Publications by authors named "Takashi Kohno"

374 Publications

Different Impact of Beta-Blockers on Long-Term Mortality in Heart Failure Patients with and without Chronic Obstructive Pulmonary Disease.

J Clin Med 2021 Sep 25;10(19). Epub 2021 Sep 25.

Department of Cardiology, Sakakibara Heart Institute, Tokyo 183-0003, Japan.

The administration of beta-blockers is challenging and their efficacy is unclear in heart failure (HF) patients with chronic obstructive pulmonary disease (COPD). This study aimed to investigate the association of beta-blockers with mortality in such patients. This multicenter observational cohort study included hospitalized HF patients with a left ventricular ejection fraction <50% and evaluated them retrospectively. COPD was diagnosed based on medical records and/or the clinical judgment of each investigator. The study endpoints were two-year all-cause, cardiac, and non-cardiac mortality. This study included 83 patients with COPD and 1760 patients without. Two-year all-cause, cardiac, and non-cardiac mortality were observed in 315 (17%), 149 (8%), and 166 (9%) patients, respectively. Beta-blockers were associated with lower all-cause mortality regardless of COPD (COPD: hazard ratio [HR] 0.39, 95% CI 0.16-0.98, = 0.044; non-COPD: HR 0.62, 95% CI 0.46-0.83, = 0.001). This association in HF patients with COPD persisted after multivariate analysis and inverse probability weighting and was due to lower non-cardiac mortality (HR 0.40, 95% CI 0.14-1.18. = 0.098), not cardiac mortality (HR 0.37, 95% CI 0.07-2.01, = 0.248). Beta-blockers were associated with lower all-cause mortality in HF patients with COPD due to lower non-cardiac mortality. This may reflect selection biases in beta-blocker prescription.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10194378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509631PMC
September 2021

An Adaptive STDP Learning Rule for Neuromorphic Systems.

Front Neurosci 2021 24;15:741116. Epub 2021 Sep 24.

Institute of Industrial Science, The University of Tokyo, Tokyo, Japan.

The promise of neuromorphic computing to develop ultra-low-power intelligent devices lies in its ability to localize information processing and memory storage in synaptic circuits much like the synapses in the brain. Spiking neural networks modeled using high-resolution synapses and armed with local unsupervised learning rules like spike time-dependent plasticity (STDP) have shown promising results in tasks such as pattern detection and image classification. However, designing and implementing a conventional, multibit STDP circuit becomes complex both in terms of the circuitry and the required silicon area. In this work, we introduce a modified and hardware-friendly STDP learning (named adaptive STDP) implemented using just 4-bit synapses. We demonstrate the capability of this learning rule in a pattern recognition task, in which a neuron learns to recognize a specific spike pattern embedded within noisy inhomogeneous Poisson spikes. Our results demonstrate that the performance of the proposed learning rule (94% using just 4-bit synapses) is similar to the conventional STDP learning (96% using 64-bit floating-point precision). The models used in this study are ideal ones for a CMOS neuromorphic circuit with analog soma and synapse circuits and mixed-signal learning circuits. The learning circuit stores the synaptic weight in a 4-bit digital memory that is updated asynchronously. In circuit simulation with Taiwan Semiconductor Manufacturing Company (TSMC) 250 nm CMOS process design kit (PDK), the static power consumption of a single synapse and the energy per spike (to generate a synaptic current of amplitude 15 pA and time constant 3 ms) are less than 2 pW and 200 fJ, respectively. The static power consumption of the learning circuit is less than 135 pW, and the energy to process a pair of pre- and postsynaptic spikes corresponding to a single learning step is less than 235 pJ. A single 4-bit synapse (capable of being configured as excitatory, inhibitory, or shunting inhibitory) along with its learning circuitry and digital memory occupies around 17,250 μm of silicon area.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2021.741116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498208PMC
September 2021

Study protocol for NCCH1908 (UPFRONT-trial): a prospective clinical trial to evaluate the feasibility and utility of comprehensive genomic profiling prior to the initial systemic treatment in advanced solid tumour patients.

Jpn J Clin Oncol 2021 Oct 8. Epub 2021 Oct 8.

Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.

