal layer without vascular invasion, which was different from the preoperative diagnosis. Our case suggests the difficulties in precise diagnosis of the invasion depth of the giant polypoid cancer.

Validation of the Estimation of Physiologic Ability and Surgical Stress (E-PASS) score for maintenance hemodialysis patients undergoing elective abdominal surgery.

AIMS: This study assessed the validity of the Estimation of Physiologic Ability and Surgical Stress (E-PASS) score in maintenance hemodialysis patients undergoing elective abdominal surgery. METHODS: We retrospectively reviewed the medical records of 73 hemodialysis patients who underwent elective gastrointestinal surgery. The main outcomes analyzed were the E-PASS score and postoperative course, which were defined by mortality and morbidity. The discriminative capability of the E-PASS score was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: The overall mortality rate observed was 2.7% (2 patients) and the morbidity rate was 36.9%. There were no significant differences in the comprehensive risk score, preoperative score or surgical stress score for patients with or without complications (p = 0.556, 0.639 and 0.168, respectively). Subsequent ROC curve analysis demonstrated poor predictive accuracy for morbidity. When the results in our study population were compared with those in Haga's study population, our population exhibited a highly significant rightward shift (p < 0.001). CONCLUSION: The E-PASS score was a poor predictor of complications because maintenance hemodialysis patients already have relatively high risk factors. This scoring system should not be applied in such a special group with high risk factors.

Risk factors for maintenance hemodialysis patients undergoing elective and emergency abdominal surgery.

PURPOSE: To identify the risk factors for morbidity and mortality after elective and emergency abdominal surgeries in maintenance hemodialysis patients. METHODS: We retrospectively evaluated the medical records of 63 hemodialysis patients who underwent elective (group 1) and 24 who underwent emergency (group 2) abdominal surgeries, and classified them according to the presence/absence of postoperative complications. The clinical, laboratory and procedure-related data were obtained and compared between the groups. RESULTS: Group 2 had significantly higher morbidity and mortality rates than group 1 (58.3 and 16.6 % vs. 33.3 and 16.6 %, respectively, P < 0.05). The patients in group 1 with and without complications had significantly different blood urea nitrogen (BUN) levels of 52.3 vs. 41.6 mg/dL (P = 0.03). There were significant differences in the patients in group 2 in terms of the age (72.7 vs. 55.0 years old; P < 0.002), the length of the operation (141 vs. 107 min; P < 0.02), the total protein levels (6.2 vs. 6.7 g/dL; P < 0.03), albumin levels (3.2 vs. 3.7 g/dL; P < 0.04) and need for intra- or postoperative blood transfusions (71.4 vs. 10.0 %; P < 0.005). CONCLUSIONS: The risk factors for a poor surgical outcome included high BUN levels in the elective surgery patients and hypoproteinemia, hypoalbuminemia, a longer operation and older age in patients undergoing emergency surgery. Perioperative blood transfusion was also associated with a high complication rate in the emergency surgery group.

[Second-line FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer after resection of the primary lesion].

The efficacy and safety of bevacizumab(BV), combined with infusional 5-fluorouracil/leucovorin(5-FU/LV)plus irinotecan(FOLFIRI)as the second-line treatment for metastatic colorectal cancer(mCRC)after resection of the primary lesion, have not been fully clarified. We examined clinical results of 35 patients on BV plus FOLFIRI at our hospital, and investigated the efficacy of BV plus FOLFIRI in mCRC patients who failed oxaliplatin-containing regimens(26 patients were treated with BV at a dose of 5mg/kg, 3 patients with BV 10mg/kg, and 6 patients had BV increased from 5mg/kg to 10mg/kg). The average frequency of BV plus FOLFIRI treatment was 13. 9 times, and the average length of treatment was 10. 0 months. The overall response rate was 17. 1%(CR 1 patient, PR 5 patients, SD 21 patients, PD 8 patients). The median PFS was 11. 0 months for FOLFIRI plus BV after first-line chemotherapy, and the median OS was 23. 0 months. The adverse events were 77. 1%(>Grade 3, 55. 5%)and the BV-associated adverse event was grade 3 hypertension(2 patients). The FOLFIRI plus BV regimen is an active and well-tolerated second-line chemotherapy treatment for patients with mCRC after resection of the primary lesion.

Surgical therapy and chemoradiotherapy for postoperative recurrent esophageal cancer.

