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%

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.

A Multicenter, Phase II Trial of Schedule Modification for Nab-Paclitaxel in Combination with Ramucirumab for Patients with Previously Treated Advanced Gastric or Gastroesophageal Junction Cancer: The B-RAX Trial (JACCRO GC-09).

BACKGROUND: This study investigated whether schedule modification of bi-weekly nanoparticle albumin-bound paclitaxel (nab-PTX) plus ramucirumab (RAM) is efficacious against gastric cancer (GC) or gastroesophageal junction cancer (GJC). PATIENTS AND METHODS: Patients with unresectable GC or GJC who were previously treated with fluoropyrimidine-containing regimens received nab-PTX (100 mg/m2) on days 1, 8, and 15 and RAM (8 mg/kg) on days 1 and 15 of a 28-day cycle. Based on the incidence of severe adverse events (AEs) during the first cycle, patients were modified to bi-weekly therapy from the second cycle. The primary endpoint was progression-free survival (PFS) in the bi-weekly therapy population. Based on the hypothesis that bi-weekly nab-PTX plus RAM would improve PFS from 4.5 to 7.0 months, 40 patients were required for power of 0.8 with a one-sided α of 0.05. RESULTS: Of the 81 patients enrolled, 47 patients (58%) were assigned to bi-weekly therapy. Patient characteristics were Eastern Cooperative Oncology Group performance status of 1 (19%) and diffuse type (45%). Median PFS was 4.7 months (95% confidence interval [CI] 3.7-5.6 months) and overall response rate was 25% (95% CI 11-39%). Severe AEs of grade 3 or worse were mainly neutropenia (83%) and hypertension (23%). EQ-5D scores were maintained during the treatment. In patients who continued standard-schedule therapy, median PFS was 2.7 months (95% CI 1.8-4.0 months). CONCLUSIONS: The primary endpoint for PFS was statistically not met, but modification of nab-PTX plus RAM to a bi-weekly schedule might be a feasible treatment option as second-line treatment for advanced GC/GJC patients, especially elderly patients, with severe AEs during the first cycle.

Soluble programmed cell death ligand 1 predicts prognosis for gastric cancer patients treated with nivolumab: Blood-based biomarker analysis for the DELIVER trial.

BACKGROUND: The clinical value of soluble forms of programmed cell death-1 (sPD-1), PD ligand 1 (sPD-L1) and cytotoxic T lymphocyte-associated protein-4 (sCTLA-4) for gastric cancer (GC) patients treated with nivolumab monotherapy has remained unknown. METHODS: Blood samples collected before nivolumab treatment from 439 GC patients enrolled in the DELIVER (Japan Clinical Cancer Research Organisation GC-08) trial were analysed for sPD-1, sPD-L1 and sCTLA-4. Corresponding baseline clinical data were also retrieved. RESULTS: Higher plasma levels of sPD-1 (hazard ratio [HR] = 1.27, p = 0.020), sPD-L1 (HR = 1.86, p < 0.001) and sCTLA-4 (HR = 1.33, p = 0.008) were significantly associated with shorter overall survival (OS), whereas only higher sPD-L1 levels was significantly associated with shorter progression-free survival (HR = 1.30, p = 0.008). The sPD-L1 concentration was significantly associated with the Glasgow prognostic score (GPS) (p < 0.001), but both sPD-L1 (HR = 1.67, p < 0.001) and GPS (HR = 1.39, p = 0.009 for GPS 0 versus 1; HR = 1.95, p < 0.001 for GPS 0 versus 2) were independently associated with OS. Patients with a GPS of 0 and low sPD-L1 thus showed the longest OS (median, 12.0 months) and those with a GPS of 2 and high sPD-L1 showed the shortest OS (median, 3.1 months), yielding a HR of 3.69 (p < 0.001). CONCLUSION: Baseline sPD-L1 levels have the potential to predict survival for advanced GC patients treated with nivolumab, with the prognostic accuracy of sPD-L1 being improved by its combination with GPS.

[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.

[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.

[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.

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.

Evaluation of postgastrectomy symptoms and daily lives of small remnant distal gastrectomy for upper-third gastric cancer using a large-scale questionnaire survey.

Aim: Total gastrectomy (TG) is often performed for proximal gastric cancer. Small remnant distal gastrectomy (SRDG) can also be used in cases where surgical margins can be secured. The impact of preserving proximal small remnant stomach on postoperative quality of life (QOL) has not been fully elucidated. In the present study, we compared postgastrectomy symptoms and daily lives between patients undergoing SRDG and those undergoing TG for proximal gastric cancer using the developed Postgastrectomy Syndrome Assessment Scale (PGSAS)-45. Methods: Of the 1909 patients enrolled in the PGSAS NEXT study, univariate analysis of 19 main outcomes measures (MOMs) of PGSAS-45 was performed in patients undergoing TG (n = 1020) or SRDG (n = 54). Multiple regression analysis was performed with several clinical factors as explanatory variables. Results: There was no difference in age and sex between TG and SRDG groups. In SRDG group, postoperative period was shorter, the rates of laparoscopic approach and preservation of the celiac branch of the vagus nerve were higher, and the rates of clinical stage III/IV disease, ≥D2 dissection, and combined resection with other organs were lower than in the TG group significantly (P < .05). SRDG was associated with significantly lower symptoms and better daily lives than TG in 12 and 13 of 19 MOMs in PGSAS-45 by univariate and multiple regression analyses, respectively (P < .05). Several other clinical factors were also associated with certain MOMs. Conclusion: The PGSAS-45 revealed that SRDG was associated with better postgastrectomy symptoms and daily lives than TG.

