Identifying Risk Factors of Complications following Total Gastrectomy for Gastric Cancer: Comparison between Splenectomy and Spleen-Preserving Surgery - A Supplementary Analysis of JCOG0110.

INTRODUCTION: Splenectomy for proximal gastric cancer was found to offer no survival benefit in a randomized trial clarifying the role of splenectomy (JCOG0110 study). Although many studies have explored risk factors for morbidities following total gastrectomy, none have assessed the risk factors for postoperative complications in spleen-preserving total gastrectomy. METHODS: Using data from 505 patients enrolled in a previous randomized trial, risk factors for postoperative complications were identified by multivariable logistic regression analysis. Then, the risk factors were assessed separately between splenectomy and spleen-preserving total gastrectomy. RESULTS: Postoperative complications were identified in 119 patients (23.6%) and were more common following splenectomy than following spleen-preserving surgery (30.7% and 16.1%, respectively, p < 0.01). Multivariable analysis revealed that age ≥65 years (p = 0.032), body mass index ≥25 (p = 0.003), and blood loss ≥350 (p = 0.019) were independent risk factors for postoperative complications in the entire cohort. Among them, only body mass index was a significant independent risk factor for complications in both spleen preservation (p = 0.047) and splenectomy groups (p = 0.017). CONCLUSION: Risk factors for postoperative complications were essentially the same between splenectomy and spleen preservation. Being overweight increased the risk of postoperative complications.

Recurrence patterns after curative gastrectomy for pStage II/III gastric cancer: Exploratory analysis of the randomized controlled JCOG1001 trial.

BACKGROUND: Peritoneal, lymph node, and hematogenous recurrence patterns are common after potentially curative surgery for gastric cancer. However, clinicopathological characteristics associated with each recurrence type have rarely been comprehensively reported among patients who received a unified treatment strategy and follow-up protocol. Understanding these recurrence patterns would help with early detection of recurrence and a personalized follow-up plan. We investigated the initial recurrence patterns after curative gastrectomy using data from the randomized clinical JCOG1001 trial. METHODS: Of 1204 patients enrolled in JCOG1001, 932 pStage II/III patients were included. Initial recurrence dates and patterns were recorded by attending physicians according to the protocol. Risk factors for hematogenous, lymph node, and peritoneal recurrence were determined by univariable and multivariable analyses using the Fine-Gray model. RESULTS: Overall, 253 patients developed recurrence. Hematogenous recurrence was the most frequent pattern (n = 115), followed by peritoneal (n = 104) and lymph node recurrence (n = 70). Differentiated type (p = 0.0028), pT4 (p = 0.0466), and pN3 (p < 0.0001) were associated with hematogenous recurrence; however, D2+ lymphadenectomy reduced it (p = 0.0161). Patients with large (≥5 cm) tumors (p = 0.0312), pT4 (p < 0.0001), pN3 (p = 0.0013), and undifferentiated histologic type (p = 0.0001) had significantly higher rates of peritoneal recurrence. Extended lymph node metastasis (pN3) was the only risk factor (p < 0.0001) for lymph node recurrence. CONCLUSIONS: Clinicopathological features differed according to the recurrence patterns. Vigilant follow-up with an understanding of recurrence patterns might be beneficial for some high-risk patients.

Survival analysis of a prospective multicenter observational study on surgical palliation among patients with malignant bowel obstruction caused by peritoneal dissemination of gastric cancer.

