Prognostic impact of concomitant pH-regulating drugs in patients with non-small cell lung cancer receiving epidermal growth factor receptor tyrosine kinase inhibitors: the Tokushukai REAl-world Data project 01-S1.

PURPOSE: This study aimed to examine the prognostic impact of concomitant pH-regulating drug use in patients with epidermal growth factor receptor (EGFR)-mutation-positive non-small-cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs). METHODS: We conducted a nationwide retrospective cohort study and reviewed clinical data of consecutive patients with NSCLC treated with the first-line EGFR-TKIs in 46 hospitals between April 2010 and March 2020. Cox regression analyses were conducted to examine the differences in overall survival (OS) between patients treated with and without concomitant pH-regulating drugs, including potassium-competitive acid blockers (P-CABs), proton pump inhibitors (PPIs), and H2-receptor antagonists (H2RAs). RESULTS: A total of 758 patients were included in the final dataset, of which 307 (40%) were administered concomitant pH-regulating drugs while receiving frontline EGFR-TKIs. After adjusting for basic patient characteristics, patients administered gefitinib, erlotinib, afatinib, and osimertinib with concomitant pH-regulating drugs had lower OS than those without concomitant pH-regulating drugs, with hazard ratios of 1.74 (with a 95% confidence interval of 1.34-2.27), 1.33 (0.80-2.22), 1.73 (0.89-3.36), and 5.04 (1.38-18.44), respectively. The 2-year OS rates of patients receiving gefitinib with or without concomitant pH-regulating drugs were 65.4 and 77.5%, those for erlotinib were 55.8 and 66.6%, and those for afatinib were 63.2 and 76.9%, respectively. The 1-year OS rates of patients receiving osimertinib with or without concomitant pH-regulating drugs were 88.1% and 96.9%, respectively. CONCLUSION: In addition to the first-generation EGFR-TKIs, the second- and third-generation EGFR-TKIs also resulted in OS deterioration in patients with EGFR mutation-positive NSCLC when used concurrently with pH-regulating drugs.

Inflammation­based prognostic markers of metastatic pancreatic cancer using real­world data in Japan: The Tokushukai REAl­world Data (TREAD) project.

Inflammation-based prognostic markers based on a combination of blood-based parameters, including the modified Glasgow prognostic score (mGPS), have been associated with clinical outcomes in patients with various types of cancer. The present study aimed to evaluate and compare the accuracy of these previously reported markers in patients with metastatic pancreatic cancer receiving first-line chemotherapy. A total of 846 patients were identified between April 2010 and March 2020 as part of a nationwide real-world study from 46 Tokushukai medical group hospitals in Japan. Blood laboratory data collected within 14 days of starting first-line chemotherapy assessed 17 inflammation-based prognostic markers. Information from patients with no missing data was used to compare the accuracy and performance of the inflammation-based prognostic markers. A total of 487 patients were eligible for this supplemental analysis. The 17 inflammation-based markers demonstrated significant prognostic value. Among them, the concordance rate with overall survival (OS) was highest for mGPS. The median OS time of patients with mGPS 0, 1 and 2 was 8.2, 6.0 and 2.9 months, respectively. Compared with mGPS 0, mGPS 1 and 2 showed hazard ratios of 1.39 (95% confidence interval, 1.07-1.81) and 2.63 (2.00-3.45), respectively. The present real-world data analysis showed that various previously reported inflammation-based markers had significant prognostic value in patients with metastatic pancreatic cancer. Among these markers, the mGPS demonstrated the highest level of accuracy. This trial has been registered in the University Hospital Medical Information Network Clinical Trials Registry as UMIN000050590 on April 1, 2023.

Stepwise prolongation of overall survival from first to third generation EGFR-TKIs for EGFR mutation-positive non-small-cell lung cancer: the Tokushukai REAl-world Data project (TREAD 01).

