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Background The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. Methods The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. Results Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4–8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO2 (PaO2) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D), we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D), we suggest against routinely implementing NO inhalation therapy (GRADE 2C), and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). Conclusions This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jsicm.org/publication/guideline.html). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.

BACKGROUND: Classifying the progression pattern had been proved to be momentous for predicting efficacy and guiding treatment in the 1st/2nd generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), while lack evidence in the 3rd generation EGFR-TKIs. This study aimed to classify tumor progression of osimertinib in EGFR+ advanced non-small cell lung cancer (NSCLC), exploring the characteristics and the clinical significance of each progression pattern. METHODS: After screening 1,125 lung cancer patients, 168 EGFR T790M+ advanced patients using osimertinib were enrolled and divided into two groups and five clinical progression models according to the time course of the tumor progression. The prognosis and characteristics, such as gender, age, metastases, of each model were analyzed and compared by Kaplan-Meier method, t-test, and linear regression. RESULTS: Complete follow-up data were available for 117 of the 168 patients. Progressive disease (PD) occurred in 89 patients at an average onset of 6.59 months since using osimertinib, with 79.78% of patients experiencing enlargement of some preexisting lesions before PD. Among the five progression models, the ‘Rapid Enlargement’ (10.11%) model, the ‘Rapid New Lesion’ model (10.11%), the ‘Delayed Enlargement’ model (29.21%), the ‘Delayed New Lesion’ model (15.73%), and the ‘Non-targeted Enlargement’ model (34.83%), the ‘Non-targeted Enlargement’ model had the worst prognosis, with a median progression-free survival (mPFS) of 7.1 months (P=0.046). The mPFS of other models was similar, with the largest difference in the time interval between the beginning of osimertinib treatment to the first appearance of target lesion enlargement (T(m-e)). Smoking history (P=0.046) and the location of the initial (P=0.048), enlarged (P=0.003), and progressive lesions (P=0.002) affected the progression models, while gender, age, and treatment lines had no effect. The T(m-e) was related to the overall disease control time with a correlation coefficient of 0.667 (P=0.000). The appearance of a malignant pleural effusion had an impact on progression. CONCLUSIONS: We tried to create a classification system for describing the failure of the third-generation EGFR-TKI osimertinib including two groups, subdivided into five progression models based on the time course of tumor lesion changes. The system might be conducive to predict the prognosis and be potential to assist in selecting subsequent treatment strategies.

Despite advances in precision medicine, the clinical prospects for patients with ovarian and uterine cancers have not substantially improved. Here, we analyzed genome-scale CRISPR-Cas9 loss-of-function screens across 851 human cancer cell lines and found that frequent overexpression of SLC34A2-encoding a phosphate importer-is correlated with sensitivity to loss of the phosphate exporter XPR1, both in vitro and in vivo. In patient-derived tumor samples, we observed frequent PAX8-dependent overexpression of SLC34A2, XPR1 copy number amplifications and XPR1 messenger RNA overexpression. Mechanistically, in SLC34A2-high cancer cell lines, genetic or pharmacologic inhibition of XPR1-dependent phosphate efflux leads to the toxic accumulation of intracellular phosphate. Finally, we show that XPR1 requires the novel partner protein KIDINS220 for proper cellular localization and activity, and that disruption of this protein complex results in acidic "vacuolar" structures preceding cell death. These data point to the XPR1-KIDINS220 complex and phosphate dysregulation as a therapeutic vulnerability in ovarian cancer.

Purpose:KRAS is among the most commonly mutated oncogene in cancer including non–small cell lung cancer (NSCLC). In early clinical trials, inhibitors targeting G12C-mutant KRAS have achieved responses in some patients with NSCLC. Possible intrinsic and acquired resistance mechanisms to KRAS G12C inhibitors are not fully elucidated and will likely become important to identify.Experimental Design:To identify potential resistance mechanisms, we defined the sensitivity of a panel of KRAS G12C–mutant lung cancer cell lines to a KRAS G12C inhibitor, AMG510. Gene set enrichment analyses were performed to identify pathways related to the sensitivity, which was further confirmed biochemically. In addition, we created two cell lines that acquired resistance to AMG510 and the underlying resistance mechanisms were analyzed.Results:KRAS expression and activation were associated with sensitivity to KRAS G12C inhibitor. Induction of epithelial-to-mesenchymal transition (EMT) led to both intrinsic and acquired resistance to KRAS G12C inhibition. In these EMT-induced cells, PI3K remained activated in the presence of KRAS G12C inhibitor and was dominantly regulated by the IGFR–IRS1 pathway. We found SHP2 plays a minimal role in the activation of the PI3K pathway in contrast to its critical role in the activation of the MAPK pathway. The combination of KRAS G12C inhibitor, PI3K inhibitor, and SHP2 inhibitor resulted in tumor regressions in mouse models of acquired resistance to AMG510.Conclusions:Our findings suggest that EMT is a cause of both intrinsic and acquired resistance by activating the PI3K pathway in the presence of KRAS G12C inhibitor.

Supplementary Methods, Supplementary Table S1 to S4, and Supplementary Figure S1 to S4.

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PDF file, 106K, Supplementary Table S1. BRG1-deficient and -proficient cell lines subjected to BRM knockdown Supplementary Table S2. Verification of gene alterations in cell lines subjected to BRM knockdown Supplementary Table S3. Analysis of missense BRG1 mutations using the Polyphen software Supplementary Table S4. Negative correlation between BRG1 deficiency and alterations in therapeutic target genes in 373 NSCLC cases from three studies (this study and Refs 32 and 33) Supplementary Table S5. Correlation between BRG1 deficiency and smoking in 369 NSCLC cases from three studies (this study and Ref 32 and 33).

