Tumor Response Predicts Survival Time of Nivolumab Monotherapy for Advanced Gastric Cancer: A Subgroup Analysis of the DELIVER Trial (JACCRO GC-08).

BACKGROUND: This prospective observational study evaluated the real-world effectiveness of nivolumab monotherapy in previously treated advanced gastric cancer (GC). A preplanned 2-year final analysis was performed to confirm survival and tumor behavior with nivolumab monotherapy. PATIENTS AND METHODS: The primary endpoint was overall survival (OS). The data regarding tumor size were prospectively collected and evaluated using the RECIST criteria. Exploratory analyses were performed for survival according to the tumor response and depth of response (DpR) in patients with measurable lesions who were receiving nivolumab monotherapy as third- or later-line therapy. RESULTS: In 487 patients, the median OS and progression-free survival (PFS) were 5.8 (95% CI 5.3-6.9) months and 1.8 (95% CI 1.7-2.0) months, respectively. The response rate (RR) was 14.5% in 282 patients with measurable lesions. In 234 patients treated with third- or later-line, the DpR was found to be associated with PFS and OS in the Spearman analysis (r = 0.55 and 0.44, respectively) as well as using a discrete variable. When the DpR was divided into 5 groups (-20%≥DpR; -20%

Is Prophylactic Splenectomy Necessary for Proximal Advanced Gastric Cancer Invading the Greater Curvature with Clinically Negative Splenic Hilar Lymph Node Metastasis? A Multi-Institutional Cohort Study (YCOG2003).

BACKGROUND: Prophylactic splenectomy for hilar lymph node (#10) dissection has shown no survival benefit for patients with proximal advanced gastric cancer that does not invade the greater curvature. However, the survival benefit of prophylactic splenectomy for proximal advanced gastric cancer invading the greater curvature side, particularly for clinically negative #10 lymph node metastasis (#10[-]) cases remains controversial. METHODS: This multi-institutional retrospective study enrolled 146 consecutive patients with proximal advanced gastric cancers invading the greater curvature side with clinical #10(-) who underwent R0 total gastrectomy. For 33 of these patients, splenectomy was performed, and the remaining 113 underwent spleen-preservation gastrectomy. Short- and long-term results were compared between the splenectomy and spleen-preservation groups, with the incidence of #10 metastasis in the splenectomy group and recurrence in the spleen-preservation group compared. RESULTS: In the splenectomy group, longer operative time, greater blood loss, more frequent postoperative abdominal infection, and longer hospital stay were observed than in the spleen-preservation group. The two groups exhibited no differences in median relapse-free survival time (31.1 vs 59.8 months; P = 0.684) or median overall survival time (64.9 vs 65.1 months; P = 0.765). The pathologic #10 lymph node metastasis rate was 3% in the splenectomy group, and the #10 lymph node recurrence rate was 2.7% in the spleen-preservation group. CONCLUSIONS: Prophylactic splenectomy showed more frequent postoperative morbidities and a longer hospital stay than spleen preservation, without any long-term survival benefits.

Real-world effectiveness of nivolumab in advanced gastric cancer: the DELIVER trial (JACCRO GC-08).