OBJECTIVE: The introduction of new-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has afforded promising overall survival outcomes in clinical trials for non-small-cell lung cancer. We aim to investigate the current adoption rate of these agents and the real-world impact on overall survival among institutions. METHODS: In a nationwide retrospective cohort study of 46 Tokushukai Medical Group hospitals in Japan, we analyzed clinical data of consecutive patients with non-small-cell lung cancer receiving EGFR-TKIs between April 2010 and March 2020. Univariate and multivariate Cox regression analyses examined the associations between overall survival and patient/tumor-related factors and first-line EGFR-TKIs. RESULTS: A total of 758 patients (58.5% females; median age, 73 years) were included. Of 40 patients diagnosed in 2010, 72.5% received gefitinib, whereas 81.3% of 107 patients diagnosed in 2019 received osimertinib as the first-line EGFR-TKI. With a median follow-up of 15.8 months, the median overall survival was 28.4 months (95% confidence interval, 15.3-31.0). In a multivariate Cox regression analysis, age, body mass index, disease status, EGFR mutational status and first-line epidermal growth factor receptor tyrosine kinase inhibitor were identified as significant prognostic factors after adjusting for background factors including study period, hospital volume and hospital type. The estimated 2-year overall survival rates for gefitinib, erlotinib, afatinib and osimertinib were 70.1% (95% confidence interval 59.7-82.4), 67.8% (95% confidence interval 55.3-83.2), 75.5% (95% confidence interval 64.7-88.0) and 90.8% (95% confidence interval 84.8-97.3), respectively. The median time to treatment failure of gefitinib, erlotinib, afatinib and osimertinib were 12.8, 8.8, 12.0 and 16.9 months or more, respectively. CONCLUSIONS: Our real-world data revealed that the swift and widespread utilization of newer-generation EGFR-TKIs in patients with EGFR mutation-positive non-small-cell lung cancer, and that these newer-generation EGFR-TKIs can prolong overall survival regardless of hospital volume or type. Therefore, osimertinib could be a reasonable first choice treatment for these patients across various clinical practice settings.

Real­world treatment outcomes among patients with metastatic pancreatic cancer in Japan: The Tokushukai real­world data project.

The present study aimed to investigate temporal trends in treatment patterns and prognostic factors for overall survival (OS) among patients with metastatic pancreatic cancer. From the Tokushukai REAl-world Data project, 1,093 patients with metastatic pancreatic cancer treated with gemcitabine, tegafur/gimeracil/oteracil (S-1), gemcitabine plus S-1, gemcitabine plus nab-paclitaxel, or fluorouracil, folic acid, oxaliplatin and irinotecan (FOLFIRINOX) between April 2010 and March 2020 were identified. Stratified/conventional Cox regression analyses were conducted to examine associations between patient- and tumor-related factors, study period, hospital volume, hospital type and first-line chemotherapy regimens. Overall, 846 patients were selected (503 male patients; median age, 70 years) after excluding ineligible patients. Over a median follow-up of 5.4 months, the median OS was 6.8 months (95% confidence interval, 6.3-7.4). The median OS for gemcitabine, S-1, gemcitabine plus S-1, gemcitabine plus nab-paclitaxel and FOLFIRINOX regimens was 5.9, 5.3, 7.7, 9.0 and 9.5 months, respectively. The median OS for 2010-2013, 2014-2017 and 2017-2020 was 6.2, 7.1 and 7.8 months, respectively. Performance status, body mass index and first-line chemotherapy regimens were identified to be significant prognostic factors. In summary, the real-world data indicated that standard care, including chemotherapy, for metastatic pancreatic cancer was widely used in hospitals throughout Japan and verified the survival benefits of gemcitabine plus nab-paclitaxel and FOLFIRINOX observed in prior clinical trials. This trial has been registered in the University Hospital Medical Information Network Clinical Trials Registry as UMIN000050590 on April 1, 2023.

Real-World Outcomes of Systemic Therapy in Japanese Patients with Cancer (Tokushukai REAl-World Data Project: TREAD): Study Protocol for a Nationwide Cohort Study.

