K-ras gene mutation analysis to diagnosis pancreatic adenocarcinoma from endoscopic ultrasound-guided tissue acquisition; a systematic review and meta-analysis.

BACKGROUND: Endoscopic ultrasound-guided tissue acquisition (EUS-TA) has high sensitivity for the pathological diagnosis of pancreatic masses, but also a high false-negative rate. K-ras gene mutations occur in over 75 % of pancreatic ductal adenocarcinomas (PDAC), and this meta-analysis evaluated the utility of detecting K-ras gene mutations from EUS-TA specimens for the diagnosis of PDAC. METHODS: Relevant studies in PubMed, the Cochrane Library, and Web of Science were systematically searched. Meta-analysis was performed on data from the selected studies using a bivariate model to provide pooled values of sensitivity, specificity, and their 95 % confidence intervals (CIs). RESULTS: This meta-analysis included 1521 patients (from 10 eligible studies) who underwent EUS-TA with K-ras gene mutation analysis for diagnosis of pancreatic solid masses. The pooled estimates of sensitivity and specificity were 76.6 % (95 % CI, 70.9-81.5 %) and 97.0 % (95 % CI, 94.0-98.5 %), respectively, for pathological diagnosis, 75.9 % (95 % CI 69.5-81.4 %) and 95.3 % (95 % CI, 92.3-97.2 %) for K-ras gene mutation analysis, and 88.7 % (95 % CI 87.1-91.7 %) and 94.9 % (95 % CI, 91.5-97.0 %) for pathological diagnosis in combination with K-ras gene mutation analysis. The sensitivity for diagnosis of PDAC was significantly higher for pathological diagnosis in combination with K-ras gene mutation analysis than for pathological diagnosis or K-ras gene mutation analysis alone (both, p < 0.001). There was no difference in specificity between pathological diagnosis in combination with K-ras gene mutation analysis and both either (p = 0.234, 0.945, respectively). CONCLUSIONS: K-ras gene mutation analysis in combination with to pathological diagnosis of EUS-TA increases the accuracy of differential diagnosis of PDAC.

Efficacy of the traction method for gastric endoscopic submucosal dissection: a randomized controlled trial (with videos).

BACKGROUND AND AIMS: To overcome the technical difficulties associated with gastric endoscopic submucosal dissection (ESD), a novel traction device that can alter the direction of traction was developed. This study compared the efficacy and safety of conventional ESD versus those of traction-assisted gastric ESD. METHODS: Patients with a single gastric epithelial neoplasm were randomized to receive conventional (n = 75) or traction-assisted (n = 73) gastric ESD. The primary outcome was ESD procedure time. RESULTS: There were no differences between the conventional and traction-assisted groups with respect to treatment results or adverse events. The mean procedure time was similar for both groups (78.9 vs 88.3 minutes, respectively; P = .3); however, times for the traction device tended to be shorter for lesions in the lesser curvature of the upper or middle stomach (84.6 vs 123.2 minutes; P = .057). CONCLUSIONS: Traction-assisted ESD for lesions in the lesser curvature of the upper or middle stomach were shorter, thereby reducing the procedure time of conventional ESD. (Clinical trial registration: University Hospital Medial Information Network Clinical Trials Registry, identifier 000044450.).

Adverse events of self-expandable metal stent placement for malignant distal biliary obstruction: a large multicenter study.

BACKGROUND AND AIMS: Endoscopic placement of self-expandable metal stents (SEMSs) for malignant distal biliary obstruction (MDBO) may be accompanied by several types of adverse events. The present study analyzed the adverse events occurring after SEMS placement for MDBO. METHODS: The present study retrospectively investigated the incidence and types of adverse events in patients who underwent SEMS placement for MDBO between April 2018 and March 2021 at 26 hospitals. Risk factors for acute pancreatitis, cholecystitis, and recurrent biliary obstruction (RBO) were evaluated by univariate and multivariate analyses. RESULTS: Of the 1425 patients implanted with SEMSs for MDBO, 228 (16.0%) and 393 (27.6%) experienced early adverse events and RBO, respectively. Pancreatic duct without tumor involvement (P = .023), intact papilla (P = .025), and SEMS placement across the papilla (P = .037) were independent risk factors for acute pancreatitis. Tumor involvement in the orifice of the cystic duct was an independent risk factor for cholecystitis (P < .001). Use of fully and partially covered SEMSs was an independent risk factor for food impaction and/or sludge. Use of fully covered SEMSs was an independent risk factor for stent migration. Use of uncovered SEMSs and laser-cut SEMSs was an independent risk factor for tumor ingrowth. CONCLUSIONS: Pancreatic duct without tumor involvement, intact papilla, and SEMS placement across the papilla were independent risk factors for acute pancreatitis, and tumor involvement in the orifice of the cystic duct was an independent risk factor for cholecystitis. The risk factors for food impaction and/or sludge, stent migration, and tumor ingrowth differed among types of SEMSs.

