Trastuzumab Deruxtecan in Advanced Solid Tumors With Human Epidermal Growth Factor Receptor 2 Amplification Identified by Plasma Cell-Free DNA Testing: A Multicenter, Single-Arm, Phase II Basket Trial.

PURPOSE: HERALD/EPOC1806 was conducted as a multicenter phase II trial assessing trastuzumab deruxtecan (T-DXd) therapy for patients with human epidermal growth factor receptor 2 (HER2)-amplified progressive stage solid tumors detected by cell-free DNA (cfDNA) testing. PATIENTS AND METHODS: Patients exhibited advanced solid tumors with HER2 amplification that was identified via next-generation sequencing of cfDNA testing, without the requirement for immunohistochemical HER2 testing. The studied group was administered T-DXd at 5.4 mg/kg once every 3 weeks until onset of disease progression or intolerable toxicity. RESULTS: Overall, 4,734 patients underwent cfDNA testing from December 2019 to January 2022, and 252 demonstrated HER2 amplification. Finally, the study included 62 patients with 16 cancer types with a median baseline plasma HER2 copy number (CN) of 8.55 (range, 2.4-73.9). Confirmed overall response rate (ORR) by investigator assessment was 56.5% (95% CI, 43.3 to 69.0), thus showing a value beyond the 5% threshold. Responses were evaluated for 13 cancer types, including KRAS-mutant colorectal (1/3), PIK3CA-mutant endometrial (5/6), and tissue HER2-negative gastric (1/2) cancers. Plasma HER2 CN above versus below the baseline median value did not differ for impact response; however, clearance of HER2 amplification in cfDNA on cycle 2 day 1 had higher response values compared with persistence. Median progression-free survival and response duration were 7.0 (95% CI, 4.9 to 9.7) and 8.8 (95% CI, 5.8 to 11.2) months, respectively, with the majority of complications being mild to moderate. Interstitial lung diseases were identified in 16 (26%) patients, including 14 patients with grade 1 disease, one patient with grade 2 disease, and one patient with grade 3 disease. CONCLUSION: T-DXd treatment demonstrated high ORR with durable response in patients with advanced HER2-amplified solid tumors determined with cfDNA testing.

Novel ERBB2 Variant Potentially Associated with Resistance against Anti-HER2 Monoclonal Antibody-Based Therapy in ERBB2-Amplified Metastatic Colorectal Cancer.

PURPOSE: HER2-targeted therapies in ERBB2-amplified metastatic colorectal cancer (mCRC) are effective; however, a notable portion of patients do not respond to treatment, and secondary resistance occurs in most patients receiving these treatments. The purpose of this study was to investigate determinants of treatment efficacy and resistance in patients with ERBB2-amplified mCRC who received HER2-targeted therapy by analyzing multiomics data. EXPERIMENTAL DESIGN: We investigated genomic data from a nationwide large cancer genomic screening project, the SCRUM-Japan project. We analyzed paired genome and transcriptome data of tissue and genomic data of ctDNA collected pre- and postprogression in patients enrolled in the related trial, TRIUMPH, in ERBB2-amplified mCRC. RESULTS: In 155 patients with ERBB2-amplified solid tumors who received HER2-targeted therapy based on the SCRUM-Japan project, the objective response rate was 50%, 51%, and 35% in ERBB2 wild-type, variant of unknown significance, and pathogenic variant groups, respectively. In the paired genome and transcriptome data analyses in TRIUMPH, we identified the novel splicing-associated variant c.644-66_-2del in one of the 11 patients with paired whole-exome sequencing and whole-transcriptome sequencing data sets, which lacks the binding domain of pertuzumab, in progressed metastatic tumor as a variant with potential pathogenicity. The time-course ctDNA analysis detected c.644-66_-2del as an acquired variant. CONCLUSIONS: This study highlighted the importance of ERBB2 genomic status when evaluating the efficacy of HER2-targeted therapies in ERBB2-amplified mCRC. The identification of a novel splicing-associated variant may provide insights into potential mechanisms of treatment resistance. Furthermore, we demonstrated the utility of ctDNA to follow the acquired genomic status of mCRC tumors.