BACKGROUND: Our previous report showed that surgical palliation maintained quality of life (QOL), improved solid food intake, and had an acceptable surgical safety among patients with malignant bowel obstruction (MBO) caused by advanced gastric cancer. This study performed a survival analysis stratified by the patients' QOL to elucidate its impact on survival. METHODS: Patients who underwent resection or bypass of the small intestine/colon or ileostomy/colostomy for bowel obstruction caused by peritoneal dissemination of gastric cancer were included. Validated instruments (EuroQoL-5 Dimensions) were used to assess QOL at baseline and 2 weeks, 1 month, and 3 months following surgical palliation. Postoperative improvement in oral intake was also evaluated using the Gastric Outlet Obstruction Scoring System (GOOSS). Univariate and multivariate survival analyses were performed using baseline characteristics and changes in QOL and GOOSS scores 2 weeks after surgery to determine prognostic factors. RESULTS: We enrolled 60 patients with a median survival time of 6.64 (95% CI 4.76-10.28) months. Patients who received postoperative chemotherapy and had lower baseline C-reactive protein (CRP) levels, higher baseline albumin levels, better baseline EuroQoL-5 Dimensions (EQ-5D) scores, and improved oral intake after palliative surgery exhibited significantly better survival. Multivariate analysis identified postoperative chemotherapy, lower baseline CRP levels, and improved oral intake as independent prognostic factors. CONCLUSIONS: The current study revealed that baseline QOL and postoperative QOL changes did not affect survival. Moreover, improved oral intake, lower baseline CRP levels, and postoperative chemotherapy were significant prognostic factors in patients who underwent palliative surgery for advanced gastric cancer with MBO.

QOL assessment after palliative surgery for malignant bowel obstruction caused by peritoneal dissemination of gastric cancer: a prospective multicenter observational study.

BACKGROUND: Patients with peritoneal dissemination of gastric cancer have poor oral intake caused by malignant bowel obstruction (MBO). Palliative surgery has often been undertaken to improve quality of life (QOL), but few prospective studies on palliative surgery in this patient population have been published. PATIENTS AND METHODS: We prospectively investigated the significance of palliative surgery using patient-reported QOL measures. Patients underwent palliative surgery by small intestine/colon resection or small intestine/colon bypass or ileostomy/colostomy for MBO. The primary endpoint was change in QOL assessed at baseline, 14 days, 1 month, and 3 months following palliative surgery using the Euro QoL Five Dimensions (EQ-5D™) questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire gastric cancer module (QLQ-STO22). Secondary endpoints were postoperative improvement in oral intake and surgical complications. RESULTS: Between April 2013 and March 2018, 63 patients were enrolled from 14 institutions. The mean EQ-5D™ utility index baseline score of 0.6 remained consistent. Gastric-specific symptoms mostly showed statistically significant improvement from baseline. Forty-two patients (67%) were able to eat solid food 2 weeks after palliative surgery and 36 patients (57%) tolerated it for 3 months. The rate of overall morbidity of ≥ grade III according to the Clavien-Dindo classification was 16% (10 patients) and the 30-day postoperative mortality rate was 3.2% (2 patients). CONCLUSIONS: In patients with MBO caused by peritoneal dissemination of gastric cancer, palliative surgery did not improve QOL while improving solid food intake, with an acceptable postoperative morbidity and mortality rate.

Survival outcomes after laparoscopy-assisted distal gastrectomy versus open distal gastrectomy with nodal dissection for clinical stage IA or IB gastric cancer (JCOG0912): a multicentre, non-inferiority, phase 3 randomised controlled trial.

BACKGROUND: Laparoscopy-assisted distal gastrectomy (LADG) is increasingly being used as an alternative to open distal gastrectomy (ODG) for gastric cancer treatment. Retrospective studies have shown equivalent survival with the two procedures, but these studies are limited by selection bias because LADG is more technically difficult than ODG. We aimed to evaluate whether LADG was non-inferior to ODG in terms of long-term survival outcomes. METHODS: We did an open-label, multicentre, non-inferiority, phase 3 randomised controlled trial at 33 institutions in Japan. Patients aged 20-80 years with histologically confirmed gastric adenocarcinoma (T1N0, T1N1, or T2[MP]N0), clinical stage I, in the middle or lower third of the stomach, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with a body-mass index of less than 30 kg/m2, were randomly assigned (1:1) to receive ODG or LADG. Randomisation was done by telephone, fax, or with a web-based system in the Japan Clinical Oncology Group Data Center; a minimisation method with a random component was used to adjust for institution and clinical stage (IA or IB). Only study-accredited surgeons performed ODG and LADG. The primary endpoint was relapse-free survival and was analysed according to the intention-to-treat principle. The non-inferiority margin (LADG vs ODG) was set at a hazard ratio (HR) of 1·54. The trial was registered with the UMIN Clinical Trials Registry, UMIN000003319. FINDINGS: Between March 15, 2010, and Nov 29, 2013, 921 patients were enrolled and randomly assigned to receive ODG (n=459) or LADG (n=462). 912 (99%) participants had the assigned surgery. 5-year relapse-free survival was 94·0% (95% CI 91·4-95·9) in the ODG group and 95·1% (92·7-96·8) in the LADG group. LADG was non-inferior to ODG for relapse-free survival (HR 0·84 [90% CI 0·56-1·27]), p=0·0075). The most common grade 3 or 4 adverse event was bowel obstruction, occurring in 11 (2%) of 455 patients in the ODG group and five (1%) of 457 patients in the LADG group. There were no treatment-related deaths. INTERPRETATION: This trial supports the non-inferiority of LADG compared with ODG for clinical stage I gastric cancer relapse-free survival, suggesting that LADG should be considered a standard treatment option when performed by experienced surgeons. FUNDING: Japan National Cancer Center, Ministry of Health, Labour and Welfare of Japan, Japan Agency for Medical Research and Development.