Optimal Procedures for Double Tract Reconstruction After Proximal Gastrectomy Assessed by Postgastrectomy Syndrome Assessment Scale-45.

BACKGROUND: Although double tract reconstruction after proximal gastrectomy (PGDT) is commonly performed for proximal gastric or esophagogastric junction cancer, the impact of the procedure on postoperative quality of life (QOL) has not been clarified. We aimed to clarify the optimal PGDT procedure in terms of postoperative QOL. METHODS: Postoperative QOL was analyzed in 172 patients who underwent PGDT for proximal gastric cancer and were enrolled in the PGSAS-NEXT study, a multicenter cross-sectional study in Japan (UMIN000032221), in relation to the remnant stomach size, length of interposed jejunum between the esophagojejunostomy (E-J) and jejunogastrostomy (J-G), and size of the J-G. RESULTS: The remnant stomach size was approximately one-third in 13, half in 97, and two-thirds in 60 patients. Dissatisfaction scores for symptoms, diet, work, and daily life subscales were lower in patients with a larger stomach (p < 0.05). These patients also scored better in terms of weight loss (- 13.5%, - 14.0%, and - 11.2%, respectively) and amount of food ingested per meal (52%, 62%, and 66%). The length of the interposed jejunum was ≤ 10 cm in 62 and ≥ 11 cm in 97 patients. Weight loss (- 11.3% and - 13.8%) and dissatisfaction scores were better in the ≤ 10 cm group (p < 0.05). J-G size was ≤ 5 cm in 27 and ≥ 6 cm in 135 patients. The amount of food ingested (56%, 64%) and dissatisfaction scores were better in the > 6 cm group (p < 0.05). CONCLUSIONS: Larger remnant stomach, shorter length of interposed jejunum, and longer J-G might contribute to better postoperative QOL after PGDT.

Time interval after various types of gastrectomy until metachronous multiple gastric cancer: Analysis of data from a nationwide Japanese survey.

The factors influencing the time interval from the initial surgery for gastric cancer to the detection of metachronous multiple gastric cancer (MMGC) remain to be elucidated. The present study was performed to evaluate the association between the type of initial gastrectomy or reconstruction procedure and the time interval from initial gastrectomy to the detection of MMGC. A questionnaire survey on remnant stomach cancer was performed by the Japanese Society for Gastro-Surgical Pathophysiology in 2018. Participating facilities were requested to indicate the number of patients who underwent surgery for MMGC between 2003 and 2017, in association with the time interval from the initial gastrectomy until treatment for MMGC by type of initial gastrectomy or reconstruction procedure. Analyses were performed using data from 45 facilities. Gastrectomy for MMGC was performed on 1,234 patients during this period. Pylorus-preserving gastrectomy (PPG) accounted for only 3.6% (20/557) of the patients who underwent surgery for MMGC ≥10 years from initial gastrectomy, while PPG accounted for 10.1% (40/396) of patients who underwent surgery for MMGC within 5 years after initial gastrectomy. Billroth-II and Roux-en Y reconstruction accounted for 22.3% (103/462) and 1.3% (6/462), respectively, of patients who underwent surgery for MMGC ≥10 years from initial distal gastrectomy (DG), while such patients accounted for 8.0% (23/286) and 21.7% (65/286), respectively, of patients who underwent surgery for MMGC within 5 years after initial DG. Similarly, the proportion of each reconstruction procedure differed according to the time interval from initial proximal gastrectomy to treatment for MMGC. The types of gastrectomy or reconstruction procedure for initial gastrectomy differed significantly according to the time interval between the initial gastrectomy and treatment for MMGC, and the fact that PPG and R-Y reconstruction in DG is a relatively new method were assumed to be a major cause of these differences.

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.

Defecation disorders are crucial sequelae that impairs the quality of life of patients after conventional gastrectomy.