BACKGROUND: There is no large real-world data regarding efficacy and safety of immunotherapy in gastric cancer (GC). Although some tumors can grow rapidly after immunotherapy, the patient proportions and survival outcomes are unclear in GC. METHODS: A multicenter, prospective observational study was performed to evaluate clinical outcomes including survival time, safety, and tumor behavior of nivolumab treatment for patients with advanced GC. Primary endpoint was overall survival (OS), and secondary endpoints included response rate (RR), disease control rate (DCR), progression-free survival (PFS), tumor growth rate (TGR) at first evaluation, and safety. RESULTS: Of 501 enrolled patients, 487 were evaluable (median age 70 years, 71% male, performance status 0/1/2 [42%/44%/14%], 21% HER2-pos, 42% patients with ascites). Median OS was 5.82 months (95% CI 5.29-7.00) with a 1-year survival rate of 30% and median PFS of 1.84 months (95% CI 1.71-1.97). The DCR was 39.4% and the RR was 14.2% (95% CI 10.3-18.8) in 282 patients with measurable lesions. In 219 patients evaluable for TGR, 20.5% were identified as hyperprogressive disease (HPD). OS from the first evaluation of patients with HPD was shorter compared with non-HPD (HR 1.77, 95% CI 1.25-2.51, P = 0.001), but it was not worse than that of patients with progression and non-HPD (HR 1.05, 95% CI 0.72-1.53, P = 0.8). A multivariate analysis revealed the presence of peritoneal metastasis was a prognostic factor for OS and PFS. CONCLUSIONS: Our real-world data demonstrated the comparable survival time to a previous clinical trial and revealed the frequency and prognosis of patients with HPD in advanced GC treated with nivolumab.

[Successful Postoperative Recurrence Treatment of Malignant Melanoma of the Esophagus by Anti-PD-1 and Anti-CTLA-4 Combined Therapy-A Case Report].

Malignant melanoma of the esophagus is extremely rare and has a poor prognosis. Recently, the efficacy of anti-PD-1 antibody alone or combined with the anti-CTLA-4 antibody has been demonstrated in patients with recurrent or unresectable mucosal malignant melanoma. In this report, we describe a case of postoperative recurrent malignant melanoma of the esophagus treated using combined anti-PD-1 and anti-CTLA-4 antibodies, which resulted in long-term survival. The patient was a 64-year-old man who developed liver metastasis and left mediastinal lymph node recurrence 1 year and 2 months after resection of Stage Ⅱ malignant melanoma of the middle thoracic esophagus. After 4 courses of nivolumab and ipilimumab combined therapy, maintenance therapy with nivolumab alone was continued, and the patient survived for 47 months. During the disease course, the neutrophil/lymphocyte ratio(NLR)and lymphocyte/monocyte ratio(LMR)show - ed a trend reflecting the tumor status. Additionally, sIL-2R/%Ly was monitored as a new biomarker and seemed to be useful for disease assessment.

[Monitoring Blood Markers to Predict Nivolumab Effectiveness in Esophageal Carcinoma].

We investigated whether monitoring the neutrophil-lymphocyte ratio(NLR)and serum interleukin 2 receptor-%lymphocyte ratio(sIL-2R/%Ly)could predict nivolumab(NIVO)effectiveness in treating 9 patients with esophageal cancer. The progression-free survival(PFS)was 292±44 days and overall survival(OS)was 456±136 days. One patient who had chemotherapy intolerance and switched to NIVO achieved CR, and the others had PD. Four patients had irAEs, which did not correlate with the treatment response. Patients with pretreatment low sIL-2R/%Ly and no NLR increase during treatment had significantly longer OS and better prognosis. Therefore, host parameters, such as NLR, sIL-2R, and lymphocyte counts, were significant in the real time monitoring of NIVO therapy for esophageal carcinoma.

[A case of choroidal metastasis from postoperative esophagogastric junctional adenocarcinoma treated with local radiotherapy and systemic chemotherapy with ramucirumab].

An 80-year-old male was presented with metamorphopsia of the left eye. Two years ago, the patient was diagnosed with an esophagogastric junction (EGJ) adenocarcinoma with Barrett's esophagus. The patient subsequently underwent esophagectomy with esophagogastrostomy followed by two-field lymphadenectomy. The pathological stage of the tumor was pT1bN0M0, pStage I, tub1-2, ly1, and v0. The human epidermal growth factor receptor type 2 score was 1 plus. The patient experienced an uncomplicated recovery after being discharged from the hospital with no recurrences for the next 28 months. However, follow-up computed tomography performed at the time of the complaint of metamorphopsia of the left eye revealed systemic metastasis. An ophthalmologic evaluation showed an elevated lesion on the left fundus. Finally, brain magnetic resonance imaging indicated choroidal metastases from an EGJ adenocarcinoma. When the left eye was treated with radiotherapy combined with S-1 and oxaliplatin, complete response for choroidal metastasis and partial response for systemic metastasis were achieved. Due to early diagnosis and treatment, the patient's eyesight was salvaged. Furthermore, the availability and contribution of ramucirumab, an angiogenesis inhibitor used as a second line of treatment for advanced gastric cancer, to choroidal metastasis following irradiation-controlled hemorrhagic tumor was explored.