PDF file, 1764K, Supplementary Figure S1. Immunohistochemical staining for BRG1 and BRM in cancer cell lines. Supplementary Figure S2. E431* and E608* Supplementary Figure S3. Fluorescence in situ hybridization for the detection of FGFR1 amplification in a case of squamous lung cell carcinoma. Supplementary Figure S4. Immunoblot analysis of SWI/SNF and ACF chromatinremodeling proteins. Supplementary Figure S5. Survival of H1299 (BRG1-deficient) and HeLa (BRG1-proficient) cells after shRNA-mediated knockdown of BRM (shBRM). Supplementary Figure S6. The effects of BRM knockdown on the morphologies of BRG1-deficient and proficient cancer cells. Supplementary Figure S7. Effect of BRM knockdown on the induction of senescence in BRG1-deficient and -proficient non-small-cell lung carcinoma cells.

Studies elucidating detailed characteristics of pneumonitis in association with chemo-immunotherapy are limited. We aimed to investigate the characteristics of images, prognostic factors, and clinical course of combination therapy associated with pneumonitis. A multicenter, retrospective cohort study of patients with non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed, and pembrolizumab was conducted. Patients with confirmed pneumonitis established by an independent multidisciplinary team were enrolled. For 53 patients with pneumonitis, radiographic features at diagnosis predominantly comprised an organizing pneumonia pattern (62%, 33/53). Twelve (23%) patients experienced a worsening respiratory status during pneumonitis management, which was associated with a high mortality rate (58%, 7/12) during treatment. Severe grade at pneumonitis diagnosis (p p = 0.002), and disease extent ≥ 25% in the lungs (p = 0.009) were significantly associated with worsening respiratory status. Furthermore, post-diagnosis survival was significantly worse in severe pneumonitis (p = 0.02) than in mild and in patients with the DAD pattern than in those without (p

Considering the increasing number of identified driver oncogene alterations, additional genetic tests are required to determine the treatment for advanced non‐small‐cell lung cancer (NSCLC). Next‐generation sequencing can detect multiple driver oncogenes simultaneously, enabling the analysis of limited amounts of biopsied tissue samples. In this retrospective, multicenter study (UMIN ID000039523), we evaluated real‐world clinical data using the Oncomine Dx Target Test Multi‐CDx System (Oncomine DxTT) as a companion diagnostic system. Patients with NSCLC who were tested for a panel of 46 genes using the Oncomine DxTT between June 2019 and January 2020 were eligible for enrollment. Patients from 19 institutions affiliated to the West Japan Oncology Group were recruited. The primary endpoint of the study was the success rate of genetic alteration testing in four driver genes (EGFR, ALK, ROS1, and BRAF) using the Oncomine DxTT. In total, 533 patients were enrolled in the study. The success rate of genetic alteration testing for all four genes was 80.1% (95% CI 76.5%‐83.4%). Surgical resection was associated with the highest success rate (88.0%), which was significantly higher than that for bronchoscopic biopsy (76.8%, P = .005). Multivariate analysis revealed a significant difference for surgical resection alone (P = .006, 95% CI 1.36‐6.18, odds ratio 2.90). Although the success rate of genetic alteration testing immediately after Oncomine DxTT induction was not sufficient in this study, optimizing specimen quantity and quality may improve the use of driver gene testing in clinical settings., The mutation identification success rate for all four genes was 80.1%. Surgical resection was associated with the highest success rate. Multivariate analysis showed a significant difference for surgical resection alone.

Here, we report a highly sensitive and easy-to-use electrochemical immunoassay using a dual-signal amplification strategy of redox cycling within a nanoscale gap and the Limulus amebocyte lysate (L...

Histone acetylation is a post-translational modification of histones that is catalyzed by histone acetyltransferases (HATs) and plays an essential role in cellular processes. The HAT domain of EP300/CBP has recently emerged as a potential drug target for cancer therapy. Here, we describe the identification of the novel, highly potent, and selective EP300/CBP HAT inhibitor DS-9300. Our optimization efforts using a structure-based drug design approach based on the cocrystal structures of the EP300 HAT domain in complex with compounds

A 50-year-old man with a 20-year history of left-sided ulcerative colitis (UC) presented to our hospital with sudden onset of watery diarrhea. To this point, he had been treated with mesalazine 2.0 g/day for UC and had maintained remission. We considered that the UC had worsened. We immediately performed surveillance colonoscopy, which revealed a normal mucous membrane. The results of blood laboratory examinations were normal. Histopathology of colonic biopsies revealed new-onset collagenous colitis (CC), with a thickened subepithelial collagen band (SECB) and inactive UC. We herein report the importance of random colonic biopsies to diagnose CC even when the endoscopic appearance of the colon is normal in patients with inflammatory bowel disease with worsened diarrhea.

Here, we report a high-sensitivity dual immunoassay using

Clinical Practice Points • Immune checkpoint inhibitor (ICI) therapy could exacerbate preexisting active autoimmune diseases (AIDs), and the presence of preexisting AIDs might be associated with a greater risk of developing new immune-related adverse events (irAEs). • The safety of ICIs for patients with Lambert-Eaton myasthenic syndrome (LEMS), a neuromuscular autoimmune disease known as a paraneoplastic syndrome mainly associated with small-cell lung cancer (SCLC), is fully unknown. • We experienced an extensive-stage (ES)-SCLC patient with LEMS successfully treated with chemotherapy in combination with ICI without a flare-up of LEMS. • Phase III trials have shown that ICIs in combination with platinum doublet therapy significantly improved the overall survival of patients with ES-SCLC in first-line settings, therefore, patients diagnosed with ES-SCLC with the complication of LEMS have the widespread opportunity to receive ICIs as standard care. This report suggests that treatment using ICIs may be a treatment option to consider for ES-SCLC patients with LEMS.