Cohort studies using large-scale databases have become increasingly important in recent years. The Tokushukai Medical Group is a leading medical group in Japan that includes 71 general hospitals nationwide from Hokkaido to Okinawa, with a total of 18,000 beds, and a unified electronic medical record system. This retrospective cohort study aims to evaluate the real-world outcomes of systemic therapy for Japanese patients with cancer using this merit of scale. All adult patients with cancer who received systemic therapy using a centrally registered chemotherapy protocol system at 46 hospitals from April 2010 to March 2020 will be identified (~48,850 patients). Key exclusion criteria include active double cancer and inadequate data extraction. Data will be obtained through electronic medical records, diagnosis procedure combination data, medical prescription data, and the national cancer registration system that includes sociodemographic variables, diagnostic and laboratory tests, concomitant drug prescriptions, cost, and overall survival. Kaplan-Meier estimates will be calculated for time-to-event analyses. Stratified/conventional Cox proportional hazards regression analyses will be conducted to examine the relationships between overall survival and related factors. Our findings provide important insights for future research directions, policy initiatives, medical guidelines, and clinical decision-making.

A cross-population atlas of genetic associations for 220 human phenotypes.

Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (ntotal = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.

Monitoring the Sequential Organ Failure Assessment score in nonocclusive mesenteric ischemia increases the survival rate: A single-center observational study.

ABSTRACT: Several large-scale studies have assessed the endovascular and surgical treatments for nonocclusive mesenteric ischemia (NOMI); nonetheless, the prognostic factors for NOMI remain unclear.In this single-center study, we retrospectively reviewed the electronic medical records of 197, 149 patients were retrieved from the inpatient database of our hospital from January 2011 to January 2020; 79 patients with NOMI were observed. A total of 44 patients who underwent laparotomy were statistically analyzed and divided into the survivor and non-survivor groups. Prognostic factors were compared between the 2 groups. Exploratory laparotomy based on a second-look surgery was the first treatment choice.The overall mortality rate was 61.3%, with a male-to-female ratio of 1.6:1. The median Sequential Organ Failure Assessment (SOFA) score was 11.06 [5.75-17.25]. The median SOFA score was 5 [interquartile range: 3-8] in the survivor group and 14.8 [interquartile range: 10.5-19] in the non-survivor group. The log-rank test showed a significant difference in the presence of diabetes mellitus (P = .025), hypoglycemia (P = .001), SOFA score ≥10 (P < .001), hemoglobin levels ≥11 g/dL (P = .003), platelet count ≥12.9 × 104/µL (P = .01), lactate levels ≥2.6 mmol/L (P = .005), and base excess <-3.0 (P < .023). Multivariate analysis using the factors with significant differences revealed that SOFA score ≥10 (hazard ratio for death, 1.199; 95% confidence interval, 1.101-1.305; P < .001) was an independent prognostic factor.The SOFA score can be used to assess disease severity. A SOFA score of ≥10 may be associated with increased mortality.

[A Successful Case of Locally Advanced Pancreatic Cancer Undergoing Curative Total Pancreatectomy after Chemotherapy].

A 68-year-old man with jaundice was diagnosed with pancreatic cancer. The tumor seemed to invade the portal vein, the common hepatic artery, and the splenic artery plexus. The initial diagnosis was unresectable pancreatic cancer. The patient was treated with gemcitabine plus nab-paclitaxel therapy. The tumor reduced in size, and invasion of the main vessels was alleviated after 3 courses. Therefore, we performed total pancreatectomywith total gastrectomy. Histopathological findings showed pancreatic adenocarcinoma, T4(PV)N2M0, fStage Ⅳb, R0. There are reports of curative resection for unresectable pancreatic cancer after chemotherapy. However, the majorityof these reports were about pancreatoduodenectomyor distal pancreatectomy. We present a rare case of curative total pancreatectomy after chemotherapy.

Successful treatment of hepatic gas gangrene by open drainage: A case report and review of the Japanese literature.