Transanal total mesorectal excision of giant villous tumor of the lower rectum with McKittrick-Wheelock syndrome: a case report of a novel surgical approach.

BACKGROUND: McKittrick-Wheelock syndrome (MKWS) is caused by a villous tumor of the rectosigmoid colon with hypersecretion of mucus containing electrolytes. Complete resection of the tumor is needed to cure this disease. Transanal total mesorectal excision (TaTME) is currently a promising treatment for lower rectal tumor because of the reliability of its resection margin especially in bulky tumor. We present this first case report of a TaTME for MKWS with a lower rectal tumor. CASE PRESENTATION: An 81-year-old woman was admitted to our hospital with diarrhea and acute renal failure. Computed tomography and magnetic resonance imaging examinations revealed an 80-mm-sized enhanced tumor located in her lower rectum without lymph node swelling and distant metastasis. A giant villous tumor secreting mucus was seen in the lower rectum to the anal canal during colonoscopy. The result of tumor biopsy was adenocarcinoma. To preserve the anal function and ensure distal margin, we chose TaTME for curative resection. After improving the electrolyte imbalance, TaTME was performed successfully and R0 resection was achieved. There was no sign of recurrence or electrolyte depletion for 1 year after the surgery. CONCLUSION: TaTME could be a promising surgical approach for giant villous tumor with MKWS in the lower rectum.

Short-term surgical outcomes from a phase III study of laparoscopy-assisted versus open distal gastrectomy with nodal dissection for clinical stage IA/IB gastric cancer: Japan Clinical Oncology Group Study JCOG0912.

BACKGROUNDS: No confirmatory randomized controlled trials (RCTs) have evaluated the efficacy of laparoscopy-assisted distal gastrectomy (LADG) compared with open distal gastrectomy (ODG). We performed an RCT to confirm that LADG is not inferior to ODG in efficacy. METHODS: We conducted a multi-institutional RCT. Eligibility criteria included histologically proven gastric adenocarcinoma in the middle or lower third of the stomach, clinical stage I tumor. Patients were preoperatively randomized to ODG or LADG. This study is now in the follow-up stage. The primary endpoint is relapse-free survival (RFS) and the primary analysis is planned in 2018. Here, we compared the surgical outcomes of the two groups. This trial was registered at the UMIN Clinical Trials Registry as UMIN000003319. RESULTS: Between March 2010 and November 2013, 921 patients (LADG 462, ODG 459) were enrolled from 33 institutions. Operative time was longer in LADG than in ODG (median 278 vs. 194 min, p < 0.001), while blood loss was smaller (median 38 vs. 115 ml, p < 0.001). There was no difference in the overall proportion with in-hospital grade 3-4 surgical complications (3.3 %: LADG, 3.7 %: ODG). The proportion of patients with elevated serum AST/ALT was higher in LADG than in ODG (16.4 vs. 5.3 %, p < 0.001). There was no operation-related death in either arm. CONCLUSIONS: This trial confirmed that LADG was as safe as ODG in terms of adverse events and short-term clinical outcomes. LADG may be an alternative procedure in clinical IA/IB gastric cancer if the noninferiority of LADG in terms of RFS is confirmed.