Safety of skipping the tract dilation step for EUS-guided biliary drainage in patients with unresectable malignant biliary obstruction (with video).

BACKGROUND: Thin delivery system stents can be inserted directly without the need for a tract dilation step and are expected to reduce bile leakage during endoscopic ultrasound-guided biliary drainage (EUS-BD). The present study retrospectively compared the safety and efficacy of EUS-BD using a thin metal stent (< 7.5 Fr) with those of EUS-BD using a conventional stent (≥ 7.5 Fr). METHODS: The present study enrolled 112 patients who underwent EUS-BD using metal stents for unresectable malignant biliary obstruction between April 2016 and July 2022. The primary endpoint was the rate of adverse events (AEs). The secondary endpoints were clinical success rate, procedure time, procedure success rate in the absence of the tract dilation step, recurrent biliary obstruction rate, time to biliary obstruction, and overall survival. Risk factors associated with early AEs were also evaluated. RESULTS: The rate of early AEs was significantly lower (12% vs. 35%, P = 0.013) and the procedure success without the tract dilation step was significantly higher (82% vs. 33%, P < 0.001) in the thin than in the conventional delivery system stent group. None of the other secondary endpoints differed significantly between the two groups. Multivariate analysis showed that employing the tract dilation step during EUS-BD was a significant independent risk factor for early AEs (skipping vs. employing; HR, 9.66; 95% CI, 1.13-83.0, P = 0.028). CONCLUSION: Employing the tract dilation step during EUS-BD was a significant risk factor for early AEs. Metal stents with a delivery diameter < 7.5 Fr can be inserted directly without the tract dilation step, resulting in lower early AE rates.

Phase II study of S-1 plus docetaxel as first-line treatment for older patients with advanced gastric cancer (OGSG 0902).

BACKGROUND: Although there is insufficient evidence for the treatment of older patients with advanced gastric cancer, fluorouracil combined with platinum chemotherapy has been recognized as a standard first-line treatment for such populations in Japan despite the lack of efficacy and toxicity data. METHODS: Patients aged 75 years or older with advanced gastric cancer were enrolled. S-1 plus docetaxel (docetaxel: 40 mg/m2, day 1; S-1: 80 mg/m2, days 1-14; q21 days) was repeated every 3 weeks. The primary endpoint was overall response rate. Secondary endpoints were safety, progression-free survival, time to treatment failure, and overall survival. The sample size was calculated as 30 under the hypothesis of an expected response rate of 40% and a threshold response rate of 20%, at a power of 90% and a two-sided alpha value of 5%. RESULTS: From February 2010 to January 2015, 31 patients were enrolled and assessed for efficacy and toxicity. The response rate was 45.2% (95% CI 27.3%-64.0%; p = 0.001) and it exceeded the expected response rate set at 40%. Median progression-free survival was 5.8 months, the 1-year survival rate was 58.1%, and the median survival time was 16.1 months. The major grade 3/4 adverse events were neutropenia (58%), febrile neutropenia (13%), anemia (10%), anorexia (10%), and fatigue (6%). CONCLUSIONS: These findings indicate that S-1 plus docetaxel as first-line treatment for older patients is feasible and that it has promising efficacy against advanced gastric cancer.

Effects of postoperative oral elemental nutritional supplement on skeletal muscle loss after gastrectomy for gastric cancer.