Three-year outcomes of preoperative chemoradiotherapy plus nivolumab in microsatellite stable and microsatellite instability-high locally advanced rectal cancer.

BACKGROUND: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard treatment for locally advanced rectal cancer (LARC). We reported the short-term outcomes of the VOLTAGE trial that investigated the safety and efficacy of preoperative CRT followed by nivolumab and surgery. Here, we present the 3-year outcomes of this trial. METHODS: Thirty-nine patients with microsatellite stable (MSS) LARC and five patients with microsatellite instability-high (MSI-H) LARC underwent CRT (50.4 Gy) followed by five doses of nivolumab (240 mg) and surgery. The 3-year relapse-free survival (RFS), overall survival (OS), and associations with biomarkers were evaluated. RESULTS: The 3-year RFS rates in patients with MSS and MSI-H were 79.5% and 100%, respectively, and the 3-year OS rates were 97.4% and 100%, respectively. Of the MSS patients, those with pre-CRT PD-L1 positivity, pre-CRT high CD8 + T cell/effector regulatory T cell (eTreg) ratio, pre-CRT high expression of Ki-67, CTLA-4, and PD-1 had a trend toward better 3-year RFS than those without. CONCLUSIONS: Three-year outcomes of patients with MSI-H were better than those of patients with MSS. PD-L1 positivity, elevated CD8/eTreg ratio, and high expression of Ki-67, CTLA-4, and PD-1 could be positive predictors of prognosis in patients with MSS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02948348.

Feasibility of self-measurement telemonitoring using a handheld heart sound recorder in patients with heart failure - SELPH multicenter pilot study.

BACKGROUND: Multi-parametric assessment, including heart sounds in addition to conventional parameters, may enhance the efficacy of noninvasive telemonitoring for heart failure (HF). We sought to assess the feasibility of self-telemonitoring with multiple devices including a handheld heart sound recorder and its association with clinical events in patients with HF. METHODS: Ambulatory HF patients recorded their own heart sounds, mono­lead electrocardiograms, oxygen saturation, body weight, and vital signs using multiple devices every morning for six months. RESULTS: In the 77 patients enrolled (63 ±â€¯13 years old, 84 % male), daily measurements were feasible with a self-measurement rate of >70 % of days in 75 % of patients. Younger age and higher Minnesota Living with Heart Failure Questionnaire scores were independently associated with lower adherence (p = 0.002 and 0.027, respectively). A usability questionnaire showed that 87 % of patients felt self-telemonitoring was helpful, and 96 % could use the devices without routine cohabitant support. Six patients experienced ten HF events of re-hospitalization and/or unplanned hospital visits due to HF. In patients who experienced HF events, a significant increase in heart rate and diastolic blood pressure and a decrease in the time interval from Q wave onset to the second heart sound were observed 7 days before the events compared with those without HF events. CONCLUSIONS: Self-telemonitoring with multiple devices including a handheld heart sound recorder was feasible even in elderly patients with HF. This intervention may confer a sense of relief to patients and enable monitoring of physiological parameters that could be valuable in detecting the deterioration of HF.

Prospective multicenter trial of the cryoballoon ablation system for superficial esophageal squamous cell carcinoma on post-endoscopic resection scars: a CRYO-SCAR study (EPOC1902).