Gastric cancer following total proctocolectomy for colon cancer associated with ulcerative colitis.

Here we report a case of advanced gastric cancer seen after total proctocolectomy for an early colon cancer associated with ulcerative colitis (UC). A 42-year-old man, diagnosed with UC at the age of 21, had undergone total proctocolectomy at the age of 38 for an early ascending colon cancer. Three years later the patient developed tarry stools and epigastric discomfort. Laboratory data showed anemia together with elevated serum p53 antibody. Gastric endoscopy showed thickening folds around a lesion in the stomach body. The pathological diagnosis was poorly differentiated adenocarcinoma with signet-ring cell carcinoma. Total gastrectomy was performed and the resected specimens showed a diffuse infiltrating tumor (scirrhous gastric carcinoma), 11 × 15 cm in size, with multiple lymph node metastases. Histopathological examination revealed diffuse infiltration of cancer cells throughout the gastric wall and invasion of the serosa. Results of cytology on abdominal lavage were positive for cancer cells. Likewise, immunohistochemical staining showed gastric mucin phenotype cancer cells positive for p53. In conclusion, it is important to bear in mind that patients with UC, especially chronically active pancolitis, potentially bear the risk of upper gastrointestinal complications.

[Problems of adjuvant chemotherapy with S-1 for gastric cancer].

From results of ACTS-GC,postoperative adjuvant chemotherapy,administration of S-1 for one year has become the standard for gastric cancer of Stage II and III except T1. We inspected problems of adjuvant chemotherapy by S-1 by dose rate, an adverse event,and compliance. For the period from July 2006 to December 2008,among 41 cases of stage II/stage III gastric cancer, S-1 was as started as adjuvant therapy by for 28 cases (68.3%). Among 14 cases (63.6%) considered able to complete S-1 treatment for one year, 7 cases (31.8%) had to have their dose reduced or their administration schedule changed. No adverse event of grade 3/4 was found, but cancellation or reduced dose was necessary due to anorexia, malaise, diarrhea, severe skin reaction, and leukopenia resulting from myelosuppression. Thirteen patients took no S-1, and two (4.9%) of them took UFT, while 11 cases (26.8%) became a no-treatment follow-up group for reasons of age, coexisting symptoms and other reasons. The problem in the future is to improve compliance, and to establish a treatment strategy for patients who do not meet administration criteria and for patients for whom continuation of drug administration is impossible.

Overexpression of laminin-5 gamma2 chain in clear cell carcinoma of the ovary.

One of the characteristic microscopic features of ovarian clear cell carcinoma (CCC) is the densely hyaline basement membrane material expanding the stroma. The biological significance of this material, however, has remained unclear. Recent studies have shown that laminin-5 (LN-5), a major component of the epithelial basement membrane, plays a more active role in cell migration or tumor invasion. In the present study, 20 CCCs and 5 borderline clear cell tumors were examined for LN-5 expression immunohistochemically, using an antibody against LN-5 gamma2 chain. All of the 20 CCCs showed a focal or diffuse immunoreactivity with the LN-5 gamma2 chain in the tumor stroma; whereas, borderline clear cell tumors rarely showed a stromal immunoreactivity. Cytoplasmic accumulation of the LN-5 gamma2 chain was far less common than stromal accumulation, suggesting an accelerated secretion in CCC. In vitro, CCC cell lines showed a significant increase in cell migration over excessive LN-5, and the migration was blocked by an antibody against integrin alpha3. These results indicate that an interaction between CCC cells and extracellularly accumulated LN-5 is responsible for cell migration and the subsequent stromal invasion of CCC.

Supplemental effects and metabolic fate of crystalline arginine in juvenile shrimp Marsupenaeus japonicus.