BACKGROUND: We previously showed that daily nutritional intervention with an oral elemental diet (ED) at 300 kcal/day for 6-8 weeks postoperatively decreased the percentage of body weight loss (%BWL), and that the effect was maintained for 1 year. This post hoc analysis aimed to determine whether this intervention decreased skeletal muscle mass loss 1-year post-gastrectomy. METHODS: Data from consecutive, untreated patients with histopathologically confirmed stage I-III gastric adenocarcinoma who planned to undergo total gastrectomy (TG) or distal gastrectomy (DG) and were enrolled in a previously published randomized trial were used. The primary endpoint was the percentage of skeletal muscle mass index (%SMI) loss from baseline at 1 year postoperatively, based on abdominal computed tomography images obtained preoperatively and at 1 year postoperatively. RESULTS: The overall median %SMI loss was lower in the ED versus control group, but the difference was not significant. The difference in %SMI loss in the ED and control groups was greater in patients with TG (10.1 vs. 13.0; P = 0.12) than in those with DG (5.5 vs. 6.8; P = 0.69). A correlation was observed between %BWL and %SMI loss in both groups (ED group, coefficient 0.591; control group, coefficient 0.644; P < 0.001 for both). Type of gastrectomy (coefficient 7.38; P = 0.001) and disease stage (coefficient - 6.43; P = 0.04) were independent predictors of postoperative skeletal muscle mass loss. CONCLUSION: ED administration for 6-8 weeks following gastrectomy had no inhibitory effect on skeletal muscle loss at 1 year postoperatively. CLINICAL TRIAL REGISTRATION: UMIN000023455.

Impact of sarcopenia on recurrent biliary obstruction after EUS-guided biliary drainage in patients with malignant biliary obstruction.

BACKGROUND AND AIMS: Sarcopenia is an important prognostic factor for cancer patients. The aim of this study was to assess the ability of sarcopenia to predict recurrent biliary obstruction (RBO) in patients with unresectable cancer after EUS-guided biliary drainage (EUS-BD). METHODS: The study enrolled 113 patients who underwent EUS-BD using the self-expandable metal stent (SEMS) for unresectable malignant biliary obstruction (MBO) between April 2016 and December 2021 at Wakayama Medical University Hospital. The skeletal muscle index at the third lumbar spine level (L3) was calculated from computed tomography images. We analyzed the cumulative incidence of RBO at 180 days after stent insertion. Univariate and multivariate analyses were performed to identify variables significantly associated with RBO. RESULTS: Seventy-six patients were assigned to the sarcopenia group, and 37 were assigned to the non-sarcopenia group. The 180-day cumulative incidence of RBO was 11% in the non-sarcopenia group and 29% in the sarcopenia group (p = 0.034). The time to RBO was significantly shorter for the sarcopenia group (p = 0.028; Gray's test). Multivariate analyses identified sarcopenia as an independent prognostic factor for RBO (present vs absent; HR 4.61; 95% CI 1.76-12.10, p = 0.001). The rates of biliary sludge/food impaction were significantly higher in the sarcopenia group for the causes of RBO (p = 0.048). There were no significant differences between the sarcopenia and the non-sarcopenia groups with respect to related EUS-BD adverse events. CONCLUSION: Sarcopenia is an independent indicator of RBO in patients with MBO who receive EUS-BD with SEMS.

The Phase II Study of Panitumumab in Chemotherapy-Naïve Frail or Elderly Patients with RAS Wild-type Colorectal Cancer: OGSG 1602 Final Results.

BACKGROUND: We previously reported the response rate of a phase II OGSG1602 study on panitumumab in chemotherapy-naive frail or elderly patients with RAS wild-type unresectable colorectal cancer (CRC) [Terazawa T, Kato T, Goto M, et al. Oncologist. 2021;26(1):17]. Herein, we report a survival analysis. METHODS: Patients aged ≥65 years and considered unsuitable for intensive chemotherapy or aged ≥76 years were enrolled. Primary tumors located from the cecum to the transverse colon were considered right-sided tumors (RSTs); those located from the splenic flexure to the rectum were considered left-sided tumors (LSTs). RESULTS: Among the 36 enrolled patients, 34 were included in the efficacy analysis, with 26 and 8 having LSTs and RSTs, respectively. The median progression-free survival (PFS) and overall survival (OS) were 6.0 [95% CI, 5.4-10.0] and 17.5 months (95% CI, 13.8-24.3), respectively. Although no significant differences existed in PFS between patients with LST and RST {6.6 (95% CI, 5.4-11.5) vs. 4.9 months [95% CI, 1.9-not available (NA), P = .120]}, there were significant differences in OS [19.3 (95% CI, 14.2-NA) vs.12.3 months (95% CI, 9.9-NA), P = .043]. CONCLUSION: Panitumumab showed favorable OS in frail or elderly patients with RAS wild-type CRC and no prior exposure to chemotherapy. Panitumumab may be optimal for patients with LSTs (UMIN Clinical Trials Registry Number UMIN000024528).