BACKGROUND AND AIMS: Endoscopic resection is a minimally invasive treatment for superficial esophageal squamous cell carcinoma (SESCC). Post-endoscopic resection scars complicate en-bloc resection, even with advanced techniques, such as endoscopic submucosal dissection. The cryoballoon ablation system (CBAS) effectively manages Barrett's esophagus but has limited evidence in SESCC treatment, particularly on post-endoscopic resection scars. This study aimed to evaluate the efficacy and safety of the CBAS for treating SESCC on post-endoscopic resection scars. METHODS: This prospective study was conducted at 2 tertiary referral centers in Japan in patients endoscopically diagnosed with T1a SESCC on the post-endoscopic resection scar. Focal CBAS was used for cryoablation, with specific criteria for lesion selection and treatment method. The primary endpoint was the rate of local complete response (L-CR) of the primary lesion 48 weeks after the first cryoablation as evaluated by an independent central evaluation committee. RESULTS: From October 2020 to October 2021, 15 patients with 17 lesions underwent cryoablation, with 2 requiring repeat cryoablation. The L-CR rate for primary and all lesions evaluated by the central evaluation committee was 100%. The endoscopist's evaluation was consistent with these results. The median procedure time was 9 minutes. Eight patients experienced no pain, and the highest pain score reported on a numeric rating scale from 1 to 10 was 3. The technical success rate was 94.7% (18/19). Throughout the median follow-up period of 14.3 months, recurrences, deaths, or severe treatment-related adverse events were not reported. CONCLUSIONS: CBAS is a potentially safe and effective approach for SESCC on post-endoscopic resection scars and represents an encouraging alternative to traditional endoscopic treatments. (Clinical trial registration numbers: NCT03097666 and jRCT1080225331.).

Impact of sleep-disordered breathing on overnight changes in arterial stiffness in patients with acute heart failure.

Overnight increases in arterial stiffness associated with sleep-disordered breathing may adversely affect patients with acute heart failure. Thus, we investigated overnight changes in arterial stiffness and their association with sleep-disordered breathing in patients hospitalized for acute heart failure. Consecutive patients with acute heart failure were enrolled. All participants underwent overnight full polysomnography following the initial improvement of acute signs and symptoms of acute heart failure. The arterial stiffness parameter, cardio-ankle vascular index (CAVI), was assessed before and after polysomnography. Overall, 60 patients (86.7% men) were analyzed. CAVI significantly increased overnight (from 8.4 ± 1.6 at night to 9.1 ± 1.7 in the morning, P < 0.001) in addition to systolic and diastolic blood pressure (from 114.1 mmHg to 121.6 mmHg, P < 0.001; and from 70.1 mmHg to 78.2 mmHg, P < 0.001, respectively). Overnight increase in CAVI (ΔCAVI ≥ 0) was observed in 42 patients (70%). The ΔCAVI ≥ 0 group was likely to have moderate-to-severe sleep-disordered breathing (i.e., apnea-hypopnea index ≥15, 55.6% vs 80.9%, P = 0.047) and greater obstructive respiratory events (29.4% vs 58.5%, P = 0.041). In multivariable analysis, moderate-to-severe sleep-disordered breathing and greater obstructive respiratory events were independently correlated with an overnight increase in CAVI (P = 0.033 and P = 0.042, respectively). In patients hospitalized for acute heart failure, arterial stiffness, as assessed by CAVI, significantly increased overnight. Moderate-to-severe sleep-disordered breathing and obstructive respiratory events may play an important role in the overnight increase in cardio-ankle vascular index.

Diurnal Variations in Serum Uric Acid, Xanthine, and Xanthine Oxidoreductase Activity in Male Patients with Coronary Artery Disease.

Hyperuricemia is influenced by diet and can cause gout. Whether it is a potential risk factor for cardiovascular disease (CVD) remains controversial, and the mechanism is unclear. Similar to CVDs, gout attacks occur more frequently in the morning and at night. A possible reason for this is the diurnal variation in uric acid (UA), However, scientific data regarding this variation in patients with CVD are not available. Thus, we aimed to investigate diurnal variations in serum levels of UA and plasma levels of xanthine, hypoxanthine, and xanthine oxidoreductase (XOR) activity, which were measured at 18:00, 6:00, and 12:00 in male patients with coronary artery disease. Thirty eligible patients participated in the study. UA and xanthine levels significantly increased from 18:00 to 6:00 but significantly decreased from 6:00 to 12:00. By contrast, XOR activity significantly increased both from 18:00 to 6:00 and 6:00 to 12:00. Furthermore, the rates of increase in UA and xanthine levels from night to morning were significantly and positively correlated. In conclusion, UA and xanthine showed similar diurnal variations, whereas XOR activity showed different diurnal variations. The morning UA surge could be due to UA production. The mechanism involved XOR activity, but other factors were also considered.