In this work, we report a simple electrochemical sensor that detects proteinuria upon immersion into a sample. We immobilized peptidases in conjunction with glutamate oxidase (GluOx) on a Prussian blue-modified glassy carbon (PB-GC) electrode. In the sensor, albumin, which is a major protein in urine, was degraded by peptidases to produce glutamate that was detected by GluOx on PB-GC. Initially, we validated the strategy for the detection of proteinuria using glutamate sensing. We quantified the amount of glutamate produced by degrading human serum albumin with HCl and carboxypeptidase A (CPA). The results indicated that an increase in the enzyme degradation rate was necessary for daily proteinuria sensing that needs to be completed within 1 h. Therefore, we investigated the use of endopeptidase in conjunction with CPA. The combination of proteinase K and CPA liberated glutamate from albumin at 17.5 times higher comparing to solely CPA. The subsequent glutamate assay using peptidase-modified GluOx-PB-GC electrode did not exhibit changes in the electrochemical signal with increases in the glutamate concentration, because peptidase degraded the GluOx on the modified electrode. To prevent this, GluOx was encapsulated in ZIF-8. Glutamate was successfully detected using peptidase and GluOx encapsulated in the ZIF-8-modified PB-GC (peptidase-ZIF-8/GluOx-PB-GC) electrode. Finally, an albumin assay was performed using the peptidase-ZIF-8/GluOx-PB-GC electrode, wherein albumin was detected with a sensitivity of 0.1 mg/mL within 30 min. Our simple and easy-to-use method for albumin detection provides a viable sensor for daily urinalysis.

Most pivotal clinical trials in advanced non-small cell lung cancer (NSCLC) have excluded patients with poor performance status (PS), and data on the efficacy and safety of pharmacotherapy have not been fully accumulated. For NSCLC patients with PS 2 and without druggable genetic alterations, monotherapy with cytotoxic agents or carboplatin-based combination therapy is usually administered based on the results of several randomized trials. However, the evidence of cytotoxic chemotherapy for patients with PS 2 is insufficient, with limited efficacy and toxicity concerns. Immune checkpoint inhibitors (ICIs) are a promising treatment for patients with PS 2 because of lower incidence of severe toxicity compared to cytotoxic chemotherapy. Meanwhile, several reports suggest that anti-PD-1 antibodies monotherapy is less effective for patients with PS 2, especially for those with PS 2 caused by disease burden. Although the combination therapy of nivolumab and ipilimumab is a promising treatment option, there is a divergence in efficacy data between clinical trials. The standard of care for advanced NSCLC with PS 2 has not been established, and future therapeutic strategies should take into account the heterogeneity of the PS 2 population.

Here, we report a highly sensitive immunoassay for human immunoglobulin G (IgG) that uses signal amplification of the coagulation cascade. Z-Phe-Pro-Lys

Adding an immune checkpoint inhibitor to chemotherapy to treat extensive-stage small cell lung cancer is effective. However, there are no reports of an effective second-line treatment in patients previously treated with chemotherapy and immune checkpoint inhibitors as a first-line treatment. Here, we assessed the efficacy and safety of amrubicin as a second-line treatment for extensive-stage small cell lung cancer after chemotherapy and immune checkpoint inhibitor combination therapy. The study enrolled 150 patients with extensive-stage small cell lung cancer. The efficacy and the incidence of adverse events were compared between patients previously treated with immune checkpoint inhibitors and patients without previous immune checkpoint inhibitor treatment. One hundred and twenty-three patients were eligible. There was no difference in objective response rate, time-to-treatment failure, progression-free survival, and overall survival between both groups. The incidence of adverse events was similar in both treatment groups. Pretreatment with immune checkpoint inhibitors was not associated with an increase in amrubicin-related adverse events. This study shows that the efficacy of amrubicin in extensive-stage small cell lung cancer remains unchanged irrespective of previous treatment with immune checkpoint inhibitors. Amrubicin-related adverse events did not increase in patients previously treated with immune checkpoint inhibitors.

Background Consolidation therapy with durvalumab after concurrent chemoradiotherapy has been reported to significantly prolong progression‐free survival and overall survival in patients with stage III unresectable non‐small cell lung cancer (NSCLC). However, which chemotherapy regimen should be selected for consolidation therapy with durvalumab is currently unknown. Methods We retrospectively reviewed consecutive patients with unresectable stage III NSCLC who received concurrent definitive chemoradiotherapy with platinum‐based chemotherapy. We reviewed the timing and severity of radiation pneumonitis by assessing chemotherapy regimens and histology. Results A total of 103 patients were identified. Fourteen patients (13.6%) developed grade 2 or greater radiation pneumonitis within 42 days after chemoradiotherapy. No adenocarcinoma patients treated with a regimen of cisplatin plus pemetrexed developed grade 2 or greater radiation pneumonitis within 42 days; however, 20% of patients who were treated with carboplatin plus paclitaxel developed grade 2 or greater radiation pneumonitis. Furthermore, the objective response rates and disease control rates of cisplatin plus pemetrexed were equal to or greater than those of carboplatin plus paclitaxel in adenocarcinoma patients. Conclusion Cisplatin plus pemetrexed regimen may be a preferable option to consider for subsequent consolidation therapy with durvalumab in patients with unresectable stage III adenocarcinoma., Among a total of 103 patients with unresectable stage III NSCLC who received concurrent definitive chemoradiotherapy, 13.6% of patients developed grade 2 or greater radiation pneumonitis within 42 days after chemoradiotherapy. No adenocarcinoma patients treated with cisplatin plus pemetrexed developed grade 2 or greater radiation pneumonitis within 42 days; however, 20% of patients treated with carboplatin plus paclitaxel developed grade 2 or greater radiation pneumonitis.