Afatinib plus osimertinib in the treatment of osimertinib-resistant non-small cell lung carcinoma: a phase I clinical trial.

BACKGROUND: Conquering acquired resistance to osimertinib remains a major challenge in treating patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Thus, we aimed to determine the safety and efficacy of combination treatment with osimertinib and afatinib for patients with acquired resistance to osimertinib. METHODS: This open-label phase I study was a feasibility study of the combination of afatinib and osimertinib for patients with advanced EGFR-positive NSCLC who had progressive disease after receiving osimertinib. The primary endpoint was to determine the maximum tolerated dose (MTD). We enrolled patients who received afatinib at three different dose levels (level 1, 20 mg; level 2, 30 mg; level 3, 40 mg) combined with osimertinib at a standard dose of 80 mg once per day. RESULTS: Thirteen patients were enrolled in this study. The MTD was defined as 30 mg afatinib when combined with daily oral administration of osimertinib (80 mg). The most frequent adverse events were diarrhea (76.9%), anemia (76.9%), and rash (69.2%). Considering the toxicity profiles during all treatment periods, the recommended oral dose of afatinib was determined as 20 mg daily, with an osimertinib dose of 80 mg. For all evaluable patients (n = 12), the response rate was 7.7% and the disease-control rate was 46.2%. CONCLUSION: Combination therapy with osimertinib and afatinib was tolerable; however, the synergistic effect of afatinib with osimertinib may be limited in osimertinib-resistant patients. TRIAL REGISTRATION: Japan Registry of Clinical Trials ID: jRCTs051180008, registered date: 08/11/2018.

Shear-wave versus strain elastography in endoscopic ultrasound for the diagnosis of chronic pancreatitis.

BACKGROUND: /Objectives: Endoscopic ultrasound (EUS) elastography is a non-invasive diagnostic method for evaluating tissue elasticity. The aims of this study were to compare shear-wave elastography (SWE) and conventional strain elastography (SE) in determination of the diagnosis and degree of chronic pancreatitis (CP). METHODS: Forty-nine patients who underwent computed tomography (CT), EUS-SWE, EUS-SE, and pancreatic exocrine function testing between January 2019 and January 2022 were prospectively evaluated. CP was diagnosed according to Japan Pancreatic Society criteria (JPSC) 2019, Rosemont criteria (RC), CT findings, and pancreatic exocrine dysfunction. The cut-off values, sensitivity, and specificity for CP diagnosed according to the four criteria were calculated for EUS-SWE and EUS-SE. Relationships between values measured by either of the EUS elastography methods and the number of EUS features were also assessed. RESULTS: EUS-SWE values were positively correlated with the severity grades of RC and JPSC, but EUS-SE values were not. EUS-SWE was significantly better than EUS-SE for diagnosing CP defined according to CT findings (area under the receiver operating characteristics curve [AUROC]: 0.77 vs. 0.61, P < 0.001), RC (AUROC: 0.85 vs. 0.56, P < 0.001), JPSC 2019 (AUROC: 0.83 vs. 0.53, P < 0.001), and exocrine dysfunction (AUROC: 0.78 vs. 0.61, P < 0.001). EUS-SWE values were positively correlated with the number of EUS features, but EUS-SE values were not. CONCLUSIONS: EUS-SWE provides objective assessment for diagnosing and assessing the degree of CP defined according to the criteria of CT findings, RC, JPSC, or exocrine dysfunction, and it can be considered a non-invasive diagnostic tool for CP and exocrine dysfunction.

Rule ensemble method with adaptive group lasso for heterogeneous treatment effect estimation.