Immune escape and waning immunity of COVID-19 monovalent mRNA vaccines against symptomatic infection with BA.1/BA.2 and BA.5 in Japan.

BACKGROUND: Repeated emergence of variants with immune escape capacity and waning immunity from vaccination are major concerns for COVID-19. We examined whether the surge in Omicron subvariant BA.5 cases was due to immune escape or waning immunity through vaccine effectiveness (VE) evaluation. METHODS: A test-negative case-control study was conducted in 16 clinics/hospitals during the BA.1/BA.2-dominant and BA.5-dominant periods. VE against symptomatic infection was estimated after adjusting for age, sex, comorbidity, occupation, testing frequency, prior infection, close contact history, clinic/hospital, week, and preventive measures. Absolute VE (aVE) was calculated for 2/3/4 doses, compared to the unvaccinated. Relative VE (rVE) was calculated, comparing 3 vs 2 and 4 vs 3 doses. RESULTS: 13,025 individuals were tested during the BA.1/BA.2-dominant and BA.5-dominant periods with similar baseline characteristics. For BA.1/BA.2, aVE was 52 % (95 %CI:34-66) 14 days-3 months post-dose 2, 42 % (29-52) > 6 months post-dose 2, 71 % (64-77) 14 days-3 months post-dose 3, and 68 % (52-79) 3-6 months post-dose 3. rVE was 49 % (38-57) 14 days-3 months post-dose 3 and 45 % (18-63) 3-6 months post-dose 3. For BA.5, aVE was 56 % (27-73) 3-6 months post-dose 2, 32 % (12-47) > 6 months post-dose 2, 70 % (61-78) 14 days-3 months post-dose 3, 59 % (48-68) 3-6 months post-dose 3, 50 % (29-64) > 6 months post-dose 3, and 74 % (61-83) ≥ 14 days post-dose 4. rVE was 56 % (45-65) 14 days-3 months post-dose 3, 39 % (27-48) 3-6 months post-dose 3, 25 % (-2-45) > 6 months post-dose 3, and 30 % (-6-54) ≥ 14 days post-dose 4. CONCLUSIONS: Booster doses initially provided high protection against BA.5 at a level similar to that against BA.1/BA.2. However, the protection seemed shorter-lasting against BA.5, which likely contributed to the surge. Furthermore, rVE post-dose 4 was low even among recent vaccinees. These results support the introduction of variant-containing vaccines and emphasize the need for vaccines with longer duration of protection.

Fibroblast inhibition by tocilizumab enabled gemcitabine/nab-paclitaxel rechallenge for pancreatic cancer.

Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway inhibition may overcome chemoresistance of metastatic pancreatic cancer (MPC). We sought to determine the safety and recommended dose of tocilizumab (TCZ), an IL-6 receptor monoclonal antibody, and biological correlates of tumor shrinkage in patients with gemcitabine (GEM)/nanoparticle albumin-bound paclitaxel (nab-PTX)-refractory MPC. This phase 1 study enrolled 10 patients with MPC who had progressed after GEM/nab-PTX. Patients initially received TCZ 8 mg/kg on Day 1 and nab-PTX 100 mg/m2 + GEM 750 mg/m2 on Days 2, 9, and 16. Before and at the end of Cycle 1, biopsy of liver metastases was performed 3-5 h after levofloxacin (LVFX) administration to measure LVFX infiltration into tumor tissue. No dose-limited toxicities occurred, and the recommended dosage of TCZ was determined to be 8 mg/kg. Treatment-emergent adverse events occurred in 80% of patients, of which decreased neutrophil count was the most common. Tumor reduction during Cycle 1 was observed in four patients, who were defined as responders. In paired-biopsy samples, responder-related biological activities were an increase of cleaved PARP expression of tumor nuclei (p = 0.01), a decrease of proliferative cancer-associated fibroblasts (CAFs) (p = 0.08), and an increase of LVFX infiltration in the tumor (p = 0.04). A decrease of phosphorylated STAT3 expression (p = 0.02) favored an increase in LVFX infiltration. In conclusion, TCZ + GEM/nab-PTX-rechallenge had a manageable safety profile and showed preliminary activity via inhibition of CAF and improved intratumoral drug infiltration in MPC.