 : Comprehensive genomic profiling has been approved for use in patients with advanced solid tumours; however, it is only indicated in advanced solid tumour patients without available standard chemotherapeutic treatment or those who have completed standard treatments in Japan, and there are no available data on the clinical feasibility and utility of comprehensive genomic profiling in treatment-naive patients. This multicentre, single-arm, prospective study aims to evaluate the feasibility and utility of the OncoGuide NCC Oncopanel System in treatment-naive patients with six advanced major malignancies: non-small cell lung cancer, breast cancer, gastric cancer, colon cancer, pancreatic cancer and biliary tract cancer (NCCH1908). This study (study cohort) will be compared with the other prospective observational study (control cohort), which enrols patients not receiving comprehensive genomic profiling prior to initial systemic treatment. A total of 200 patients will be enrolled in the study over 21 months. This study has been registered in the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) (UMIN000040743).

Clinical Trial Registration: This study, initiated in June 2020, has been registered in the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) (registration number: UMIN000040743). We plan to enrol a total of 200 patients over a period of 21 months.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jjco/hyab159DOI Listing
October 2021

Temporal trends in tolvaptan use after revision of national heart failure guidelines in Japan.

Sci Rep 2021 Sep 29;11(1):19360. Epub 2021 Sep 29.

Department of Cardiology, Sakakibara Heart Institute, Tokyo, Japan.

Within no definite diuretic protocol for acute heart failure (AHF) patients and its variation in regional clinical guidelines, the latest national guidelines in Japan commends use of tolvaptan in diuretic-resistant patients. This study aimed to examine trends in tolvaptan usage and associated outcomes of AHF patients requiring hospitalization. Between April, 2018 and October, 2019, 1343 consecutive AHF patients (median 78 [69-85] year-old) were enrolled in a prospective, multicenter registry in Japan. Trends over time in tolvaptan usage, along with the severity of heart failure status based on the Get With The Guideline-Heart Failure [GWTG-HF] risk score, and in-hospital outcomes were investigated. During the study period, tolvaptan usage has increased from 13.0 to 28.7% over time (p for trend = 0.07), and 49.4% started tolvaptan within 3 days after admission. The GWTG-HF risk score in the tolvaptan group has significantly decreased over time, while that in the non-tolvaptan group has unchanged. There were no differences in the in-hospital mortality rate between the patients with and without tolvaptan (6.7% vs. 5.8%). After revision of the Japanese clinical practice guidelines for AHF in March 2018, tolvaptan usage for AHF patients has steadily increased. However, in-hospital outcomes including mortality do not seem to be affected.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-98173-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481277PMC
September 2021

TP53 mutants and non-HPV16/18 genotypes are poor prognostic factors for concurrent chemoradiotherapy in locally advanced cervical cancer.

Sci Rep 2021 Sep 28;11(1):19261. Epub 2021 Sep 28.

Department of Gynecology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Targeted sequencing for somatic mutations across the hotspots of 50 cancer-related genes was performed using biopsy specimens to investigate whether clinicopathological factors and genomic alterations correlated with prognosis in locally advanced cervical cancer. Seventy patients diagnosed with International Federation of Obstetrics and Gynecology (FIGO) stage III to IVA cervical cancer underwent radiotherapy or concurrent chemoradiotherapy at the National Cancer Center Hospital between January 2008 and December 2017. Mutations were detected in 47 of 70 [67% of cases; frequency of genetic alterations was as follows: PIK3CA (51%), FBXW7 (10%), PTEN (7.1%), and TP53 (5.7%)]. The Cancer Genome Atlas (TCGA) datasets showed a similar distribution of somatic mutations, but PIK3CA mutation frequency was significantly higher in our cohort than in TCGA datasets (P = 0.028). Patients with TP53 mutation were significantly related to poor progression-free survival (PFS) (hazard ratio [HR] = 3.53, P = 0.042). Patients with tumor diameters > 70 mm were associated with poor prognosis (HR = 2.96, P = 0.0048). Patients with non-HPV16/18 genotypes had worse prognosis than those with HPV16/18 genotypes (HR = 2.15, P = 0.030). Hence, patients with locally advanced cervical cancer, TP53 mutation, large tumor diameter, and non-HPV16/18 genotype were independently correlated with poor PFS, despite concurrent chemoradiotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-98527-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478905PMC
September 2021

Assessment of Physical Activity Using Waist-Worn Accelerometers in Hospitalized Heart Failure Patients and Its Relationship with Kansas City Cardiomyopathy Questionnaire.