Feeding experiments with juvenile kuruma shrimp (Marsupenaeus japonicus) were conducted to understand the effects of supplemental levels of crystalline arginine hydrochloride on the growth and assimilation of arginine. In experiment 1 the juvenile shrimp were maintained on diets with and without arginine supplements. The addition of 3.0% arginine to a casein-based diet was slightly effective in improving the growth of the juveniles. In experiment 2, tracer experiments using [14C] arginine were conducted to clarify the ingestion and assimilation of arginine, 9 and 24 h after feeding, at different levels of supplemental arginine. Tracer experiments showed that the leaching rate of arginine 1 h after feeding ranged from 16 to 26% in the diets with different levels (0, 0.1, 1.5, 3.0 and 6.0%) of supplemental arginine; that is, 74-84% of the given arginine was actually ingested by the shrimp fed the diets. However, with increasing levels of supplemental arginine the incorporation rate of arginine into the whole body decreased and the utilization of absorbed arginine for body protein synthesis was reduced, whereas the excretion of absorbed arginine was increased. Thus, the absorbed arginine was not effectively utilized for body protein synthesis when large amounts of arginine were supplemented to the diets.

Treatment strategy of limited surgery in the treatment guidelines for gastric cancer in Japan.

Surgical practice for gastric cancer in Japan is based on the Gastric Cancer Treatment Guidelines issued in 2001 by the Japanese Gastric Cancer Association. These recommendations list options for treatment of each stage of cancer, with clear distinctions between interventions recommended for routine use and those that should be confined to trial settings until further evidence for their curative potential becomes available. In this review, we discuss standard surgery, local resection, segmental resection, and pylorus-preserving gastrectomy (PPG) as examples of limited resection and describe in detail the indications for limited lymph-node dissection in cases of early-stage gastric cancer. At present, evidence does not support the conclusion that limited surgery is effective for local resection or for improving quality of life. Thus, use of limited surgery should be considered an experimental approach both in Japan and the West. We conclude that surgeons who are familiar with the criteria for selecting surgical procedures should decide on a case-by-case basis which technique is most appropriate. Choices should be made with consideration of the stage of the cancer, invasiveness of the surgical procedure, and the patient's history. For all procedures, the patient must give informed consent and the surgeons must accurately assess the success of the operation after surgery.

Dietary amino acid profiles and growth performance in juvenile kuruma prawn Marsupenaeus japonicus.

To assess the reference dietary amino acid profiles for juvenile kuruma prawn Marsupenaeus japonicus a feeding trial was conducted using six semi-purified diets containing casein-gelatin and pre-coated supplemental crystalline amino acids (CAA) and a control diet containing intact protein (casein-gelatin). Pre-coated CAA were supplemented to the diets to simulate dietary amino acid profiles to those of the prawn egg protein (PEP), prawn larvae whole body protein (PLP), prawn juvenile whole body protein (PJP), squid meal protein (SMP), short-necked clam protein (SNP) and brown fish meal protein (BFP). The result showed that kuruma prawn juveniles are capable of utilizing the pre-coated CAA and higher growth performances were observed in the groups fed the PJP, SMP and the control diets than those fed the PLP, SNP, BFP and PEP diets. The essential amino acid proportions (A/E ratios) of the whole body of kuruma prawn differ slightly when compared with the other penaeids or freshwater prawn. The results suggest that PJP and SMP would be suitable as a reference dietary amino acid profile for juvenile prawn.

Early and late recurrences after gastrectomy for gastric cancer: a multiple logistic regression analysis.

PURPOSE: Although many studies have focused on clinical risk factors for prognosis of patients with surgically treated gastric cancer, little information is available regarding the timing of recurrent malignant disease. The purpose of this study was to determine the factors that are predictive of early and late recurrences after gastrectomy. PATIENTS AND METHODS: We reviewed the hospital records of patients with hisotological proof of gastric cancer who were admitted to Sendai National Hospital during the period from 1985 to 1995. A total of 923 records were examined, and 251 patients with recurrent disease were identified. The patients were divided into an "early recurrence group" consisting of 195 patients (died within one year after surgery) and a "late recurrence group" of 56 patients (died two years or more after surgery). Clinicopathological characteristics were examined, and independent risk factors influencing the timing of recurrence were determined by a multiple logistic regression analysis. RESULTS: The mean tumor size of early recurrence cases was larger than that of late recurrence cases (p=0.0294). Tumors penetrating the serosa with direct invasion to continuous structures were found more frequently in the early recurrence group than in the late recurrence group. The patients with early recurrence showed a higher tendency to have nodal involvement, lymphatic invasion and vascular invasion. The relative risks of early and late recurrences associated with different variables were estimated by a multiple logistic regression method. The following variables were found to be significant risk factors for early recurrence: male gender (p=0.0382), lymph node metastasis (p=0.0016), and vascular invasion (p=0.0006). CONCLUSION: Male patients who have node-positive gastric cancer with vascular invasion have a high risk of early recurrence.