The increasing scientific attention given to precision medicine based on real-world data has led to many recent studies clarifying the relationships between treatment effects and patient characteristics. However, this is challenging because of ubiquitous heterogeneity in the treatment effect for individuals and the real-world data on their backgrounds being complex and noisy. Because of their flexibility, various machine learning (ML) methods have been proposed for estimating heterogeneous treatment effect (HTE). However, most ML methods incorporate black-box models that hamper direct interpretation of the relationships between an individual's characteristics and treatment effects. This study proposes an ML method for estimating HTE based on the rule ensemble method RuleFit. The main advantages of RuleFit are interpretability and accuracy. However, HTEs are always defined in the potential outcome framework, and RuleFit cannot be applied directly. Thus, we modified RuleFit and proposed a method to estimate HTEs that directly interpret the relationships among the individuals' features from the model. Actual data from an HIV study, the ACTG 175 dataset, was used to illustrate the interpretation based on the ensemble of rules created by the proposed method. The numerical results confirm that the proposed method has high prediction accuracy compared to previous methods, indicating that the proposed method establishes an interpretable model with sufficient prediction accuracy.

Effect of the number of cycles of docetaxel + S-1 therapy on long-term survival in adjuvant chemotherapy for stage III gastric cancer. A pooled analysis of the OGSG0604 and OGSG1002 trials.

BACKGROUND: S-1 plus docetaxel (DS) therapy followed by S-1 is the standard of care in Japan in postoperative adjuvant chemotherapy for stage III gastric cancer, but long-term survival and the number of DS cycles required are unclear. The purpose of this study was to investigate the impact of the number of cycles of DS therapy on the 5-year survival in stage III gastric cancer in a pooled analysis of two phase II trials (OGSG0604 and OGSG1002). PATIENTS AND METHODS: Patients with histologically confirmed stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were enrolled in this pooled analysis. They received DS therapy for four or eight cycles, followed by S-1 until 1 year postgastrectomy. The 5-year overall survival (OS) and the 5-year disease free survival (DFS) by the landmark analysis was evaluated. RESULTS: In total, 113 patients from the OGSG0604 and OGSG1002 trials were enrolled in this study. The landmark analysis showed a 5-year OS that was better with four to eight cycles of DS therapy than with one to three cycles of DS therapy, with the best 5-year OS of 77.4% (95% confidence interval, 66.5-90.1%) for eight cycles. The 5-year DFS was approximately 66% when four or eight cycles of DS therapy were given. CONCLUSION: Although eight cycles of DS therapy may prolong prognosis, the present study did not provide a clear conclusion as to how many DS therapy cycles are needed to improve prognosis after D2 gastrectomy for stage III gastric cancer. TRIAL REGISTRATION: Registration number: UMIN00000714 and UMIN000004440.

Long-term outcomes of a phase II study of neoadjuvant imatinib in large gastrointestinal stromal tumors of the stomach.

BACKGROUND: Neoadjuvant treatment is recommended for large GISTs due to their friability and risk of extensive operations; however, studies on the indications and long-term results of this approach are lacking. METHODS: Patients with large (≥ 10 cm) gastric GISTs were enrolled from multiple centers in Korea and Japan after a pathologic confirmation of c-KIT ( +) GISTs. Imatinib (400 mg/d) was given for 6-9 months preoperatively, and R0 resection was intended. Postoperative imatinib was given for at least 12 months and recommended for 3 years. RESULTS: A total of 56 patients were enrolled in this study, with 53 patients receiving imatinib treatment at least once and 48 patients undergoing R0 resection. The 5-year overall survival and progression-free survival rates were 94.3% and 61.6%, respectively. Even patients with stable disease by RECIST criteria responded well to preoperative imatinib treatment and could undergo R0 resection, with most being evaluated as partial response by CHOI criteria. The optimal reduction in tumor size was achieved with preoperative imatinib treatment for 24 weeks or more. No resumption of imatinib treatment was identified as an independent prognostic factor for recurrence after R0 resection. No additional size criteria for a higher risk of recurrence were identified in this cohort with a size of 10 cm or more. CONCLUSIONS: Neoadjuvant imatinib treatment is an effective treatment option for gastric GISTs 10 cm or larger. Postoperative imatinib treatment is recommended even after R0 resection to minimize recurrence.

Uncovered versus covered expandable metal stents for malignant gastric outlet obstruction caused by intrinsic and extrinsic tumors: meta-analysis and meta-regression analysis.