J Clin Med 2021 Sep 11;10(18). Epub 2021 Sep 11.

Department of Cardiology, Keio University School of Medicine, Tokyo 160-8582, Japan.

The health benefits of physical activity have been widely recognized, yet there is limited information on associations between accelerometer-related parameters and established patient-reported health status. This study investigated the association between the waist-worn accelerometer measurements, cardiopulmonary exercise testing (CPX), and results of the Kansas City Cardiomyopathy Questionnaire (KCCQ) in heart failure (HF) patients hospitalized for acute decompensation. A total of 31 patients were enrolled and wore a validated three-axis accelerometer for 2 weeks and completed the short version of the KCCQ after removing the device. Daily step counts, exercise time (metabolic equivalents × hours), and %sedentary time (sedentary time/device-equipped time) were measured. Among the measured parameters, the best correlation was observed between %sedentary time and the KCCQ overall and clinical summary scores (r = -0.65 and -0.65, each < 0.001). All of the individual domains of the KCCQ (physical limitation, symptom frequency, and quality of life), with the exception of the social limitation domain, showed moderate correlations with %sedentary time. Finally, oxygen consumption assessed by CPX demonstrated only weak associations with the accelerometer-measured parameters. An accelerometer could complement the KCCQ results in accurately assessing the physical activity in HF patients immediately after hospitalization, albeit its correlation with CPX was at most moderate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10184103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470222PMC
September 2021

Phenomapping in patients experiencing worsening renal function during hospitalization for acute heart failure.

ESC Heart Fail 2021 Sep 20. Epub 2021 Sep 20.

Department of Cardiology, Sakakibara Heart Institute, Tokyo, Japan.

Aims: The impact of worsening renal function (WRF) on the prognosis of patients with acute heart failure (AHF) remains controversial. We aimed to identify phenotypically distinct subgroups among individuals with both AHF and WRF using cluster analysis.

Methods And Results: Overall, the data of 483 patients with both AHF and WRF enrolled in the West Tokyo Heart Failure Registry were analysed. Using cluster analysis, we identified three phenotypically distinct subgroups (phenogroups 1, 2, and 3). We assessed the impact of WRF on the prognosis of each phenogroup by comparing the incidence of composite endpoints, including all-cause death and re-hospitalization due to heart failure, with those of a propensity score-matched, non-WRF control group. Participants in phenogroup 1 (N = 122) were the youngest (69.3 ± 13.7 years), had relatively preserved estimated glomerular filtration rate (eGFR, 70.0 ± 27.7 mL/min/1.73 m ), and reduced left ventricular ejection fraction (LVEF) (41.8 ± 13.7%). Conversely, participants in phenogroup 3 (N = 122) were the oldest (81.7 ± 8.5 years), had the worst eGFR (33.0 ± 20.9 mL/min/1.73 m ), and had preserved LVEF (51.7 ± 14.8%). The characteristics of the participants in phenogroup 2 (N = 239) were between those of phenogroups 1 and 3. The propensity score matching analysis showed that WRF was associated with a higher incidence of composite endpoints in phenogroup 1, whereas this association was not observed in phenogroups 2 and 3.

Conclusions: Using cluster analysis, we revealed three phenotypically distinct subgroups of patients with both AHF and WRF. WRF was associated with worse clinical outcomes in the subgroup of younger patients with reduced LVEF and preserved renal function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ehf2.13598DOI Listing
September 2021

Preferences on advance care planning and end-of-life care in patients hospitalized for heart failure.

ESC Heart Fail 2021 Sep 4. Epub 2021 Sep 4.

Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.

Aims: Early engagement in advance care planning (ACP) is recommended in heart failure (HF) management. We investigated the preferences of patients with HF regarding ACP and end-of-life (EOL) care, including their desired timing of ACP initiation.