Clinicopathological study for gastric cancer with liver metastasis.

Clinicopathological characteristics, stromal volume (Vvf), nuclear DNA content and cell protein were retrospectively analyzed in order to scrutinize the risk factors of hepatic metastasis from carcinoma of the stomach. We conducted a clinicopathological study of 327 patients with gastric cancer, including 34 patients with liver metastasis (synchronous, 22; metachronous, 12) and 294 patients without liver metastasis. Univariate analysis revealed significant inter-group differences in tumor size (p<0.001), depth of invasion (p<0.001), lymph node metastasis (p<0.001), vascular involvement (p<0.001), lymphatic involvement (p<0.001), peritoneal dissemination (p<0.05), Vvf (p<0.01) and DNA content (p<0.01). Vvf and DNA content were estimated in the liver metastasis group (n=20) and in the group of patients with stage III-IVa carcinoma but without liver metastasis (n=11). In multivariate analysis, only Vvf and DNA content showed significant correlations with liver metastasis (p<0.01). A comparison of Vvf and expression of the amount of interstitial connective tissue showed that there as a significant correlation between them. Our results indicate that gastric cancer with low Vvf and high DNA content carries a high risk of hepatic metastasis. Therefore, mean DNA content and Vvf are useful indices for predicting liver metastasis from gastric carcinoma.

Is tumor size a prognostic indicator for gastric carcinoma?

BACKGROUND: Retrospective studies using multivariate analysis of clinical and pathological features in gastric cancer have identified a number of high-risk, independent prognostic factors. In these clinical features, tumor size can be measured easily before or during the operation without the requirement of any special equipment, but its prognostic value in patients with gastric cancer is unclear. The aim of this study was to review the experience at our institution of gastric adenocarcinoma to determine the influence of tumor size on outcome. PATIENTS AND METHODS: Between January 1985 and December 1995, 697 patients with gastric adenocarcinoma underwent resection of the stomach at the Department of Surgery, Sendai National Hospital, Japan. Data on age, gender, tumor location, structure and size, evidence of local invasion, and type of operation performed for each patient were obtained. The sizes of tumors were derived from measurements made in fresh resected specimens. The patients were divided into three groups: 102 patients with tumors of less than 2 cm in diameter, 392 patients with tumors of 2-7 cm in diameter, and 203 patients with tumors of more than 7 cm in diameter. RESULTS: In these three groups, there were statistical differences in tumor location, macroscopic type, depth of invasion, lymph node metastasis, histological type, lymphatic invasion, vascular invasion and cancer-stromal relationship. Patients with larger tumors had more invasion into the gastric wall in terms of depth of invasion and more frequent lymph node metastasis than did patients with smaller tumors. Histologically, diffuse, scirrhous-type was more common in the larger tumor group. The frequency of lymphatic and vascular permeation in the larger tumor group was higher than that in the other groups. The 5-year survival rates according to tumor size were 94.3% in cases of tumors of less than 2 cm, 75.1% in cases of tumors of 2-7 cm, and 26.3% in cases of tumors of more than 7 cm. Multivariate analysis revealed that the prognosis of gastric cancer patients was affected most by depth of invasion, followed by lymph node metastasis and tumor location. Tumor size is not an independent prognostic factor. CONCLUSION: In conclusion, according to the results of univariate analysis, tumor size is clinically a predictor of survival of patients with gastric cancer. In multivariate analysis, however, it is not an independent factor, and the presence of lymph node metastasis, depth of invasion and tumor location are more important than tumor size.