Although objective response rate and disease control rate are commonly used as primary endpoints of lung cancer trials, it remains unclear whether objective response rate and disease control rate correctly reflect the overall survival in a non-small cell lung cancer phase II trial evaluating a non-first-line chemotherapy. Objective response rate might be easily affected by chance because the small number of patients in each trial achieved complete or partial response in the phase II non-first-line setting. This study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (UMIN000040412). Four databases were searched for eligible trials. A Spearman’s rank correlation with hazard ratio of overall survival was calculated each for odds ratio of objective response rate, difference of objective response rate (%), odds ratio of disease control rate, and difference of disease control rate (%). Of 74 eligible trials, 73 reported objective response rate and 68 reported disease control rates. Nine (12%) trials included patients with driver mutation status. Thirteen (18%) and two (3%) RCTs specifically included adenocarcinoma/non-squamous and squamous subtype of non-small cell lung cancer, respectively. The Eastern Cooperative Oncology Group performance status 0−2 (N=41, 55%) and the performance status 0-1 (N=25, 34%) were frequently used performance status criteria. The median number of patients in the two arms was 116 (interquartile range, 82–159). The correlation between trial-level odds ratio of objective response rate and hazard ratio of overall survival was weak (r=−0.29, 95% CI: −0.49 to −0.05, P=0.014). An exploratory subgroup analysis suggested that fewer responders were associated with poorer correlation. Odds ratio of disease control survival (r=−0.53, 95% CI: −0.68 to −0.32, P

BACKGROUND Splenic abscess is a rare infectious disease that occurs after bloodstream infection and trauma. It has become more common due to an increase in the number of immunocompromised patients. They typically present with round cystic lesions demonstrated by ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Clostridioides difficile (formerly Clostridium difficile) is a well-known cause of pseudomembranous colitis, but extraintestinal manifestations are very rare. To the best of our knowledge, only 9 cases of splenic abscess due to C. difficile have been reported in the literature. CASE REPORT A 90-year-old man presented with weight loss, fever, and abdominal pain. Contrast-enhanced CT revealed splenomegaly with irregular hypodense nodules. Image-guided biopsy or drainage was not performed for a technical reason. MRI showed atypical nodules with mixed high and low signals on both T1- and T2-weighted images, which were inconclusive. A laparoscopic splenectomy was performed, which resulted in partial removal due to severe adhesion of the spleen to the surrounding tissues. Cultures of splenic pus yielded C. difficile, Enterococcus faecium, and Bacteroides fragilis. Pathological examination of the spleen showed widespread abscesses with hemorrhage and necrosis, leading to the diagnosis of splenic abscesses. Intravenous administration of vancomycin, clindamycin or metronidazole was ineffective. He died of fatal arrhythmia 5 months after the initial diagnosis of splenic abscess. CONCLUSIONS Splenic abscess can present with atypical imaging findings owing to chronic inflammation, bleeding, and necrosis. Although polymicrobial, this is the tenth reported case of splenic abscess caused by C. difficile.

The use of immune checkpoint inhibitors (ICIs) with chemotherapy has increased the survival of patients with advanced NSCLC. Nevertheless, the efficacy of ICI treatment for NSCLC withThis study performed a retrospective analysis of the association between clinical characteristics and ICI efficacy in patients withAmong 80 patients withThe PFS of osimertinib might be a predictor of PFS of chemoimmunotherapy in patients with

Background The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited. Methods We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the ‘TTF of CRZ’ plus the ‘TTF of ALEC’ if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group. Results Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P Conclusion The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.

A 71-year-old woman with rheumatoid arthritis who had been taking NSAIDs for many years consulted our hospital for abdominal pain. She was diagnosed with a small bowel obstruction due to an enterolith according to an abdominal CT scan that showed dilation from the enterolith in the small intestine on the oral side. It was considered that the intestinal stone was formed due to stagnation of intestinal contents and had gradually increased in size, resulting in an intestinal obstruction. We performed antegrade double-balloon endoscopy (DBE) to observe and remove the enterolith. We used forceps and a snare to fracture the enterolith. During this attempt, we found a seed in the center of the enterolith. Since the intestinal stone was very hard, cola dissolution therapy was administered from an ileus tube for 1 week. The following week, DBE was performed again, and it was found that the stone had further softened, making attempts at fracture easier. Finally, the enterolith was almost completely fractured. Intestinal stenosis, probably due to ulcers caused by NSAIDs, was found. Small bowel obstruction with an enterolith is rare. In this case, it was considered that the seed could not pass through the stenotic region of the small intestine and the intestinal contents had gradually built up around it. It has been suggested that DBE may be a therapeutic option in cases of an enterolith. Further, cola dissolution therapy has been shown to be useful in treating an enterolith, with the possible explanation that cola undergoes an acid–base reaction with the enterolith. In summary, we report, for the first time, treatment of an enterolith with a combination of DBE and cola dissolution therapy, thereby avoiding surgery and its risks.