Methods And Results: Data were collected using a 92-item questionnaire survey, which was directly distributed to hospitalized patients by dedicated physicians and nurses in a university hospital setting. One-hundred eighty-seven patients agreed to participate (response rate: 92.6%), and 171 completed the survey [valid response rate: 84.7%; men: 67.3%; median age: 73.0 (63.0-81.0) years]. Logistic regression analyses were conducted to identify the predictors of positive attitudes towards ACP. Most recognized ACP as important for their care (n = 127, 74.3%), 48.1% stated that ACP should be initiated after repeated HF hospitalizations in the past year, and 29.0% preferred ACP to begin during the first or second HF hospitalization. Only 21.7% of patients had previously engaged in ACP conversations during HF management. Positive attitudes towards ACP were associated with lower depressive symptoms [two-item Patient Health Questionnaire; odds ratio (OR): 0.75, 95% confidence interval (CI): 0.61-0.92, P-value: 0.006], marriage (OR: 2.53, 95% CI: 1.25-5.12, P-value: 0.010), and a high educational level (OR: 2.66, 95% CI: 1.28-5.56, P-value: 0.009), but not with severity of HF (represented by Seattle Heart Failure Model risk score). Regarding EOL care, while 'Saying what one wants to tell loved ones' (83.4%), 'Dying a natural death' (81.8%), and 'Being able to stay at one's favorite place' (75.6%) were the three most important factors for patients, preferences for 'Receiving sufficient treatment' (56.5%) and 'Knowing what to expect about future condition' (50.3%) were divergent.

Conclusions: Despite patients' preferences for ACP conversations, there was a discrepancy between preference and engagement in ACP among patients hospitalized for HF. Patients' preferences regarding EOL care may differ; physicians need to consider the appropriate ACP approach to align with patients' care goals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ehf2.13578DOI Listing
September 2021

Differential Immune-Related Microenvironment Determines Programmed Cell Death Protein-1/Programmed Death-Ligand 1 Blockade Efficacy in Patients With Advanced NSCLC.

J Thorac Oncol 2021 Aug 20. Epub 2021 Aug 20.

Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.

Introduction: Programmed death-ligand 1 (PD-L1) expression is not a completely reliable predictive marker of the efficacy of anti-programmed cell death protein-1 (PD-1)/PD-L1 therapy in patients with advanced NSCLC. Immune-related tumor microenvironment (TME) is classified into four different types based on the tumor-infiltrating lymphocyte (TIL) status and PD-L1 expression.

Methods: We retrospectively reviewed patients with advanced NSCLC treated with anti-PD-1/PD-L1 therapy between 2015 and 2019. We investigated the association between the efficacy of anti-PD-1/PD-L1 therapy, the types of TME based on PD-L1 (clone: 22C3) expression, the density of CD8-positive TILs assessed by immunohistochemistry, and mutational profiles by next-generation sequencing.

Results: Overall, 228 patients were included in the analysis. The patients were classified into the following four groups: type I: PD-L1 (tumor proportion score ≥ 50%)/TIL (≥85/mm; n = 73); type II: PD-L1 (tumor proportion score < 50%)/TIL (<85/mm; n = 70); type III: PD-L1/TIL (n = 37); and type IV: PD-L1/TIL (n = 48). The objective response rate (ORR) and progression-free survival (PFS) of anti-PD-1/PD-L1 therapy clearly differed according to the different TME types (ORR and PFS; type I: 64%, 14.5 mo; type II: 12%, 2.1 mo; type III: 24%, 3.6 mo; type IV; 41%, 10.8 mo). In patients with PD-L1 tumors, type I tumors had significantly better ORR and PFS than type III tumors (ORR: p < 0.001 and PFS: p < 0.001). The presence of TP53 and KRAS mutation was related to the density of CD8-positive TILs and PD-L1 expression, respectively.

Conclusions: Differential types of TME, including PD-L1 expression and TIL status, could accurately predict the efficacy of anti-PD-1/PD-L1 therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2021.07.027DOI Listing
August 2021

Sudden cardiac death after acute decompensation in heart failure patients: implications of discharge haemoglobin levels.

ESC Heart Fail 2021 Oct 29;8(5):3917-3928. Epub 2021 Jul 29.

Department of Cardiology, Sakakibara Heart Institute, Tokyo, Japan.