BACKGROUND/AIMS: A retrospective analysis of therapeutic modalities used in postoperative recurrent esophageal cancer. METHODOLOGY: Among 43 esophageal cancer patients who underwent esophagectomy between 2003 and 2010, recurrence was found in 15. Best supportive care was given to two patients and another patient was referred to another hospital. The remaining 12 patients were treated by the following modalities: Surgical resection: 2 cases; chemoradiotherapy: 7 cases; chemotherapy: 2 cases; and radiotherapy: 1 case. The median survival time, 1-year survival rates, and response rates were examined. Data from 13 esophageal cancer patients who underwent chemoradiotheray as an initial therapy in the same period were collected and compared with recurrent cases treated with chemoradiotherapy. RESULTS: For all 12 patients, the median overall survival time was 19.5 months, and the 1-year survival rate was 83%. Among 7 chemoradiotherapy patients, the response rate was 57%. The median survival time was 23 months, and the 1-year survival rate was 86%. The response rate of 13 patients receiving chemoradiotherapy as an initial therapy was 69%. The median overall survival time was 12 months and the 1-year survival rate was 54%. CONCLUSIONS: Re-operation and chemoradiotherapy for recurrent esophageal cancer might be as effective as the same treatment used initially.

Postoperative long-term evaluation of interposition reconstruction compared with Roux-en-Y after total gastrectomy in gastric cancer: prospective randomized controlled trial.

BACKGROUND: The postoperative clinical superiority of the interposition of jejunum reconstruction (INT) to Roux-en-Y reconstruction (RY) after total gastrectomy has not been clarified. Postoperative quality of life (QOL) was evaluated between the 2 methods by a multi-institutional prospective randomized trial. METHODS: A total of 103 patients with gastric cancer were prospectively randomly divided into groups for RY (n = 51) or INT reconstruction (n = 52) after total gastrectomy. They were stratified by sex, age, institute, histology, and degree of lymph node dissection. Postoperatively, body mass index (BMI) and nutritional conditions were measured serially, and QOL and postoperative squalor scores were evaluated at 3, 12, and 60 months and compared between the 2 groups. RESULTS: After removing patients who did not complete the follow-up survey or censured cases, 24 patients in the RY group and 18 patients in the INT group were clinically available and their postoperative status was assessed. QOL scores were increased and complication scores were improved in the postoperative periods (P < .01). Postoperative BMI significantly deteriorated compared with preoperative BMI in each group. The postoperative QOL and complication scores at 60 months after surgery were significantly better than those at 3 months after surgery in each group (P < .01). However, there was no significant difference of QOL scores and postoperative complication scores between the 2 reconstruction groups. The nutritional condition in the INT group was nearly the same as that in the RY group. CONCLUSIONS: Although our patient sample was small and patients who did not complete the follow-up survey were present, we could not identify any clinical difference between INT and RY after total gastrectomy 60 months after surgery. The safer and simpler RY method may be a more suitable reconstruction method than INT after total gastrectomy.

Physiological evaluation of residual stomach motility after local resection in conscious dogs.

PURPOSE: To investigate the phenomenon of remnant gastric motility and emptying after local resection. METHODS: Fifteen dogs were divided into three groups: a control (CONT) group, a group that underwent local resection of the greater (GREAT) curvature, and a group that underwent resection of the lesser (LESS) curvature. We conducted a strain gauge force transducer study, a [(13)C]octanoic acid breath test ((13)C-OBT), and a mosapride citrate effect test. Based on these results, we worked out the receptive relaxation (RR), motility index (MI), and postprandial period (PP) in the postprandial state, and the frequency, duration, and MI of phase III in the fasted state. The half emptying time (T (1/2)) of (13)C-OBT was also calculated. The MI was compared according to the mosapride effect test results. RESULTS: Postprandial RR, antro-pyloro-duodenal coordination, and fasting contractions were maintained in all three groups. Receptive relaxation was significantly shorter in the LESS group than in the other groups. Motility index was significantly lower in both treatment groups than in the CONT group. The PP was significantly longer in the GREAT group than in the other two groups. The (13)CO(2) excretion curves did not differ significantly among the groups. The duration of phase III was remarkably less in the treatment groups than in the CONT group, and MI was significantly lower in the LESS group than in the other groups in the fasted state. The MI increased remarkably after mosapride administration in the CONT group, showing no differences in other objective groups. CONCLUSION: Gastric function was maintained after gastric local resection, although its motility decreased.

Sustained aberrant localization of KL-6 mucin and beta-catenin at the invasion front of human gastric cancer cells.