High postoperative neutrophil-lymphocyte ratio and low preoperative lymphocyte-monocyte ratio predict poor prognosis in gastric cancer patients receiving gastrectomy with positive lavage cytology: a retrospective cohort study.

BACKGROUND: Long-term outcomes in gastric cancer patients with positive lavage cytology (CY1) are generally poor. This multi-institutional retrospective cohort study aims to evaluate the clinical significance of the neutrophil-lymphocyte ratio (NLR) and the lymphocyte-monocyte ratio (LMR) in CY1 gastric cancer patients. METHODS: A total of 121 CY1 gastric cancer patients without other non-curative factors, who underwent macroscopically curative resection, were enrolled in this study. The cutoff values of preoperative NLR (pre-NLR), postoperative NLR (post-NLR), preoperative LMR (pre-LMR), and postoperative LMR (post-LMR) were defined by the Contal and O'Quigley method as 2.3, 3.0, 2.5, and 3.2, respectively. A Cox proportional hazard model was used to identify the independent prognostic factors among NLR, LMR, and other clinicopathological factors. RESULTS: There were significant differences in the overall survival (OS) between the two groups: high post-NLR groups vs. low post-NLR group (median survival time, months) (10.9 vs. 22.8, P = 0.006) and high pre-LMR group vs. low pre-LMR group (21.3 vs. 11.0, P = 0.001). The LMR value elevated significantly after gastrectomy (P = 0.020), although not in the NLR value (P = 0.733). On multivariate analysis, high post-NLR (hazard ratio = 1.506; 95% confidence interval = 1.047-2.167; P = 0.027), low pre-LMR (1.773; 1.135-2.769, 0.012), and no postoperative chemotherapy (1.558; 1.053-2.305, 0.027) were found to be independent prognostic factors for adverse OS. CONCLUSIONS: Because a combination of high post-NLR and low pre-LMR may be an adverse prognostic marker in resectable CY1 gastric cancer patients, it is necessary to conduct a prospective trial to confirm a useful perioperative chemotherapeutic regimen for these patients.

[A case of gastric cancer treated with nivolumab in which the sIL-2R/ lymphocyte ratio changed with tumor status].

A 90-year-old woman diagnosed with stage IV gastric cancer (pT4a[SE]N2M1 [P, CY1]) after distal gastrectomy for her tarry stool was treated with S-1 monotherapy for 7 months, nab-PTX monotherapy for 3 months, and wPTX+RAM therapy for 3 months. Ascending colon tumor was revealed as peritoneal recurrence treated via right hemicolectomy. The nivolumab therapy was started as the fourth treatment. As the tumor progressed, sIL-2R, a destruction product of regulatory T cell surface antigens, tended to increase and the lymphocyte count tended to decrease, with the sIL-2R/lymphocyte count ratio changing in parallel with CA19-9. Throughout the course after gastrectomy, NLR increased and LMR decreased as the tumor status and general condition worsened.

Biweekly S-1 plus oxaliplatin (SOX) reintroduction in previously treated metastatic colorectal cancer patients (ORION 2 study): a phase II study to evaluate the efficacy and safety.