Aims: Heart failure (HF) patients have a high risk of mortality due to sudden cardiac death (SCD) and non-SCD, including pump failure death (PFD). Anaemia predicts more severe symptomatic burden and higher morbidity, as noted by markedly increased hospitalizations and readmission rates, and mortality, underscoring its importance in HF management. Herein, we aimed to determine whether haemoglobin (Hb) level at discharge affects the mode of death and influences SCD risk prediction.

Methods: We evaluated the data of 3020 consecutive acute HF patients from a Japanese prospective multicentre registry. Patients were divided into four groups based on discharge Hb levels. SCD was defined as an unexpected and otherwise unexplained death in a previously stable patient or death due to documented or presumed cardiac arrhythmia without a clear non-cardiovascular cause. The mode of death (SCD, PFD or other cause) was adjudicated by a central committee. Finally, we investigated whether adding Hb level to the Seattle Proportional Risk Model (SPRM; established risk score utilized to estimate 'proportion' of SCD among death events) would affect its performance.

Results: The mean age of studied patients was 74.3 ± 12.9 years, and 59.8% were male. The mean Hb level was 12.0 ± 2.1 g/dL (61.3% of patients had anaemia defined by World Health Organization criteria). During the 2-year follow-up, 474 deaths (15.7%) occurred, including 93 SCDs (3.1%), 171 PFDs (5.7%) and 210 other deaths (7.0%; predominantly non-cardiac death). Absolute risk of PFD (P < 0.001) or other death (P < 0.001) increased along with the severity of anaemia, whereas the incidence of SCD was low but remained consistent across all four groups (P = 0.440). As a proportion of total deaths in each Hb level group, the contributions from non-SCD increased and from SCD decreased along with anaemia severity (P = 0.007). Adding Hb level to the SPRM improved the overall discrimination (c-index: 0.62 [95% confidence interval (CI) 0.56-0.69] to 0.65 [95% CI 0.59-0.71]), regardless of the baseline ejection fraction (EF) (c-index: 0.64 [95% CI 0.55-0.73] to 0.67 [95% CI 0.58-0.75] for reduced EF and 0.55 [95% CI 0.45-0.66] to 0.61 [95% CI 0.52-0.70] for preserved EF).

Conclusions: The discharge Hb level provides information about both absolute and proportional risks for each mode of death in acute HF patients, and the addition of Hb level improves the performance of SPRM by identifying more non-SCD cases. Future 'proportional' SCD risk models should incorporate Hb level as a covariate to meet this high performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ehf2.13414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497203PMC
October 2021

Exercise tolerance and quality of life in hemodynamically partially improved patients with chronic thromboembolic pulmonary hypertension treated with balloon pulmonary angioplasty.

PLoS One 2021 23;16(7):e0255180. Epub 2021 Jul 23.

Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.

The efficacy of extensive balloon pulmonary angioplasty (BPA) beyond hemodynamic improvement in chronic thromboembolic pulmonary hypertension (CTEPH) patients has been verified. However, the relationship between extensive BPA in CTEPH patients after partial hemodynamic improvement and exercise tolerance or quality of life (QOL) remains unclear. We prospectively enrolled 22 CTEPH patients (66±10 years, females: 59%) when their mean pulmonary artery pressure initially decreased to <30 mmHg during BPA sessions. Hemodynamic and echocardiographic data, cardiopulmonary exercise testing, and QOL scores using the 36-item short form questionnaire (SF-36) were evaluated at enrollment (entry), just after the final BPA session (finish), and at the 6-month follow-up (follow-up). We analyzed whether extensive BPA improves exercise capacity and QOL scores over time. Moreover, the clinical characteristics leading to improvement were elucidated. The peak oxygen uptake (VO2) showed significant improvement at entry, finish, and follow-up (17.3±5.5, 18.4±5.9, and 18.9±5.3 mL/kg/min, respectively; P<0.001). Regarding the QOL, the physical component summary (PCS) scores significantly improved (32±11, 38±13, and 43±13, respectively; P<0.001), but the mental component summary scores remained unchanged. Linear regression analysis revealed that age and a low peak VO2 at entry were predictors of improvement in peak VO2, while low PCS scores and low TAPSE at entry were predictors of improvement in PCS scores. In conclusion, extensive BPA led to improved exercise tolerance and physical QOL scores, even in CTEPH patients with partially improved hemodynamics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255180PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301648PMC
July 2021

MUSASHI-2 confers resistance to third-generation EGFR-tyrosine kinase inhibitor osimertinib in lung adenocarcinoma.