Effectiveness of BA.1- and BA.4/BA. 5-Containing Bivalent COVID-19 mRNA Vaccines Against Symptomatic SARS-CoV-2 Infection During the BA.5-Dominant Period in Japan.

In this multicenter, prospective, test-negative, case-control study in Japan, the effectiveness of both BA.1-containing and BA.4/BA.5-containing bivalent coronavirus disease 2019 mRNA vaccines against symptomatic infection during the BA.5-dominant period was high compared with no vaccination (65% and 76%) and moderate compared with monovalent vaccines administered over half a year earlier (46% combined).

Overnight changes in uric acid, xanthine oxidoreductase and oxidative stress levels and their relationships with sleep-disordered breathing in patients with coronary artery disease.

Serum uric acid (UA) level is associated with the high cumulative incidence or prevalence of coronary artery disease (CAD), and hyperuricemia is considered as an independent risk marker for CAD. Sleep-disordered breathing (SDB) is also associated with an increased risk of CAD. Several studies have shown that SDB is associated with hyperuricemia, but the mechanisms are unclear. We measured serum levels of UA and xanthine oxidoreductase (XOR) activity and urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), all of which were assessed at 6 p.m. and the following 6 a.m. in males with CAD. In addition, nocturnal pulse oximetry was performed for the night. Overall 32 eligible patients with CAD were enrolled. Serum UA levels significantly increased overnight. (5.32 ± 0.98 mg/dl to 5.46 ± 1.02 mg/dl, p < 0.001) Moreover, XOR activity and urinary 8-OHdG levels significantly increased from 6 p.m. to 6 a.m. Furthermore, 3% Oxygen desaturation index (ODI) was correlated with the overnight changes in XOR activity (r = 0.36, P = 0.047) and urinary 8-OHdG levels (r = 0.41, P = 0.02). In addition, 3%ODI was independently correlated with the changes in XOR activity (correlation coefficient, 0.36; P = 0.047) and 8-OHdG (partial correlation coefficient, 0.63; P = 0.004) in multivariable analyses. SDB severity was associated with the overnight changes in XOR activity and urinary 8-OHdG, suggesting that SDB may be associated with oxidative stress via UA production. This trial is registered at University Hospital Medical Information Network (UMIN), number: UMIN000021624.

Couette flow fluorescence detected linear dichroism for analytes in lipid bilayers.

Membranes are important sites of intermolecular interactions in biological systems. However, they present significant analytical challenges as they contain multiple analytes and are dynamic in nature. In this work, we show how a Jasco J-1500 circular dichroism spectropolarimeter can be used with a microvolume Couette flow cell and appropriate cut-off filters to measure excitation fluorescence detected linear dichroism (FDLD) of fluorophores embedded in liposomal membranes. The result is a spectrum that selectively probes the fluorophore(s) and eliminates the scattering that is apparent in the corresponding flow linear dichroism (LD) spectrum. The FDLD spectrum is opposite in sign from the LD spectrum with relative magnitudes modified by the quantum yields of the transitions. FDLD thus enables analyte orientations to be identified in a membrane. Data for a membrane peptide, gramicidin, and two aromatic analytes, anthracene and pyrene, are presented. Issues with the "leakage" of photons by the long pass filters used is also discussed.

Prognostic Value of Cheyne-Stokes Respiration and Nutritional Status in Acute Decompensated Heart Failure.