AIMS: This study sought to analyze the clinicopathological significance of KL-6 mucin, a type of MUC1, in gastric cancer and its relationship to ß-catenin. PATIENTS AND METHODS: Subcellular localization of KL-6 mucin and ß-catenin in gastric cancer tissues (n = 96) was detected immunohistochemically and its clinicopathological significance was evaluated. RESULTS: Samples with localization of KL-6 mucin in the surrounding membrane and/or cytoplasm of cancer cells at the invasion front (n = 50, 52%) had a higher incidence of deeper invasion (p < 0.0001), lymphatic vessel invasion (p = 0.0003), venous invasion (p < 0.0001), lymph node metastasis (p < 0.0001) and an advanced TNM stage (p = 0.0005). Furthermore, this localization of KL-6 mucin was associated with accumulated nuclear localization of ß-catenin. CONCLUSION: In concert with aberrant localization of ß-catenin, sustained localization of KL-6 mucin in the surrounding membrane and/or cytoplasm of cancer cells at the invasion front has a significant role in cancer progression.

A case of esophageal cancer with mesojejunal lymph node metastasis after total gastrectomy.

A 56-year-old man was diagnosed with esophageal cancer by upper gastrointestinal endoscopy for examination of dysphagia. The patient had undergone total gastrectomy and jejunal interposition 4 years previously for a gastric cancer at the pT1N0M0 stage according to the UICC-TNM classification. Enhanced CT findings revealed a 3-cm-diameter mass located near the superior mesenteric artery. We conducted subtotal esophagectomy associated with partial jejunectomy including mesojejunectomy. The mass was histologically diagnosed to be mesojejunal lymph node metastasis from esophageal cancer. Mesojejunal lymph node metastasis from esophageal cancer developing after total gastrectomy has been reported in only three cases including ours. The present lymph node metastases may have occurred via the newly developed lymphatic drainage route through the esophagojejunostomy, and this metastatic lymph node can be considered the regional lymph node. Therefore, resection of the interposed jejunal limb with mesojejunectomy may be rational in surgery on esophageal cancer developing after total gastrectomy.

Appearance of high-molecular weight sialoglycoproteins recognized by Maackia amurensis leukoagglutinin in gastric cancer tissues: a case report using 2-DE-lectin binding analysis.

Aberrant expression of sialoglycoconjugates has been thought to play an important role in cancer progression. Our previous lectin-histochemical study showed that overexpression of sialoglycoconjugates recognized by alpha2,3-sialic acid-specific Maackia amurensis leukoagglutinin (MAL) was significantly related to the malignancy of gastric cancer. The present study analyzed the sialoglycoproteins in gastric cancer tissues by 2-dimensional electrophoresis (2-DE) in combination with lectin-binding analysis using MAL. Various MAL-positive sialoglycoproteins were detected in cancer tissues but not in non-cancer tissues. The sialoglycoproteins have a high molecular weight of near 200 kDa and over 200 kDa with different pI values for the two. This suggests that the MAL-positive sialoglycoproteins detected in gastric cancer tissues have high molecular weights and may contain different numbers of alpha2,3-linked sialic acid residues in the carbohydrate moiety.

Stomach-partitioning gastrojejunostomy for gastroduodenal outlet obstruction.

HYPOTHESIS: The outcome of the stomach-partitioning gastrojejunostomy (SPGJ) procedure is superior to that of stenting procedures. DESIGN: Data from patients who underwent an SPGJ were collected retrospectively from hospital medical records (body weight, hemoglobin and albumin levels, assessment of food intake, duration of hospitalization, complications, and survival rates), and we compared the results with those obtained from patients treated with stenting. SETTING: Departments of Gastrointestinal Surgery and Gastroenterology, Tokyo University Hospital, Tokyo, Japan. PATIENTS: A series of 16 consecutive patients with gastroduodenal outlet obstruction who underwent an SPGJ and 9 patients who were treated with stenting between January 5, 1998, and August 18, 2004. MAIN OUTCOME MEASURES: Mann-Whitney, Fisher exact, and generalized Wilcoxon tests were used for statistical analyses. RESULTS: There were no differences between the 2 groups concerning background data, physiological status, or laboratory data. The starting point of food intake by patients treated with stenting was significantly earlier (at 4.2 days in the stent group vs at 6.0 days in the SPGJ group, P < .004). The numbers of patients taking a regular meal at 2 weeks after treatment were 12 of 16 patients in the SPGJ group and 1 of 9 patients in the stent group (P < .001). There was no significant difference between the 2 groups regarding the duration of hospitalization. The complication rates were significantly different between the 2 groups (P = .48). The median survival was 7.3 months in the SPGJ group and 2.8 months in the stent group (P = .008), and the mean 6-month survival rates were 81% (13 of 16) and 33% (3 of 9), respectively (P < .04). CONCLUSION: Stomach-partitioning gastrojejunostomy achieved improved quality of life and a better prognosis compared with stenting procedures, and it is the treatment of choice for gastroduodenal outlet obstruction.