BACKGROUND: Defecation disorders are obscure sequelae that occurs after gastrectomy, and its implication on daily lives of patients have not been sufficiently investigated. AIM: To examine the features of defecation disorders after gastrectomy and to explore its implication on daily lives of patients in a large cohort using the Postgastrectomy Syndrome Assessment Scale (PGSAS)-45. METHODS: We conducted a nationwide multi-institutional study using PGSAS-45 to examine the prevalence of postgastrectomy syndrome and its impact on daily lives of patients after various types of gastrectomy. Data were obtained from 2368 eligible patients at 52 institutions in Japan. Of these, 1777 patients who underwent total gastrectomy (TG; n = 393) or distal gastrectomy (DG; n = 1384) were examined. The severity of defecation disorder symptoms, such as diarrhea and constipation, and their correlation with other postgastrectomy symptoms were examined. The importance of defecation disorder symptoms on the living states and quality of life (QOL) of postgastrectomy patients, and those clinical factors that affect the severity of defecation disorder symptoms were evaluated using multiple regression analysis. RESULTS: Among seven symptom subscales of PGSAS-45, the ranking of diarrhea was 4th in TG and 2nd in DG. The ranking of constipation was 5th in TG and 1st in DG. The symptoms that correlated well with diarrhea were dumping and indigestion in both TG and DG; while those with constipation were abdominal pain and meal-related distress in TG, and were meal-related distress and indigestion in DG. Among five main outcome measures (MOMs) of living status domain, constipation significantly impaired four MOMs, while diarrhea had no effect in TG. Both diarrhea and constipation impaired most of five MOMs in DG. Among six MOMs of QOL domain, diarrhea impaired one MOM, whereas constipation impaired all six MOMs in TG. Both diarrhea and constipation equally impaired all MOMs in DG. Male sex, younger age, division of the celiac branch of vagus nerve, and TG, independently worsened diarrhea, while female sex worsened constipation. CONCLUSION: Defecation disorder symptoms, particularly constipation, impair the living status and QOL of patients after gastrectomy; therefore, we should pay attention and adequately treat these relatively modest symptoms to improve postoperative QOL.

[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.

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.

Prognostic impact of dimensional factors in pT1 gastric cancer.

BACKGROUND: The significance of the dimensional factors (tumor diameter, area and volume) as the prognostic factor has not been precisely evaluated in pT1 gastric cancer. OBJECTIVES: This study aimed to identify the clinical impact and to confirm the clinical feasibility of the dimensional factors as prognostic factors in pT1 gastric cancer. METHODS: We analyzed prognostic factors for disease-specific survival (DSS), overall survival (OS) using clinicopathological factors by univariate and multivariate analyses and the pattern of recurrence in 2011 pT1 gastric cancer (mucosal and submucosal cancers) undergoing R0 gastrectomy. The cut-off values of each dimensional factor was decided by the ROC curve. RESULTS: Cox proportional hazard regression model showed that older age (≥75) and more advanced pN stage were adverse independent prognostic factors for DSS, and revealed that older age (≥75), greater preoperative co-morbid diseases, proximal and total gastrectomy, operative method and Clavien-Dindo classification (≥grade III) were independent adverse factors for OS. Any dimensional factors were not independent prognostic factors for any survival. CONCLUSIONS: The dimensional factors do not influence both OS and DSS in pT1 gastric cancer patients and so it is difficult to apply these dimensional factors for conducting therapeutic strategies.

Magnetic heating of nanoparticles as a scalable cryopreservation technology for human induced pluripotent stem cells.

Scale-up of production is needed for industrial applications and clinical translation of human induced pluripotent stem cells (hiPSCs). However, in cryopreservation of hiPSCs, successful rewarming of vitrified cells can only be achieved by convective warming of small volumes (generally 0.2 mL). Here, we present a scalable nano-warming technology for hiPSC cryopreservation employing inductive heating of magnetic nanoparticles under an alternating magnetic field. The conventional method by water bath heating at 37 °C resulted in a decrease of cell viability owing to devitrification caused by slow warming of samples with large volumes (≥ 20 mL). Nano-warming showed uniform and rapid rewarming of vitrified samples and improved viability of hiPSCs in the 20-mL system. In addition to single cells, hiPSC aggregates prepared using a bioreactor-based approach were successfully cryopreserved by the nano-warming technique. These results demonstrate that nano-warming is a promising methodology for cryopreservation in mass production of hiPSCs.

Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial.

PURPOSE: S-1 is a standard postoperative adjuvant chemotherapy for patients with stage II or III gastric cancer in Asia. Neoadjuvant or perioperative strategies dominate in Western countries, and docetaxel has recently shown significant survival benefits when combined with other standard regimens in advanced cancer and perioperative settings. PATIENTS AND METHODS: This randomized phase III study was designed to prove the superiority of postoperative S-1 plus docetaxel over S-1 alone for R0 resection of pathologic stage III gastric cancer. The sample size of 1,100 patients was necessary to detect a 7% increase in 3-year relapse-free survival as the primary end point (hazard ratio, 0.78; 2-sided α = .05; ß = .2). RESULTS: The second interim analysis was conducted when the number of events reached 216 among 915 enrolled patients (median follow-up, 12.5 months). Analysis demonstrated the superiority of S-1 plus docetaxel (66%) to S-1 (50%) for 3-year relapse-free survival (hazard ratio, 0.632; 99.99% CI, 0.400 to 0.998; stratified log-rank test, P < .001), and enrollment was terminated as recommended by the independent data and safety monitoring committee. Incidences of grade 3 or greater adverse events, particularly neutropenia and leukopenia, were higher in the S-1 plus docetaxel group, but all events were manageable. CONCLUSION: Addition of docetaxel to S-1 is effective with few safety concerns in patients with stage III gastric cancer. The present findings may also be applicable in countries in which perioperative adjuvant chemotherapy or chemoradiation is not standard.

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.