BACKGROUND: The reintroduction of oxaliplatin as a third-or-later-line regimen has been a promising option for patients with metastatic colorectal cancer (mCRC) who previously received chemotherapy including oxaliplatin. In this single-arm phase II study, we evaluated the efficacy of biweekly SOX, which is the combination of oxaliplatin reintroduction and S-1, as a third-or-later-line treatment. METHODS: Patients with mCRC who had previously received prior chemotherapy including oxaliplatin and irinotecan and were planned to receive the reintroduction of oxaliplatin were enrolled. Oxaliplatin (85 mg/m2) with/without bevacizumab (5 mg/kg) was given intravenously on day 1. Oral S-1 was administered on day 2-8 at a dose of 40-60 mg (calculated according to the body surface area) twice a day. Cycles were repeated every 2 weeks. The primary endpoint was the progression-free survival (PFS); our hypothesis was that the median PFS would be 3.5 months with a minimum threshold above 2.0 months. The secondary endpoints included the adverse events (AEs), response rate and overall survival (OS). RESULTS: A total of 41 patients from 12 institutes were enrolled. The median PFS and OS survival were 3.3 months (95% confidence interval [CI] 2.7-4.2) and 10.1 months (8.3-14.6), and response rate and disease control rate were 10.0% and 65.0%, respectively. Grade 3 AEs included thrombocytopenia (5.0%), anorexia (5.0%), pneumonia (5.0%) and fatigue (5.0%). There were no cases of grade 4 AEs or treatment-related death. CONCLUSION: Biweekly SOX regimen with reintroduction of oxaliplatin could be exploitable as the third- and/or later-line treatments for patients with mCRC.

A phase II trial of capecitabine plus cisplatin (XP) for patients with advanced gastric cancer with early relapse after S-1 adjuvant therapy: XParTS-I trial.

BACKGROUNDS: In Japan, standard regimens for advanced gastric cancer (AGC) include S-1 chemotherapy. The standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine alone is platinum-based chemotherapy, while the standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine plus platinum is second-line chemotherapy. To evaluate the efficacy and safety of capecitabine plus cisplatin (XP) treatment for AGC patients who relapse within 6 months after S-1-based therapy, we conducted a multicenter phase II trial (NCT01412294). METHODS: HER2-negative gastric cancer patients treated with adjuvant chemotherapy including S-1 for more than 12 weeks and relapsed within 6 months were treated with capecitabine 1000 mg/m2 bid for 14 days plus cisplatin 80 mg/m2 on day 1 of a 3-week cycle. The primary endpoint was PFS; secondary endpoints were OS, time to treatment failure, overall response rate (ORR) and safety. RESULTS: Forty patients (median age 64) were enrolled; of those, 37 (92.5%) received adjuvant S-1 monotherapy. Median PFS was 4.4 months (95% CI 3.6-5.1), which was longer than the 2-month protocol-specified threshold (p < 0.001). Median OS was 13.7 months (95% CI 9.0-17.7) and ORR was 8/30 (26.7%) (95% CI 14.2-44.4). Most common grade ≥ 3 adverse events were neutropenia (23%), anemia (18%), elevated serum creatinine (18%), fatigue (13%), diarrhea (7.5%), and anorexia (7.5%). CONCLUSIONS: XP was safe and effective in patients with early relapse after S-1 adjuvant chemotherapy for curatively resected gastric cancers. XP may be a good option for the treatment of patients after early failure after adjuvant S-1. TRIAL REGISTRATION: NCT01412294.

Randomized phase II study of daily and alternate-day administration of S-1 for advanced gastric cancer (JFMC43-1003).

PURPOSE: Although S-1 based chemotherapy for patients with advanced gastric cancer has generally been accepted in Japan, discontinuations of treatment have been reported due to grade 3 or more adverse events. The present randomized phase II study was conducted to test whether alternate-day administration of S-1 would be comparably efficient and reduce adverse events compared with conventional daily administration in the first-line chemotherapy for advanced gastric cancer. METHODS: 132 patients with advanced gastric cancer were randomly assigned to 1:2 ratios to receive treatment with daily at a standard dose of 80 mg/m2/day or alternate-day administration group received S-1 on 4 days a week. The primary end point was progression-free survival (PFS), and the secondary end points were safety, overall survival, time to treatment failure (TTF), disease control rate, and response rate. RESULTS: The 6-month PFS rate of the alternate-day administration group was 20.9% and failed to show significant difference from the pre-specified threshold at 15% (p = 0.117), whereas that of the daily administration group was 39.1% and significantly higher than the threshold (p = 0.001). The hazard ratio of the alternate-day administration group compared with the daily administration group was 1.753 (95% confidence interval (CI) 1.15-2.68, p = 0.010). With regard to OS, the hazard ratio of the alternate-day administration group compared with the daily administration group was 1.487 (95% CI 0.97-2.29, p = 0.072). The median TTF were 4.2 and 2.8 months in the daily and alternate-day administration group, respectively (p = 0.007). CONCLUSION: The alternate-day administration of S-1 was not recommended as the first-line therapy for patients with advanced gastric cancer.