BACKGROUND AND AIMS: Malignant gastric outlet obstruction (GOO) can be palliated by endoscopic placement of self-expandable metal stents (SEMSs). Studies comparing uncovered (USEMSs) and covered (CSEMSs) SEMSs have yielded inconclusive results. This meta-analysis compared USEMSs with CSEMSs in patients with GOO caused by intrinsic and extrinsic tumors. METHODS: Potentially relevant articles were identified by searching PubMed, the Cochrane Library, and Medline. The primary outcome was stent dysfunction. Relationships between characteristics of tumors causing GOO and the stent dysfunction rate following USEMSs and CSEMS placement were assessed. RESULTS: Overall, six randomized controlled trials and 12 observational studies, including 2431 patients, were identified. Rate of stent dysfunction did not differ significantly between USEMSs and CSEMSs (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.73-1.25, I2 = 44%), but there was heterogeneity. Meta-regression analysis showed that heterogeneity of stent dysfunction was caused by a difference in the ratio of intrinsic-to-extrinsic tumors causing GOO between studies (coefficient, 0.944; 95% CI, 0.30-1.58). Studies were divided into intrinsic and extrinsic tumor groups. Subgroup analysis showed that the stent dysfunction rate did not differ between USEMSs and CSEMSs in the intrinsic tumor group (OR, 1.10; 95% CI, 0.85-1.41; I2 = 32%). In the extrinsic tumor group, USEMS was associated with a lower rate of stent dysfunction than CSEMS (OR, 0.64; 95% CI, 0.47-0.87; I2 = 25%). CONCLUSION: USEMS and CSEMS placement generally showed comparable outcomes among patients with GOO. USEMS was more effective than CSEMS for patients with GOO caused by extrinsic tumors.

Gastrojejunostomy versus endoscopic duodenal stent placement for gastric outlet obstruction in patients with unresectable pancreatic cancer: a propensity score-matched analysis.

BACKGROUND: Treatments for patients with gastric outlet obstruction (GOO) due to unresectable pancreatic cancers (URPC) include gastrojejunostomy (GJJ) and endoscopic duodenal stent placement (EDSP). This study compared the efficacy and safety of GJJ and EDSP in patients with GOO due to URPC. METHODS: This study retrospectively evaluated consecutive patients with GOO due to URPC who underwent GJJ or EDSP between April 2016 and March 2020. The efficacy and safety of GJJ and EDSP were compared with propensity score analysis. Subgroup analyses of overall survival (OS) were compared after propensity matching. RESULTS: Data were obtained from 54 patients who underwent GJJ and from 73 who underwent EDSP at five tertiary care hospitals. After propensity matching, OS was significantly longer in patients who underwent GJJ than EDSP (110 vs. 63 days, respectively; p = 0.019). Evaluation of long-term adverse events showed that the frequency of cholangitis and obstructive jaundice was significantly lower in the matched GJJ than in the matched EDSP group (p = 0.012). Subgroup analyses showed that OS in patients with good performance status (PS; p = 0.041), biliary obstruction (p = 0.007), and duodenal obstruction near the papilla (p = 0.027), and those receiving chemotherapy (p = 0.010), was significantly longer in the matched GJJ group than in matched EDSP group. CONCLUSION: GJJ provides longer OS than EDSP for patients with GOO caused by URPC, especially for patients with good PS, biliary obstruction, and duodenal obstruction near the papilla, and those receiving chemotherapy.

A prospective analysis of optimal total weight gain ranges and trimester-specific weight gain rates for Chinese pregnant women.

BACKGROUND: Gestational weight gain (GWG) criteria recommended by the Institute of Medicine may not be appropriate for Asians. Our aims are to investigate the association between GWG and adverse pregnancy outcomes, and to propose optimal total GWG and rates of GWG for Chinese women. METHODS: Prospective data of 51,125 mother-child pairs from 27 hospitals and community health care centers from Guizhou, Yunnan and Sichuan provinces in China between 2014 and 2018 were analyzed. Generalized Additive Models were performed to determine the associations of GWG with the risk of aggregated adverse outcomes (gestational diabetes mellitus, preeclampsia, cesarean delivery, stillbirth, preterm birth, macrosomia, large for gestational age, and small for gestational age). The range that did not exceed a 2.5% increase from the lowest risk of aggregated adverse outcomes was defined as the optimal GWG range. RESULTS: Among all participants, U-shaped prospective association was found between GWG and the risk of aggregated adverse pregnancy outcomes. The optimal GWG range of 8.2-13.0 kg was proposed for underweight, 7.3-12.5 kg for normal weight, and 2.0-9.4 kg for overweight/obese women. Meanwhile, a higher GWG rate in the first two trimesters than that in the last trimester was suggested, except for overweight/obese women. After stratified by maternal age, mothers ≥35 years were suggested to gain less weight compared to younger mothers. CONCLUSIONS: To keep a balance between maternal health and neonatal growth, optimal GWG ranges based on Asia-specific BMI categories was suggested for Chinese women with different pre-gravid BMIs and maternal ages.