INTRODUCTION: Liver gas gangrene is rare and has a low prognosis. This case, reports a successful treatment of hepatic gas gangrene using an open drainage technique, followed by antibiotics and hyperbaric oxygen therapy (HBO). PRESENTATION OF THE CASE: An 82-year-old male with a history of left hepatectomy and bile duct resection for hilar cholangiocarcinoma presented with chilling, lethargy and dyspnea. He had a history of diabetes mellitus, hypertension, atrial fibrillation, and angina pectoris. Physical examination revealed scleric icterus, right hypochondrium tenderness and percussion tenderness of the liver, with warm extremities. Laboratory findings revealed leukocytosis and increased levels of hepatobiliary enzymes. A computed tomography (CT) scan showed gas accumulation in an S8 lesion with portal vein gas. Percutaneous drainage was performed immediately, and broad-spectrum antibiotics were started, but the drainage was insufficient. Consequently, laparotomy drainage was carried out, followed by HBO. No abscess was detected at one-year of follow-up. DISCUSSION: Hepatic gas gangrene progresses rapidly and has a high mortality rate. Malignant disease and diabetes mellitus may be predisposing factors. While half of non-clostridial cases survive, most cases of hepatic gas gangrene are associated with clostridial infection and have a fatal outcome. CONCLUSION: All survival cases of hepatic gas gangrene were treated by laparotomy drainage, thus immediate laparotomy seems essential to prevent a fatal outcome.

Small intestinal metastases from esophageal carcinoma presenting as a perforation: A case report and review of the literature.

INTRODUCTION: Small intestinal metastasis from oesophageal carcinoma is rare. We report a case of small intestinal metastases from oesophageal carcinoma presenting as a perforation and discuss the aetiology with other cases of small intestinal metastasis from oesophageal carcinoma reported in previous literature. PRESENTATION: An 86-year-old man presented with fever and coughing. He had choked while eating and had history of weight loss. He was diagnosed with aspiration pneumonia. Two days after the admission, he complained of abdominal pain. Physical examination revealed guarding and rebound tenderness in the upper abdomen. A contrast computed tomography of the abdomen showed ascites, free air, and irregular thickness of the small intestinal walls. Small intestinal perforation was noted, and surgical resection of the small intestine was performed. The pathological findings of the resected small intestine revealed ulcers with squamous cell carcinoma, and upper gastrointestinal endoscopy demonstrated oesophageal tumour, whose biopsy revealed squamous cell carcinoma. A diagnosis of small intestinal metastases from oesophageal carcinoma was made, but the patient died one month after the diagnosis. DISCUSSION: Most cases found in the literature of oesophageal tumour involve squamous cell carcinoma with male patients, and specific symptoms are divided into obstruction and perforation. All patients with small intestinal metastasis from oesophageal carcinoma who survived were treated by a combination of resection and radiation and/or chemotherapy; thus, immediate treatments seem essential to improve the prognosis. CONCLUSION: Physicians should keep in mind the possibility of small intestinal metastasis when patients with a history of oesophageal cancer have abdominal symptoms.

Successful surgical resection of ruptured cholangiolocellular carcinoma: A rare case of a primary hepatic tumor.

Spontaneous rupture is one of the most fatal complications of hepatic tumors such as hepatocellular carcinoma. In fact, many studies have shown that the in-hospital and 30-d mortality rates are as high as 25%-100%. Cholangiolocellular carcinoma (CoCC) is a rare primary hepatic tumor, usually small in size, that is thought to originate from the ductules and/or canals of Hering. Here, we present a case of spontaneous rupture of a CoCC that was successfully resected by radical surgery. Although CoCC is a rare primary hepatic tumor, it demonstrates certain specific clinical features, including a better prognosis than for other primary liver cancers, and thus should be distinguished from those other cancers. Moreover, CoCC can appear as a ruptured huge tumor, and when it does, radical hepatectomy can be an effective measure to achieve both absolute hemostasis and curability of tumor.