Background Next-generation sequencing (NGS) has been implemented in clinical oncology to analyze multiple genes and to guide targeted therapy; however, little is known about the performance of the Oncomine Dx Target Test compared with conventional single gene tests for detecting EGFR mutations. The objective of this study was to evaluate the performance of the Oncomine Dx Target Test compared with a PNA-LNA PCR clamp test to detect EGFR mutations. Methods We retrospectively reviewed consecutive patients with non-small cell lung cancer (NSCLC) from whom FFPE samples were simultaneously submitted for the Oncomine Dx Target Test, and a PNA-LNA PCR clamp test using the same specimen. We subsequently compared the analysis success rates and detection rates between the two tests. Results A total of 116 samples were identified. The success rates and detection rates of EGFR mutations in the total number of samples were 90% and 28%, respectively for the Oncomine Dx Target Test, and 100% and 35% for the PNA-LNA PCR clamp test. The Oncomine Dx Target Test was unable to analyze three samples (2%) due to the samples not passing the nucleic acid concentration threshold, and nine (8%) samples had invalid results. The exon 19 deletion was not detected by the Oncomine Dx Target Test in four cases (4%). Conclusions The analytical performance of the Oncomine Dx Target Test analysis for EGFR mutations may not be comparable with conventional single gene tests due to both invalid and false-negative results. Key points Significant findings of the study The success rate of the Oncomine Dx Target Test was significantly lower than the PNA-LNA PCR clamp test. Among the samples successfully analyzed, four exon 19 deletions were not detected by the Oncomine Dx Target Test. What this study adds The analytical performance of the Oncomine Dx Target Test may not be comparable with conventional single gene tests. We should revise the sampling procedures, and review the sample quality assessment methods, to improve the analytical performance.

Purpose: KRAS is among the most commonly mutated oncogene in cancer including non–small cell lung cancer (NSCLC). In early clinical trials, inhibitors targeting G12C-mutant KRAS have achieved responses in some patients with NSCLC. Possible intrinsic and acquired resistance mechanisms to KRAS G12C inhibitors are not fully elucidated and will likely become important to identify. Experimental Design: To identify potential resistance mechanisms, we defined the sensitivity of a panel of KRAS G12C–mutant lung cancer cell lines to a KRAS G12C inhibitor, AMG510. Gene set enrichment analyses were performed to identify pathways related to the sensitivity, which was further confirmed biochemically. In addition, we created two cell lines that acquired resistance to AMG510 and the underlying resistance mechanisms were analyzed. Results: KRAS expression and activation were associated with sensitivity to KRAS G12C inhibitor. Induction of epithelial-to-mesenchymal transition (EMT) led to both intrinsic and acquired resistance to KRAS G12C inhibition. In these EMT-induced cells, PI3K remained activated in the presence of KRAS G12C inhibitor and was dominantly regulated by the IGFR–IRS1 pathway. We found SHP2 plays a minimal role in the activation of the PI3K pathway in contrast to its critical role in the activation of the MAPK pathway. The combination of KRAS G12C inhibitor, PI3K inhibitor, and SHP2 inhibitor resulted in tumor regressions in mouse models of acquired resistance to AMG510. Conclusions: Our findings suggest that EMT is a cause of both intrinsic and acquired resistance by activating the PI3K pathway in the presence of KRAS G12C inhibitor.

Next-generation sequencing (NGS) has been implemented in clinical oncology to analyze multiple genes and to guide targeted therapy. Although the pathological diagnosis and biomarker tests for patients with advanced lung cancer have mostly been obtained with small biopsy samples, especially with bronchoscopic approaches, the performance for NGS with respect to the different sizes of biopsy forceps remains little known.We retrospectively reviewed consecutive patients with non-small cell lung cancer, whose FFPE samples were obtained by endobronchial biopsy/transbronchial biopsy and were submitted for the Oncomine Dx Target Test (ODxTT). We compared the analytical performance for ODxTT with respect to the size of biopsy forceps.A total of 103 samples were identified. The success rate of the ODxTT for the group with all samples obtained with small forceps biopsies (70%) was lower than that of the group with some or all samples obtained with standard forceps biopsies (83%), although without a statistically significant difference (p = 0.20). With regard to the reason for unsuccessful analysis, the proportion of the samples which did not pass the nucleic acid concentration threshold in the former group (15%) was higher compared with that of the latter group (4%) (p = 0.08). The proportion of tissue size 4 mmThe analysis of ODxTT for specimens biopsied using only small forceps is prone to be unsuccessful due to an insufficient amount of nucleic acid.

We constructed a data set of EGFR‐mutant non–small‐cell lung carcinoma (NSCLC) patients, and compared the overall survival of first‐generation (1G), and second‐generation (2G) EGFR‐tyrosine kinase inhibitors (TKIs) in clinical practice using a propensity score. We reviewed the clinical data of consecutive EGFR‐mutated NSCLC patients who received EGFR‐TKI therapy between January 2008 and August 2017 at 11 institutions in Japan. The primary endpoint was overall survival (OS). When comparing OS between 1G and 2G EGFR‐TKIs, propensity score analyses were performed using 2 methods: matching and inverse probability of treatment weighting (IPTW). (Clinical Trial information: UMIN000030121) In total, 1400 patients from 11 institutions were enrolled in this study, and the data from the 1366 patients who received only EGFR‐TKI therapy were analyzed (gefitinib [GEF], N = 732; erlotinib [ERL], N = 416; afatinib, N = 218). Median OS times (months [95%CI]) were 29.7 [27.5‐33.5] in the 1G group (gefitinib, 32.0 [28.1‐35.8]; erlotinib, 27.5 [23.9‐31.7]), and 38.6 [32.2‐NR] in the 2G group (afatinib), respectively. The trend of longer OS for afatinib against 1G EGFR‐TKIs remained, even after adjusted by propensity score. (unadjusted, hazard ratio [HR] 0.676, P = .0023; adjusted by IPTW, HR 0.685 P