Phase I dose-escalation study on irinotecan, cisplatin, and S-1 combination in chemotherapy-naïve patients with HER2-negative advanced gastric cancer (HERBIS-4B, OGSG 1106).

BACKGROUND: The development of triplet regimens for advanced gastric cancer is challenging. The aim of this phase I dose-escalation study was to determine the maximum tolerated dose and recommended dose of the combination of irinotecan, cisplatin, and S-1 in chemotherapy-naïve patients with HER2-negative advanced gastric cancer. METHODS: The 3 + 3 design was adopted. Every 4 weeks, patients received an escalating dose of intravenous irinotecan (100-150 mg/m2) on day 1 and fixed doses of intravenous cisplatin (60 mg/m2) on day 1 and oral S-1 (80 mg/m2) on days 1 to 14. RESULTS: Twelve patients were enrolled in two dose level cohorts. In the level 1 cohort (irinotecan 100 mg/m2, cisplatin 60 mg/m2, and S-1 80 mg/m2), dose-limiting toxicity including grade 4 neutropenia and febrile neutropenia occurred in one of six patients, whereas in the level 2 cohort (irinotecan 125 mg/m2, cisplatin 60 mg/m2, and S-1 80 mg/m2), dose-limiting toxicities including grade 4 neutropenia developed in two of six patients. Thus, the level 1 and 2 doses were determined to be the recommended and maximum tolerated doses, respectively. Common grade 3 or higher adverse events were neutropenia (75%; n = 9), anemia (25%; n = 3), anorexia (8%; n = 1), and febrile neutropenia (17%; n = 2). Irinotecan, cisplatin, and S-1 combination therapy achieved an overall response rate of 67% with a median progression-free survival and overall survival of 19.3 and 22.4 months, respectively. CONCLUSIONS: The potential treatment efficacy of this triplet regimen in HER2-negative advanced gastric cancer warrants further evaluation, especially in patients requiring intensive chemotherapy.

Meta-analysis of three randomized trials of capecitabine plus cisplatin (XP) versus S-1 plus cisplatin (SP) as first-line treatment for advanced gastric cancer.

BACKGROUND: S-1 plus cisplatin (SP) and capecitabine plus cisplatin (XP) are standard first-line regimens for advanced gastric cancer (AGC) worldwide. We conducted a meta-analysis using individual participant data (IPD) to investigate which is more suitable. METHODS: IPD from three randomized trials were collected. In these trials, patients with AGC were randomly allocated to SP (S-1 80-120 mg for 21 days plus cisplatin 60 mg/m2 (q5w)) or XP (capecitabine 2000 mg/m2 for 14 days plus cisplatin 80 mg/m2 (q3w)). RESULTS: In 211 eligible patients, median overall survival (OS) for SP versus XP was 13.5 and 11.7 months (hazard ratio [HR], 0.787; p = 0.114), progression-free survival (PFS) was 6.2 and 5.1 months (HR, 0.767; P = 0.076), and TTF was 5.1 and 4.0 months (HR, 0.611; P = 0.001). The most common grade ≥ 3 adverse events with SP or XP were neutropenia (18% vs. 29%) and anorexia (16% vs.18%). Subgroup analysis demonstrated significant interaction between treatment effect and performance status > 1 (HR, 0.685; P = 0.036), measurable lesion (HR, 0.709; P = 0.049), primary upper third tumor (HR, 0.539; P = 0.040), and differentiated type (HR, 0.549; interaction, 0.236; P = 0.019). For the differentiated type, OS was significantly longer in the SP group (13.2 months) than in the XP group (11.1 months) (HR, 0.549; P = 0.019). For the undifferentiated type, OS was similar in the SP group (14.2 months) and in the XP group (12.4 months) (HR, 0.868; P = 0.476). CONCLUSIONS: SP and XP were both effective and well tolerated. SP might be suitable for the pathological differentiated subtype of AGC. CLINICAL TRIAL REGISTRATION: The HERBIS-2, HERBIS-4A, and XParTS II trials were registered with UMIN-CTR as UMIN000006105, UMIN000006755, and UMIN000006045, respectively.