Cancer Sci 2021 Sep 13;112(9):3810-3821. Epub 2021 Jul 13.

Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Japan.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in patients with non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, due to acquired resistance to EGFR-TKIs, even patients on third-generation osimertinib have a poor prognosis. Resistance mechanisms are still not fully understood. Here, we demonstrate that the increased expression of MUSASHI-2 (MSI2), an RNA-binding protein, is a novel mechanism for resistance to EGFR-TKIs. We found that after a long-term exposure to gefitinib, the first-generation EGFR-TKI lung cancer cells harboring the EGFR-TKI-sensitive mutations became resistant to both gefitinib and osimertinib. Although other mutations in EGFR were not found, expression levels of Nanog, a stemness core protein, and activities of aldehyde dehydrogenase (ALDH) were increased, suggesting that cancer stem-like properties were increased. Transcriptome analysis revealed that MSI2 was among the stemness-related genes highly upregulated in EGFR-TKI-resistant cells. Knockdown of MSI2 reduced cancer stem-like properties, including the expression levels of Nanog, a core stemness factor. We demonstrated that knockdown of MSI2 restored sensitivity to osimertinib or gefitinib in EGFR-TKI-resistant cells to levels similar to those of parental cells in vitro. An RNA immunoprecipitation (RIP) assay revealed that antibodies against MSI2 were bound to Nanog mRNA, suggesting that MSI2 increases Nanog expression by binding to Nanog mRNA. Moreover, overexpression of MSI2 or Nanog conferred resistance to osimertinib or gefitinib in parental cells. Finally, MSI2 knockdown greatly increased the sensitivity to osimertinib in vivo. Collectively, our findings provide proof of principle that targeting the MSI2-Nanog axis in combination with EGFR-TKIs would effectively prevent the emergence of acquired resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.15036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409425PMC
September 2021

Novel diagnostic and therapeutic approaches to pulmonary hypertension due to the unilateral absence of a pulmonary artery.

ESC Heart Fail 2021 Aug 16;8(4):3427-3430. Epub 2021 Jun 16.

Department of Cardiovascular Medicine, Kyorin University Hospital, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.

We report the case of a 64-year-old female diagnosed with severe pulmonary hypertension due to the unilateral absence of a pulmonary artery. The four-dimensional computed tomography scan is a useful modality for revealing detailed anatomical findings for differential diagnoses and surgical decision-making. The patient had severe pulmonary hypertension with a mean pulmonary artery pressure (PAP) of 74 mmHg and was treated with triple upfront combination therapy, leading to significant improvement in pulmonary haemodynamics (to 27 mmHg in mean PAP) and functional capacity (WHO functional class, from III to II; 6-min walk distance, from 211 to 276 m).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ehf2.13459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318494PMC
August 2021

Upregulation of FGF9 in Lung Adenocarcinoma Transdifferentiation to Small Cell Lung Cancer.

Cancer Res 2021 Jul 3;81(14):3916-3929. Epub 2021 Jun 3.

Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.

Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of and alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors through cell autonomous activation of the FGFR pathway. treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9-FGFR axis as a therapeutic target for transdifferentiated SCLC. SIGNIFICANCE: This study demonstrates that FGF9 plays a role in the transdifferentiation of lung adenocarcinoma to small cell lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-4048DOI Listing
July 2021

Impact of ALK Inhibitors in Patients With -Rearranged Nonlung Solid Tumors.

JCO Precis Oncol 2021 3;5. Epub 2021 May 3.

Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.

Purpose: Anaplastic lymphoma kinase () rearrangement is a well-known driver oncogene in non-small-cell lung cancer and has also been identified in other types of tumors. However, there is limited evidence on the clinical response to ALK tyrosine kinase inhibitors (TKIs), such as alectinib and crizotinib, in rare tumors with ALK fusion. We evaluated the therapeutic effect of ALK-TKIs in rare -rearranged tumors.

Patients And Methods: Between April 2012 and April 2019, clinical outcomes and characteristics of patients with -rearranged nonlung solid tumors who received ALK-TKIs (alectinib and/or crizotinib) outside of clinical trials were reviewed. Expression and/or rearrangement of ALK was evaluated by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. The tumor response was assessed according to RECIST (version 1.1). Progression-free survival was estimated from initial ALK-TKI initiation until progression.