Background Whether hazard ratio (HR) of progression-free survival (HRpfs), odds ratio (OR) of response rate (ORrr), OR of disease control rate (ORdcr), and OR of 1-year overall survival (ORos1y) used for extensive-disease small-cell lung cancer (ED-SCLC) correlate with HR of overall survival (HRos) at a randomized-trial level, especially for a trial that evaluates molecular-targeted therapy (MTT) or immune-checkpoint inhibitor (ICI), is unclear. Methods We included an individually randomized controlled trial (RCT) comparing two regimens as the first-line treatment for chemo-naive ED-SCLC, which have been reported in English-language since 2000. A weighted Spearman's rank correlation coefficient (r) was evaluated. Results We finally found 42 eligible articles consisted of 11,478 cases. Estimated r with HRos were as followings: HRpfs (29 trial, 8,573 cases, r=0.87), ORrr (39 trials, 11,030 cases, r=0.47), ORdcr (29 trials, 7,799 cases, r=0.48), and ORos1y (40 trials, 11,250 cases, r=0.69). Phase III subgroup (16 trials, 7,079 cases) yielded an excellent r between HRpfs and HRos of 0.96. ORdcr presented the best correlation with HRos for phase II trial subgroup (r=-0.64); however, this result was mainly calculated from MTT trials. HRpfs may overestimate the efficacy of MMT in a phase II trial. ORrr and ORdcr might undervalue the efficacy of ICI even in a phase III trial. Conclusions HRpfs can be a good surrogate of HRos, especially in a phase III trial. Depending on a single outcome in a randomized phase II trial may result in unneeded phase III trial or inappropriate abandonment of the regimen.

Theoretical models on the movement of colonial animals predict that neighbouring colonies may segregate their foraging areas, and many seabird studies have reported the presence of such segregations. However, these studies have often lacked the appropriate null model to test the effect of neighbouring colonies on foraging areas, especially in small colonies or in short‐ranging species. Here, we examined the foraging areas of Adelie Penguins Pygoscelis adeliae from two neighbouring (2 km apart) colonies by using bird‐borne GPS loggers. The field study was conducted at Hukuro Cove colony (104 pairs) and Mizukuguri Cove colony (338 pairs) in Lutzow‐Holm Bay, East Antarctica. We obtained GPS tracks for 504 foraging trips from 48 chick‐rearing Adelie Penguins and quantified the degree of overlap in the foraging areas between two colonies. We also produced simulated movement tracks by using correlated random‐walks assuming no inter‐colony competition and quantified the degree of overlap in the simulated foraging areas. Finally, we compared the results from real GPS tracks with those from simulated tracks to examine the effect of neighbouring colonies on Adelie Penguin movement. The results indicate that the degree of overlap was significantly smaller in real tracks than in simulated tracks. In real tracks, the foraging area of the smaller Hukuro Cove colony extended to the other side of the larger Mizukuguri Cove colony, unlike in simulated tracks. Consequently, we suggest that Adelie Penguins from two neighbouring colonies segregated their foraging areas and that the larger colony appeared to affect the foraging area of the smaller colony.

Plasma aldosterone concentration increases in proportion to the severity of heart failure, even during treatment with renin-angiotensin system inhibitors. This study investigated alternative regulatory mechanisms of aldosterone production that are significant in heart failure. Dahl salt-sensitive rats on a high-salt diet, a rat model of heart failure with cardio-renal syndrome, had high plasma aldosterone levels and elevated β3-adrenergic receptor expression in hypoxic zona glomerulosa cells. In H295R cells (a human adrenocortical cell line), hypoxia-induced β3-adrenergic receptor expression. Hypoxia-mediated β3-adrenergic receptor expression augmented aldosterone production by facilitating hydrolysis of lipid droplets though ERK-mediated phosphorylation of hormone-sensitive lipase, also known as cholesteryl ester hydrolase. Hypoxia also accelerated the synthesis of cholesterol esters by acyl-CoA:cholesterol acyltransferase, thereby increasing the cholesterol ester content in lipid droplets. Thus, hypoxia enhanced aldosterone production by zona glomerulosa cells via promotion of the accumulation and hydrolysis of cholesterol ester in lipid droplets. In conclusion, hypoxic zona glomerulosa cells with heart failure show enhanced aldosterone production via increased catecholamine responsiveness and activation of cholesterol trafficking, irrespective of the renin-angiotensin system.

Objectives: Currently, combination therapy of ramucirumab (RAM) + docetaxel (DOC) must play a more important role as a second-line treatment. Epithelial growth factor receptor (EGFR) mutation accounts for around 50% of oncogenic driver mutations in patients with advanced non-small cell lung cancer (NSCLC) in Asian subsets. The number of brain metastases (BM) is relatively higher in EGFR mutation-positive patients compared to EGFR wild-type patients. The objective of this study is to evaluate the efficacy of RAM + DOC focusing on EGFR mutation and BM. Methods: We retrospectively reviewed consecutive advanced NSCLC patients who received combination therapy of RAM + DOC at three institutions. A total of 112 patients with NSCLC were enrolled for efficacy analyses. We evaluated the efficacy of RAM + DOC for EGFR-mutated NSCLC with endpoints including progression-free survival (PFS), time to treatment failure (TTF) and overall survival. Results: Median PFS was 5.7 months for the EGFR mutant group compared with 3.6 months for the EGFR wild-type group (HR 0.53, 95% CI 0.32–0.87; p = 0.01). Median TTF was 5.1 months for the EGFR mutant group compared with 2.8 months for the EGFR wild-type group (HR 0.53, 95% CI 0.33–0.85; p = 0.007). Median PFS and TTF of the EGFR mutant group was significantly longer than median PFS and TTF of the EGFR wild-type group. The multivariate analysis identified EGFR mutation status as an independent favorable factor of PFS. In subset analyses of BM, median PFS of the EGFR mutant group (2.8 months) was significantly shorter than that of the EGFR wild-type group (5.1 months) (HR 7.27, 95% CI 1.78–29.68; p = 0.002). Conclusion: This study revealed that EGFR mutation status and BM might be predictive or prognostic factors for PFS.