Nutritional comparisons between a pylorus-preserving gastrectomy with and without suprapyloric lymph node clearance: a preliminary report.

BACKGROUND/AIMS: A pylorus-preserving gastrectomy (PPG) is a procedure for gastric cancer (GC) patients which attempts to control gastric emptying and to minimize postoperative nutritional disadvantages. The persistence of conflicting stances concerning qualifying candidates for PPG--a narrower or wider segment of patients--is attributable to a lack of decisive evidence concerning the precise nutritional impact of suprapyloric lymph node clearance. METHODOLOGY: Forty-eight patients underwent a PPG with (30 patients; dissection group) or without (18 patients; preservation group) suprapyloric lymph node clearance between 2002 and 2004. Patients with mucosal GC located in the middle third of the stomach were assigned to the preservation group and the other early GC patients formed the dissection group. Those who were followed up more than one year postoperatively were selected from the preservation (8 patients) and the dissection (16 patients) groups, and changes in body weight, hemoglobin, total protein, and albumin were compared between the two groups. Baseline clinicopathological characteristics, surgically related events, and supportive medications were also compared between the two groups. RESULTS: Dissection group patients received significantly longer surgery (p < 0.01) and a wider scope of lymphadenectomy (p < 0.0001) than preservation group patients. Other factors including the length of postoperative hospital stay and morbidity rate did not differ between the two groups. Percent changes in body weight, hemoglobin, total protein, and albumin, as well as postoperative profiles of each parameter were similar between the two groups. CONCLUSIONS: These results suggest that suprapyloric lymph node clearance resulted in more traumatic surgery while it did not exacerbate postoperative nutritional status as compared with suprapyloric lymph node preservation. PPG is justifiable for submucosal GC or an even wider segment of patients by suprapyloric lymph node clearance without nullifying the anticipated nutritional benefit.

The intergroup/RTOG 85-01 concurrent chemoradiation regimen for Japanese esophageal cancer.

BACKGROUND/AIMS: To evaluate outcome of the U.S. RTOG/Intergroup Protocol 85-01 for 44 Japanese esophageal cancer patients. METHODOLOGY: Between 1996 and 2004, patients with esophageal cancer received the Intergroup concurrent chemoradiation therapy regimen for the primary treatment (n=44, group A). We compared the data with those of patients receiving radiotherapy (RT) combined with the weekly chemotherapy regimen (n=12, group B) and with those of patients receiving RT combined with the daily low-dose chemotherapy regimen (n=24, group C). RESULTS: The median survival period was 14.9 months in group A, 5.7 months in group B, and 6.3 months in group C. The survival rates at 1 and 3 years were 56% and 26% in group A, 42% and 21% in group B (p=0.3307), and 27% and 18% in group C (p=0.0462), respectively. CONCLUSIONS: The prognosis of patients who received the Intergroup regimen for esophageal cancer was significantly better than that of patients who received the daily low-dose chemotherapy regimen. The Intergroup regimen is well tolerable for the Japanese patients too.

Helicobacter pylori-negative / API2-MALT1 translocation-negative low-grade MALT lymphoma.

A 71-year-old man with a Helicobacter pylori infection-negative and API2-MALT1 translocation-negative extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type of the stomach has been followed conservatively for over 5 years. The lesion has shown no major morphological changes or malignant progression into a diffuse large-cell type during the time course. The absence of genetic translocation of API2-MALT1 was confirmed with fluorescence in situ hybridization (FISH). The prognosis of H. pylori-negative and API2-MALT1 translocation-negative low-grade MALT lymphoma is unknown, and a standard treatment for such lymphoma has yet to be defined. The case of MALT lymphoma negative for both of the above factors that we report has shown no obvious rapid progression or malignant change over the long-term course. Although curative operation and/or chemoradiotherapy should still be discussed as the treatment of choice, the treatment of this type of lymphoma must be carefully determined on a case-by-case basis, according to its biological status and prognosis.