Malnutrition frequently coexists with heart failure (HF), leading to series of negative consequences. Cheyne-Stokes respiration (CSR) is predominantly detected in patients with HF. However, the effect of CSR and malnutrition on the long-term prognosis of patients with acute decompensated HF (ADHF) remains unclear. We enrolled 162 patients with ADHF (median age, 62 years; 78.4% men). The presence of CSR was assessed using polysomnography and the controlling nutritional status score was assessed to evaluate the nutritional status. Patients were divided into four groups based on CSR and malnutrition. The primary outcome was all-cause mortality. In total, 44% of patients had CSR and 67% of patients had malnutrition. The all-cause mortality rate was 26 (16%) during the 35.9 months median follow-up period. CSR with malnutrition was associated with lower survival rates (log-rank p < 0.001). Age, hemoglobin, albumin, lymphocyte count, total cholesterol, triglyceride, low-density lipoprotein cholesterol, creatinine, estimated glomerular filtration rate, B-type natriuretic peptide, administration of loop diuretics, apnea-hypopnea index and central apnea-hypopnea index were significantly different among all groups (p < 0.05). CSR with malnutrition was independently associated with all-cause mortality. In conclusion, CSR with malnutrition is associated with a high risk of all-cause mortality in patients with ADHF.

[Development of a X-ray Exposure Dose Control Tool for CT Examination by Using Spreadsheet Software].

PURPOSE: We developed X-ray dose monitoring and optimization software for computed tomography (CT) by using a spreadsheet software. METHODS: The analysis was carried out on 1,212 patients using 2,128 CT examinations at our institution, in the period of April 2020 to April 2022. These cases were extracted in the limitation of patient's weight in the range of 50 to 70 kg. The individual radiation report, including CTDIvol and DLP, on the console displayed by a CT system was used and manually transferred to our software. The X-ray dose distribution was evaluated by using a boxplot chart and a scatter plot, and the data were referred to Japan DRLs 2020 (National Diagnostic Reference Levels in Japan 2020). RESULTS: Almost all patient's doses in our institution were distributed in the acceptable ranges in comparison with the Japan DRLs 2020. Neither extremely high nor low dose data were recorded. However, seven cases recorded outlier dose values. Three cases were caused by errors during manually inputting the data. Four from seven cases were explored the reason to record outlier dose values. CONCLUSION: Our software on a spreadsheet software worked well to explore the CT dose data, such as CTDIvol and DLP. Our software was able to find cases that were recorded as outlier dose values, but their values were not extremely high/low values. The cautionary notice of either high or low dose, as a function of our software, will be able to keep our patient's CT dose in the universal-standard "justification and optimization" level.

Coronavirus Disease 19 (COVID-19) Vaccine Effectiveness Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection During Delta-Dominant and Omicron-Dominant Periods in Japan: A Multicenter Prospective Case-control Study (Factors Associated with SARS-CoV-2 Infection and the Effectiveness of COVID-19 Vaccines Study).

BACKGROUND: Although several coronavirus disease 2019 (COVID-19) vaccines initially showed high efficacy, there have been concerns because of waning immunity and the emergence of variants with immune escape capacity. METHODS: A test-negative design case-control study was conducted in 16 healthcare facilities in Japan during the Delta-dominant period (August-September 2021) and the Omicron-dominant period (January-March 2022). Vaccine effectiveness (VE) against symptomatic severe acute respiratory syndrome coronavirus 2 infection was calculated for 2 doses for the Delta-dominant period and 2 or 3 doses for the Omicron-dominant period compared with unvaccinated individuals. RESULTS: The analysis included 5795 individuals with 2595 (44.8%) cases. Among vaccinees, 2242 (55.8%) received BNT162b2 and 1624 (40.4%) received messenger RNA (mRNA)-1273 at manufacturer-recommended intervals. During the Delta-dominant period, VE was 88% (95% confidence interval [CI], 82-93) 14 days to 3 months after dose 2 and 87% (95% CI, 38-97) 3 to 6 months after dose 2. During the Omicron-dominant period, VE was 56% (95% CI, 37-70) 14 days to 3 months since dose 2, 52% (95% CI, 40-62) 3 to 6 months after dose 2, 49% (95% CI, 34-61) 6+ months after dose 2, and 74% (95% CI, 62-83) 14+ days after dose 3. Restricting to individuals at high risk of severe COVID-19 and additional adjustment for preventive measures (ie, mask wearing/high-risk behaviors) yielded similar estimates, respectively. CONCLUSIONS: In Japan, where most are infection-naïve, and strict prevention measures are maintained regardless of vaccination status, 2-dose mRNA vaccines provided high protection against symptomatic infection during the Delta-dominant period and moderate protection during the Omicron-dominant period. Among individuals who received an mRNA booster dose, VE recovered to a high level.