Assessment of postoperative quality of life following pylorus-preserving gastrectomy and Billroth-I distal gastrectomy in gastric cancer patients: results of the nationwide postgastrectomy syndrome assessment study.

BACKGROUND: Pylorus-preserving gastrectomy (PPG) is increasingly being used to treat early gastric cancer in the middle third of the stomach, with the hope of ameliorating postoperative dysfunction and improving quality of life (QOL). We evaluated symptoms of postgastrectomy syndrome (PGS) and QOL by means of a newly developed integrated questionnaire, the Postgastrectomy Syndrome Assessment Scale-45 (PGSAS-45), and compared PPG with Billroth-I distal gastrectomy (DGBI). METHODS: The PGSAS-45 consists of 45 items, including items from the SF-8 and GSRS instruments, as well as 22 newly selected items. It was designed to assess the severity of PGS and the living status and QOL of gastrectomized patients. The nationwide PGSAS surveillance study enrolled 2,368 gastric cancer patients who underwent various types of gastrectomy. In this study we analyzed 313 PPG patients and 909 DGBI patients. RESULTS: Body weight loss was -6.9% in the PPG group and -7.9% in the DGBI group (P = 0.052). The PPG group scored better on the diarrhea subscale (PPG; 1.8 vs. DGBI; 2.1, P < 0.0001), dumping subscale (1.8 vs. 2.0, P = 0.003), and frequency of additional meals (1.8 vs. 1.9, P = 0.034). Multiple regression analysis revealed that age and the preservation of the celiac branch of the vagus nerve were independent factors predicting diarrhea and dumping. CONCLUSIONS: It has been suggested that PPG is superior to DGBI for ameliorating PGS. Preservation of the celiac branch of the vagus nerve is recommended to reduce postoperative disorders regardless of the reconstruction method used.

Specific Features of Dumping Syndrome after Various Types of Gastrectomy as Assessed by a Newly Developed Integrated Questionnaire, the PGSAS-45.

AIM: Dumping syndrome is a well-known adverse outcome after gastrectomy, but the precise clinical features have not been described. The aim of this study was to examine global aspects of dumping syndrome and to explore factors affecting the intensity of dumping syndrome in a large cohort using a newly developed integrated questionnaire, the Post-Gastrectomy Syndrome Assessment Scale (PGSAS)-45. METHODS: Eligible questionnaires retrieved from 2,368 patients after 6 types of gastrectomy were analyzed. The incidence, intensity and number of symptoms of early general, early abdominal and late dumping syndrome were examined across various types of gastrectomy, and clinical factors affecting the intensity of each category of dumping syndrome were identified by multiple regression analysis. RESULTS: Dumping syndromes occurred most frequently and strongly in patients who underwent total gastrectomy with Roux-en-Y (TGRY), followed by proximal gastrectomy (PG), distal gastrectomy with Billroth-I, distal gastrectomy with Roux-en-Y, pylorus-preserving gastrectomy (PPG) and local resection (LR), in that order. Significant positive correlations among different categories of dumping syndromes were observed. TGRY, female sex, younger age, division of the celiac branch of the vagus nerve, PG and shorter postoperative period were independently related to worse dumping syndrome. CONCLUSIONS: Dumping syndromes were most common after TGRY and least common after PPG and LR among the various gastrectomy procedures. Type of gastrectomy and several clinical factors were related to the intensity of dumping syndrome. PGSAS-45 could offer a useful tool for evaluating dumping syndrome after gastrectomy.