A 74-year-old Asian man was referred for numb and painful sensation in the right upper limb. He was diagnosed with lung large cell neuroendocrine carcinoma and started receiving durvalumab therapy as second-line treatment. Sixteen days after the first dose, laboratory examination revealed increased liver enzyme levels and a marked inflammatory response. Contrast-enhanced computed tomography revealed an unenhanced tumor measuring approximately 25 mm in the head of pancreas and dilation of the intra- and extra-hepatic bile ducts. Magnetic resonance cholangiopancreatography confirmed stricture in the lower common bile duct and main pancreatic duct. We suspected acute cholangitis caused by a pancreatic cancer and performed an endoscopic biliary drainage. Two weeks after the procedure, computed tomography revealed significant shrinkage of the tumor. The tumor gradually reduced and pseudoprogression in lung large cell neuroendocrine carcinoma was ultimately diagnosed. Acute cholangitis caused by pseudoprogression resembling pancreatic cancer during immune therapy has not yet been reported. We are mindful that pseudoprogression should be considered as a differential diagnosis if a rapidly developing pancreatic tumor is observed during immunotherapy.

Ti6Al4V alloy, which is commonly used for biomedical applications, has a Young modulus (110 GPa) that is higher than that of human cortical bone (11 to 20 GPa). Using an implant with a material with a low Young modulus that enhances load sharing by the bone even more than those made of Ti6Al4V could be beneficial for bone healing and further reduce the potential for stress shielding. A new β-type TiNbSn alloy has a low Young modulus of approximately 40 to 49 GPa. However, whether the new titanium alloy with a lower Young modulus is advantageous in terms of fracture healing has not been assessed, and a small-animal model seems a reasonable first step in its assessment.To assess the impact of a TiNbSn alloy plate with a lower Young modulus compared with a Ti6Al4V alloy plate on fracture healing, we evaluated: (1) bony bridging and callus volume, (2) new bone formation and remaining cartilage tissue, (3) osteoblast activity in the callus, and (4) mechanical strength and stiffness of the callus in bending.Fracture plates manufactured from TiNbSn and Ti6Al4V alloys, which have Young moduli of 49 GPa and 110 GPa, respectively, were compared. The main reason for using rabbits was the high reliability of the three-point bending mechanical test of the rabbit tibia. Forty-two male Japanese white rabbits weighing 2.8 to 3.4 kg were anesthetized. A 5-cm skin incision was made on the medial side in the mid-diaphysis of the right tibia. Eight-hole plates were used, which were 42 mm long, 5 mm wide, and 1.2 mm thick. Plate fixation was performed using three proximal and three distal screws. After the plate was installed, an osteotomy was performed using a 1-mm-wide wire saw to create a standardized tibial transverse osteotomy model with a 1-mm gap. Bone healing was quantitatively assessed by two nonblinded observers using micro-CT (bony bridging and callus volume), histomorphometry (new bone formation and remaining cartilage tissue), immunohistochemistry (osteoblast activity), and mechanical testing (mechanical strength and stiffness in bending). Measurements on nondemineralized specimens were descriptive statistics due to their small number. Four weeks after osteotomy and fixation, 30 rabbits were euthanized to undergo micro-CT and subsequent mechanical testing (n = 12), histomorphometry and immunohistochemistry with demineralized specimens (n = 12), and histomorphometry with a nondemineralized specimen (n = 6). Eight weeks postoperatively, 12 rabbits were euthanized for micro-CT and subsequent mechanical testing.Intramedullary fracture calluses treated with TiNbSn alloy plates had larger bone volumes and more numerous bridging structures than those treated with Ti6Al4V alloy plates at 4 weeks after osteotomy (Ti6Al4V alloy versus TiNbSn alloy: 30 ± 7 mm 3 versus 52 ± 14 mm 3 , mean difference 22 [95% CI 9 to 37]; p = 0.005; ICC 0.98 [95% CI 0.95 to 0.99]). Histologic assessments demonstrated there was greater new bone formation (total callus: Ti6Al4V versus TiNbSn: 16 ± 4 mm 2 versus 24 ± 7 mm 2 , mean difference 8 [95% CI 1 to 16]; p = 0.04; ICC 0.98 [95% CI 0.93 to 0.99]; intramedullary callus: Ti6Al4V versus TiNbSn: 6 ± 4 mm 2 versus 13 ± 5 mm 2 , mean difference 7 [95% CI 1 to 13]; p = 0.02; ICC 0.98 [95% CI 0.95 to 0.99]) and a higher number of osteocalcin-positive cells (Ti6Al4V alloy versus TiNbSn alloy: 1397 ± 197 cells/mm 2 versus 2044 ± 183 cells/mm 2 , mean difference 647 [95% CI 402 to 892]; p0.001; ICC 0.98 [95% CI 0.95 to 0.99]) in the TiNbSn alloy group than in the Ti6Al4V alloy group. At 4 weeks after osteotomy, both bone strength and stiffness of the healed bone in the TiNbSn alloy group were higher than those in the Ti6Al4V alloy group (maximum load: Ti6Al4V alloy versus TiNbSn alloy: 83 ± 30 N versus 127 ± 26 N; mean difference 44 [95% CI 8 to 80]; p = 0.02; stiffness: Ti6Al4V alloy versus TiNbSn alloy: 92 ± 43 N/mm versus 165 ± 63 N/mm; mean difference 73 [95% CI 4 to 143]; p = 0.047). Eight weeks after osteotomy, no between-group differences were observed in the strength and stiffness of the healed bone.The results of this study indicate that TiNbSn alloy plate with a lower Young modulus resulted in improved bone formation and stiffer callus during the early phase (4 weeks after surgery) but not the later phase (8 weeks after surgery) of bone healing.An overly stiff plate may impair callus formation and bone healing. The TiNbSn alloy plate with a low Young modulus improves the early formation of new bone and stiff callus at the osteotomy site compared with the Ti6Al4V alloy plate in the healing process, which may promote bone repair. TiNbSn alloy may be a promising biomaterial for fracture treatment devices. Further research to address concerns about the strength of TiNbSn alloy plates, such as fatigue life and plate fracture, will be necessary for clinical applications, including mechanical tests to verify fatigue life and validation in larger animals with greater body weight.