Skin-to-Renal Pelvis Distance Predicts Costovertebral Angle Tenderness in Adult Patients with Acute Focal Bacterial Nephritis.

OBJECTIVES: The aim of this study was to examine whether the distance between the skin and the renal pelvis affects the detection of costovertebral angle (CVA) tenderness in patients with acute focal bacterial nephritis (AFBN). METHODS: We retrospectively reviewed the charts of our patients between April 2013 and June 2019 who were diagnosed as having AFBN. Diagnosis was based on ultrasound or computed tomography with contrast, revealing at least one wedge-shaped area of decreased vascularity and confirmation of fever not attributable to another condition. RESULTS: We extracted 23 cases, all Japanese (mean age 60.0 years old [range 45-81 years], 7 males, 16 females). CVA tenderness was present in 8 of these 23 patients. Receiver operating characteristic curves were drawn to evaluate the ability to differentiate skin-to-renal pelvis distance (SPD), body mass index, and age. Only SPD was a useful predictor of CVA tenderness, and 66 mm was determined as the optimal cutoff point (area under the receiver operating characteristic curve 0.858, 95% confidence interval 0.70-1.00). Logistic regression analysis was performed with CVA tenderness as a dependent variable, and SPD, body mass index, and age as explanatory variables. SPD was an independent predictive variable of CVA tenderness (P = 0.038, odds ratio 0.76, 95% confidence interval 0.590-0.986). CONCLUSIONS: CVA tenderness showed low yield in the diagnosis of AFBN in patients with longer SPD. Its use for diagnosis in obese patients may therefore be limited.

Three-Year Outcomes of a Phase II Study of Perioperative Capecitabine Plus Oxaliplatin Therapy for Clinical SS/SE N1-3 M0 Gastric Cancer (OGSG 1601).

BACKGROUND: We previously reported the good feasibility and favorable efficacy of perioperative capecitabine plus oxaliplatin (CapeOx) in patients (pts) with clinical T3(SS)/T4a(SE) N1-3 M0 gastric cancer (GC) in a phase II study in which the pathological response rate, the primary endpoint, of 54.1% was demonstrated. Here, we report 3-year follow-up data. METHODS: The eligibility criteria included clinical T3(SS)/T4a(SE) N1-3 M0 GC according to the Japanese Classification of Gastric Carcinoma-3rd English Edition (JCGC). Three cycles of neoadjuvant CapeOx (capecitabine, 2000mg/m2 for 14 days; oxaliplatin, 130mg/m2 on day 1, every 3 weeks) were administered, followed by 5 cycles of adjuvant CapeOx after D2 gastrectomy. Three-year overall survival and relapse-free survival are presented here, and analyzed by cohorts based on pathologic response rate (pRR). RESULTS: Thirty-seven pts were enrolled from July 2016 to May 2017, and fully evaluated for efficacy and toxicity. Thirty-three pts (89.2%) completed the planned three cycles of neoadjuvant CapeOx and underwent gastrectomy, with an R0 resection rate of 78.4% (n = 29). The overall survival (OS) rate and relapse-free survival (RFS) rate at 3 years was 83.8% (95% CI, 72.7-96.5%) and 73.0% (95% CI, 60.0-88.8%), respectively. Further, the 3-year OS rate in pts with pathological response of grade 1a (n = 13) and grade 1b or higher (n = 20) was 69.2% (95% CI: 48.2-99.5%) and 100.0%, respectively, based on JCGC. Pathological response rate was classified according to JCGC as follows: grade 0, the tumor was not affected; grade 1a, less than one-third of the tumor was affected; grade 1b, one to two thirds of the tumor was affected; grade 2, greater than or equal to two thirds was affected; and grade 3, no residual tumor. A pathological response was defined as grade 1b or greater. CONCLUSION: Perioperative CapeOx showed good feasibility and favorable prognosis, especially in pts with pathological response of grade 1b or higher and was found to be useful in predicting prognosis. The data obtained using this novel approach warrant further investigation (Trial ID: UMIN000021641, jRCTs051180109).