Characteristics and clinical relevance of postgastrectomy syndrome assessment scale (PGSAS)-45: newly developed integrated questionnaires for assessment of living status and quality of life in postgastrectomy patients.

BACKGROUND: Lack of a suitable instrument to comprehensively assess symptoms, living status, and quality of life in postgastrectomy patients prompted the authors to develop postgastrectomy syndrome assessment scale (PGSAS)-45. METHODS: PGSAS-45 consists of 45 items in total: 8 items from SF-8, 15 items from GSRS, and an additional 22 items selected by 47 gastric surgeons. Using the PGSAS-45, a multi-institutional survey was conducted to determine the prevalence of postgastrectomy syndrome and its impact on everyday life among patients who underwent various types of gastrectomy. Eligible data were obtained from 2,368 patients operated and followed at 52 institutions in Japan. Of these, data from 1,777 patients were used in the current study in which symptom subscales of the PGSAS-45 were determined. We also considered the characteristics of the postgastrectomy syndrome and to what extent these symptoms influence patients' living status and quality of life (QOL). RESULTS: By factor analysis, 23 symptom-related items of PGSAS-45 were successfully clustered into seven symptom subscales that represent esophageal reflux, abdominal pain, meal-related distress, indigestion, diarrhea, constipation, and dumping. These seven symptom subscales and two other subscales measuring quality of ingestion and dissatisfaction for daily life, respectively, had good internal consistency in terms of Cronbach's α (0.65-0.88). CONCLUSION: PGSAS-45 provides a valid and reliable integrated index for evaluation of symptoms, living status, and QOL in gastrectomized patients.

Long-term quality-of-life comparison of total gastrectomy and proximal gastrectomy by postgastrectomy syndrome assessment scale (PGSAS-45): a nationwide multi-institutional study.

BACKGROUND: Although proximal gastrectomy (PG) is widely accepted as a function-preserving operation for early upper-third gastric cancer, postoperative disorders, such as reflux or gastric stasis, have often been pointed out. From the perspective of postoperative disorder, the choice of total gastrectomy (TG) or PG for such cancers is still controversial. By using the newly developed Postgastrectomy Syndrome Assessment Scale (PGSAS)-45, the quality of life after TG and PG was compared. METHODS: The PGSAS-45 consists of 45 items composed of the SF-8 and GSRS scales and 22 new items. The main outcomes are measured by seven subscales (SS) covering symptoms, physical and mental component summary (SF-8), meals (amount and quality), ability to work, dissatisfaction for daily life, and change in body weight. A total of 2,368 eligible questionnaires were acquired from 52 institutions. From these, 393 patients with TG and 193 patients with PG were selected and compared. RESULTS: The PG was better than TG in terms of body weight loss (TG 13.8% vs. PG 10.9%; p = 0.003), necessity for additional meals (2.4 vs. 2.0; p < 0.001), diarrhea SS (2.3 vs. 2.0; p = 0.048), and dumping SS (2.3 vs. 2.0; p = 0.043). There were no differences in the other main outcome measures. CONCLUSIONS: Proximal gastrectomy appears to be valuable as a function-preserving procedure for early upper-third gastric cancer.

Optimal Roux-en-Y reconstruction after distal gastrectomy for early gastric cancer as assessed using the newly developed PGSAS-45 scale.