Thymic carcinoma is a rare malignant tumor with a poor prognosis. No standard treatment is currently available. The present case was a 64-year-old male smoker with no symptoms referred to our hospital because of abnormal chest radiological findings. The CT study showed a tumor between the anterior mediastinum and the right lung upper lobe, multiple nodular shadows along the right pleura, and pleural effusion. A CT-guided needle biopsy revealed squamous cell carcinoma. However, the differential diagnosis between thymic carcinoma and primary lung cancer was difficult. Treatment with carboplatin, nanoparticle albumin-bound paclitaxel, and pembrolizumab was initiated. The CT scan showed tumor shrinkage and good clinical response after four treatment cycles. Therapy was switched to maintenance therapy with pembrolizumab alone. Imaging studies showed further tumor shrinkage after twelve cycles of maintenance therapy with pembrolizumab. Sixteen cycles of maintenance therapy were continued without performance status deterioration. An abnormal radiological finding was detected after a twelve-month exacerbation-free period. The diagnosis was thymic carcinoma. Treatment with lenvatinib was initiated, and tumor-size reduction was observed. This is the first report of a case showing a successful maintenance therapy with pembrolizumab after effective first-line therapy with a combination of carboplatin-based chemotherapy plus pembrolizumab in advanced thymic carcinoma.

Objectives Osimertinib has been reported to be effective against central nervous system (CNS) metastasis from activating EGFR mutation-positive NSCLC. Nevertheless, the true antitumor effects of osimertinib alone for CNS metastasis are unclear because the aforementioned studies included previously irradiated cases, in which tumor shrinkage can occur later owing to the effects of radiotherapy (RT). This study aimed to evaluate the efficacy of osimertinib against RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. Methods The OCEAN study was a two-cohort trial, involving 66 patients (T790M cohort [n = 40] and first-line cohort [n = 26]) with RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. The patients were treated once daily with 80 mg osimertinib. The primary end point was brain metastasis response rate (BMRR) according to the PAREXEL criteria. In this report, we present the results for the T790M cohort with analysis of drug concentrations and plasma circulating tumor DNA. Results The median age of the patients was 69 years, and 30% of them were males. Eight patients (20%) were symptomatic, and most had multiple CNS metastases (78%). Among the eligible 39 patients, the BMRR (PAREXEL criteria), median brain metastasis-related progression-free survival (PFS), median overall survival, overall response rate, and median PFS were 66.7% (90% confidence interval: 54.3%–79.1%), 25.2 months, 19.8 months, 40.5%, and 7.1 months, respectively. The BMRR according to the Response Evaluation Criteria in Solid Tumors criteria was 70.0% (n = 20). The brain metastasis-related PFS of patients with EGFR exon 19 deletion was significantly longer than that of exon 21 L858R (median = 31.8 versus 8.3 mo; log-rank p = 0.032). The treatment-related pneumonitis was observed in four patients (10%). On or after day 22, the median trough blood and cerebrospinal fluid concentrations of osimertinib were 568 nM and 4.10 nM, respectively, and those of its metabolite AZ5104 were 68.0 nM and 0.260 nM, respectively. The median blood to cerebrospinal fluid penetration rates of osimertinib and AZ5104 were 0.79% and 0.53%, respectively. The blood trough concentration at day 22 was not correlated with the efficacy of osimertinib against CNS metastasis. Plasma T790M and C797S mutations were detected in 83% and 3% of the patients before treatment, 11% and 3% of the patients on day 22, and 39% and 22% of the patients at the detection of progressive disease, respectively. Conclusions This study evaluated the efficacy of osimertinib against RT-naive CNS metastasis from T790M-positive NSCLC. The primary end point was met, and the results revealed the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion.

In this study, we conducted vehicle experiments and a numerical simulation based on a simple algorithm inspired by the bio-sonar system of bats to investigate how the behavioral strategy employed b...

Background Recent reports have indicated that the objective response rate (ORR) and progression-free survival (PFS) cannot serve as surrogates for predicting overall survival (OS) in immune checkpoint inhibitor (ICI) trials. We performed a trial-based correlative analysis to evaluate conventional endpoints as surrogates for predicting OS in ICI-treated non-small cell lung cancer (NSCLC) patients. Methods A systematic electronic literature search for randomized clinical trials using ICI monotherapies for NSCLC revealed 7 trials. The correlative analysis to clarify the correlations among clinical outcomes used a weighted Spearman rank correlation coefficient (wS), weighted Pearson correlation coefficient (wP), and weighted linear regression model (wL) in all patients and patients with high PD-L1 expression. Results The correlative analysis of the total population revealed that the odds ratio of the ORR (OR-ORR) and the hazard ratio of OS (HR-OS) were strongly correlated with the hazard ratio of PFS (HR-PFS) (R for wP and wS, R2 for wL; −0.869, −0.968, 0.756 between OR-ORR and HR-PFS; 0.923, 0.959, 0.851 between HR-PFS and HR-OS). The strongest correlation was observed between one-year overall survival (1y-OS) and the HR-OS (R for wP and wS, R2 for wL; 0.985, 1.000, R2: 0.968). In those with high PD-L1 expression, the ORR and PFS were strongly associated with OS (R2: 0.842 between ORR and OS; 0.771 between PFS and OS). Conclusions The OR-ORR and HR-PFS could serve as surrogate endpoints for predicting the HR-OS in randomized trials using ICIs for NSCLC, while the ORR and PFS could be useful endpoints for predicting OS in trials with patient selection based on high PD-L1 expression.