Phase II study of BKM120 in patients with advanced esophageal squamous cell carcinoma (EPOC1303).

BACKGROUND: PI3K/AKT/mTOR pathway is frequently overactive in esophageal squamous cell carcinoma (ESCC), making it an attractive treatment target. BKM120 is an oral pan-class I PI3K inhibitor with promising activity in several cancers. We prospectively investigated efficacy, safety, and biomarkers of BKM120 in advanced ESCC. We conducted a multicenter phase II study of BKM120 monotherapy in patients with pretreated advanced ESCC. METHODS: BKM120 (100 mg/day) was administered orally in a 28-day cycle. The primary end point was disease control rate (DCR). Tumor samples for all patients were collected for gene alteration analysis in a comprehensive genomic profiling assay. RESULTS: Of 42 patients enrolled, 20 had stable disease and two had confirmed partial response. One ineligible patient was excluded from the primary analysis, which met the primary end point (DCR 51.2%; 95% confidence interval [CI], 35.1-67.1). In the 42 patients, median progression-free survival and overall survival were 2.3 (95% CI 1.8-3.2) and 9.0 (95% CI 6.5-11.4) months, respectively. Common grade 3 or 4 adverse events were rash, anorexia, hyponatremia, and abnormal hepatic function; profiles of these events in this study were similar to those in previous studies of BKM120 monotherapy. No treatment-related deaths occurred. PI3K pathway activation was observed in patients with good clinical response. CONCLUSIONS: BKM120 monotherapy showed promising efficacy and a manageable toxicity profile even in patients with pretreated advanced ESCC. This study showed the potential target PI3K for ESCC, and further confirmatory trial will be necessary to confirm it. Unique ID issued by UMIN: UMIN 000011217.

Behavioral factors associated with SARS-CoV-2 infection in Japan.

BACKGROUND: The relative burden of COVID-19 has been less severe in Japan. One reason for this may be the uniquely strict restrictions imposed upon bars/restaurants. To assess if this approach was appropriately targeting high-risk individuals, we examined behavioral factors associated with SARS-CoV-2 infection in the community. METHODS: This multicenter case-control study involved individuals receiving SARS-CoV-2 testing in June-August 2021. Behavioral exposures in the past 2 weeks were collected via questionnaire. SARS-CoV-2 PCR-positive individuals were cases, while PCR-negative individuals were controls. RESULTS: The analysis included 778 individuals (266 [34.2%] positives; median age [interquartile range] 33 [27-43] years). Attending three or more social gatherings was associated with SARS-CoV-2 infection (adjusted odds ratio [aOR] 2.00 [95% CI 1.31-3.05]). Attending gatherings with alcohol (aOR 2.29 [1.53-3.42]), at bars/restaurants (aOR 1.55 [1.04-2.30]), outdoors/at parks (aOR 2.87 [1.01-8.13]), at night (aOR 2.07 [1.40-3.04]), five or more people (aOR 1.81 [1.00-3.30]), 2 hours or longer (aOR 1.76 [1.14-2.71]), not wearing a mask during gatherings (aOR 4.18 [2.29-7.64]), and cloth mask use (aOR 1.77 [1.11-2.83]) were associated with infection. Going to karaoke (aOR 2.53 [1.25-5.09]) and to a gym (aOR 1.87 [1.11-3.16]) were also associated with infection. Factors not associated with infection included visiting a cafe with others, ordering takeout, using food delivery services, eating out by oneself, and work/school/travel-related exposures including teleworking. CONCLUSIONS: We identified multiple behavioral factors associated with SARS-CoV-2 infection, many of which were in line with the policy/risk communication implemented in Japan. Rapid assessment of risk factors can inform decision making.