PURPOSE: The optimal surgical procedure for distal gastrectomy with Roux-en-Y reconstruction (DGRY) remains to be determined. Recently, a self-report assessment instrument, the Postgastrectomy Syndrome Assessment Scale-45 (PGSAS-45), was compiled to evaluate symptoms, the living status and the quality of life of patients who have undergone gastrectomy. We used this scale to evaluate procedures used for DGRY. METHODS: The subjects included 475 patients who underwent DGRY for stage IA/IB gastric cancer. We evaluated whether the size of the remnant stomach, length of the Roux limb, reconstruction route and anastomotic procedure affected the patients' symptoms, living status and quality of life assessed using the PGSAS-45. RESULTS: Patients with a residual stomach of more than half had significantly worse esophageal reflux scores than the patients with a smaller residual stomach (P = 0.0462); a residual stomach of one-third or one-fourth was favorable. A shorter length of the Roux limb was shown to be preferable to a longer Roux limb based on the results of the PGSAS-45. In addition, antecolic reconstruction and the anastomotic procedure using a linear stapler were found to be more favorable. CONCLUSIONS: The size of the remnant stomach and the length and route of the Roux limb significantly influence the patient-reported DGRY outcomes.

Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial.

BACKGROUND: The prognosis for locally advanced gastric cancer is poor despite advances in adjuvant chemotherapy. We did the Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) to assess the superiority of sequential treatment (paclitaxel then tegafur and uracil [UFT] or paclitaxel then S-1) compared with monotherapy (UFT or S-1) and also the non-inferiority of UFT compared with S-1. METHODS: We did this randomised phase 3 trial with a two-by-two factorial design at 230 hospitals in Japan. We enrolled patients aged 20-80 years with T4a or T4b gastric cancer, who had had D2 dissection and a ECOG performance score of 0-1. Patients were randomly assigned to one of four treatment groups with minimisation for tumour size, lymph node metastasis, and study site. Patients received UFT only (267 mg/m(2) per day), S-1 only (80 mg/m(2) per day) for 14 days, with a 7-day rest period or three courses of intermittent weekly paclitaxel (80 mg/m(2)) followed by either UFT, or S-1. Treatment lasted 48 weeks in monotherapy groups and 49 weeks in the sequential treatment groups. The primary endpoint was disease-free survival assessed by intention to treat. We assessed whether UFT was non-inferior to S-1 with a non-inferiority margin of 1·33. This trial was registered at UMIN Clinical Trials Registry, number C000000082. FINDINGS: We randomly assigned 1495 patients between Aug 3, 2004, and Sept 29, 2009. 374 patients were assigned to receive UFT alone, 374 to receive S-1 alone, 374 to received paclitaxel then UFT, and 373 to receive paclitaxel then S-1. We included 1433 patients in the primary analysis after at least 3 years of follow-up (359, 364, 355, and 355 in each group respectively). Protocol treatment was completed by 215 (60%) patients in the UFT group, 224 (62%) in the S-1 group, 242 (68%) in the paclitaxel then UFT group, and 250 (70%) in the paclitaxel then S-1 group. 3-year disease-free survival for monotherapy was 54·0% (95% CI 50·2-57·6) and that of sequential treatment was 57·2% (53·4-60·8; hazard ratio [HR] 0·92, 95% CI 0·80-1·07, p=0·273). 3-year disease-free survival for the UFT group was 53·0% (95% CI 49·2-56·6) and that of the S-1 group was 58·2% (54·4-61·8; HR 0·81, 95% CI 0·70-0·93, p=0·0048; pnon-inferiority=0·151). The most common grade 3-4 haematological adverse event was neutropenia (41 [11%] of 359 patients in the UFT group, 48 [13%] of 363 in the S-1 group, 46 [13%] of 355 in the paclitaxel then UFT group, and 83 [23%] of 356 in the paclitaxel then S-1 group). The most common grade 3-4 non-haematological adverse event was anorexia (21 [6%], 24 [7%], seven [2%], and 18 [5%], respectively). INTERPRETATION: Sequential treatment did not improve disease-free survival, and UFT was not non-inferior to S-1 (and S-1 was superior to UFT), therefore S-1 monotherapy should remain the standard treatment for locally advanced gastric cancer in Japan. FUNDING: Epidemiological and Clinical Research Information Network.

Early-onset diffuse gastric cancer associated with a de novo large genomic deletion of CDH1 gene.

A 41-year-old man with no familial history of gastric cancer was diagnosed as with intramucosal early gastric cancer. Two months after the first endoscopic submucosal dissection for signet-ring cell carcinoma (SRCC), the appearance of previously unrecognized multiple erosions of SRCC was noticed. Pathological examination after a total gastrectomy and Roux-en-Y reconstruction with D2 lymph node dissection were performed. Postoperative pathological examination revealed 90 and more lesions, which tempted the attending pathologist to refer to genetic tests for the predisposition though the patient had no familial history of gastric cancer. There were no mutations in all the exons of CDH1 with conventional DNA sequencing, but multiplex ligation-dependent probe amplification, and reverse transcription-polymerase chain reaction analyses disclosed a large genomic deletion (c.1566-?_1711+?del), leading to the mRNA with loss of the exon 11. Among family members, his son was found to be a carrier of this change, while his parents were negative for the familial CDH1 mutation, implying that this change is a de novo event in the proband. The present report is the first description of a de novo large genomic deletion of CDH1 gene associated with early-onset diffuse gastric cancer. When the clinician finds a relatively-young patient who has multiple SRCCs, CDH1 germline mutation should be considered, even for patients with no familial history.

Nanowarming of vitrified pancreatic islets as a cryopreservation technology for transplantation.

Biobanking of pancreatic islets for transplantation could solve the shortage of donors, and cryopreservation of vitrified islets is a possible approach. However, a technological barrier is rewarming of large volumes both uniformly and rapidly to prevent ice formation due to devitrification. Here, we describe successful recovery of islets from the vitrified state using a volumetric rewarming technology called "nanowarming," which is inductive heating of magnetic nanoparticles under an alternating magnetic field. Convective warming using a 37°C water bath as the gold standard for rewarming of vitrified samples resulted in a decrease in the viability of mouse islets in large volumes (>1 ml) owing to devitrification caused by slow warming. Nanowarming showed uniform and rapid rewarming of vitrified islets in large volumes. The viability of nanowarmed islets was significantly improved and islets transplanted into streptozotocin-induced diabetic mice successfully lowered serum glucose. The results suggest that nanowarming will lead to a breakthrough in biobanking of islets for transplantation.

Long-term Outcomes of Neoadjuvant Chemotherapy With Docetaxel, Cisplatin and S-1 for Stage III Gastric Cancer.

BACKGROUND/AIM: In the previous phase I/II study, we established neoadjuvant chemotherapy (NAC) using bi-weekly docetaxel, cisplatin, and S-1 (DCS) for clinical stage III gastric cancer. This study aimed to clarify long-term outcomes of this treatment. PATIENTS AND METHODS: Relapse-free survival (RFS) and overall survival (OS) were calculated by the Kaplan-Meier method and prognostic factors for RFS and OS were identified by univariate analysis. RESULTS: A total of 47 patients with clinical stage III gastric cancer were enrolled in this study. The 5-year RFS and OS rates were 69.8% and 74.3%, respectively, in all registered patients. Moreover, the 5-year OS and RFS rates in patients receiving R0 gastrectomy were 68.0% and 79.4%, respectively. Neutrophil-lymphocyte ratio (NLR) before NAC ≥2.41, prognostic nutritional index (PNI) before NAC ≤50.4, Glasgow prognostic score before NAC classification 2, NLR after NAC ≥1.43, PNI after NAC <48.0, and Grade 1a/1b pathological response significantly worsened RFS. NLR after NAC ≥1.43, PNI before NAC ≤50.4, NLR after NAC ≥1.43, and body weight loss >5 kg after NAC significantly worsened OS. CONCLUSION: Although bi-weekly DCS therapy as neoadjuvant setting showed acceptable long-term outcomes, poor immune-nutritional status before and after NAC caused worse long-term survival in stage III gastric cancer patients. It is warranted to conduct a well-designed prospective randomized control study to compare long-term outcomes using the bi-weekly DCS regimen between patients with and without immune-nutritional support during peri-NAC.