Results: We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare fusions, namely, K and , were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib.

Conclusion: This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with -rearranged nonlung solid tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.20.00383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140781PMC
May 2021

Distribution of genetic alterations in high-risk early-stage cervical cancer patients treated with postoperative radiation therapy.

Sci Rep 2021 05 19;11(1):10567. Epub 2021 May 19.

Department of Radiation Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Somatic genetic alteration analysis was performed for post-hysterectomy high-risk early-stage uterine cervical cancer patients who underwent post-operative radiation therapy. Post-operative radiation therapy was performed for patients with pathological features of pelvic lymph node metastasis, parametrium invasion, or positive vaginal margin, which corresponded to the post-operative high-risk category. DNA was extracted from paraffin-embedded surgical specimens, and 50 somatic hotspot genetic alternations were detected using Ion AmpliSeq Cancer Hotspot Panel. The existence of actionable mutation was assessed based on OncoKB evidence level > 3A. Between January 2008 and November 2019, 89 patients who underwent abdominal radical hysterectomy followed by post-operative radiation therapy were identified. The follow-up period for living patients was 82.3 months (range 9.3-153.9), and the 5-year relapse-free survival and overall survival rates were 72.6% and 85.9%, respectively. The most frequently detected somatic mutation was PIK3CA (26 [29.2%] patients); however, no prognostic somatic genetic alterations were identified. Actionable mutations were detected in 30 (33.7%) patients. Actionable mutations were detected in approximately one-third of patients, suggesting that precision medicine can be offered to patients with post-operative high-risk uterine cervical cancer in the near future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-90139-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134569PMC
May 2021

Patient Perspectives in the Era of Remote Medical Visits During the Coronavirus Disease (COVID-19) Pandemic - Insights From Outpatient Care of Cardiovascular Disease.

Circ Rep 2021 Apr 28;3(5):300-303. Epub 2021 Apr 28.

Department of Cardiology, Keio University School of Medicine Tokyo Japan.

Patient perspectives in cardiovascular diseases (CVD) are significantly associated with clinical outcomes. Among 100 patients who responded to a telephone survey in a university hospital setting in Tokyo during the coronavirus disease (COVID-19) pandemic, 20% reported depressive symptoms and 33% were hesitant to contact medical staff in the event of CVD exacerbation. Interestingly, the frequency of depressive symptoms was maintained even after a decline in the number of newly COVID-19-infected patients. Our telemedicine practices revealed the magnitude of our patients' mental health conditions and their hesitation to contact medical facilities in the event of CVD exacerbation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1253/circrep.CR-21-0039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099663PMC
April 2021

Genome-Wide Chromatin Analysis of FFPE Tissues Using a Dual-Arm Robot with Clinical Potential.

Cancers (Basel) 2021 Apr 28;13(9). Epub 2021 Apr 28.

Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.

Although chromatin immunoprecipitation and next-generation sequencing (ChIP-seq) using formalin-fixed paraffin-embedded tissue (FFPE) has been reported, it remained elusive whether they retained accurate transcription factor binding. Here, we developed a method to identify the binding sites of the insulator transcription factor CTCF and the genome-wide distribution of histone modifications involved in transcriptional activation. Importantly, we provide evidence that the ChIP-seq datasets obtained from FFPE samples are similar to or even better than the data for corresponding fresh-frozen samples, indicating that FFPE samples are compatible with ChIP-seq analysis. H3K27ac ChIP-seq analyses of 69 FFPE samples using a dual-arm robot revealed that driver mutations in EGFR were distinguishable from pan-negative cases and were relatively homogeneous as a group in lung adenocarcinomas. Thus, our results demonstrate that FFPE samples are an important source for epigenomic research, enabling the study of histone modifications, nuclear chromatin structure, and clinical data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13092126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125448PMC
April 2021

Abnormal Liver Function Tests and Long-Term Outcomes in Patients Discharged after Acute Heart Failure.

J Clin Med 2021 Apr 16;10(8). Epub 2021 Apr 16.

Department of Cardiology, Sakakibara Heart Institute, Tokyo 183-0003, Japan.

Abnormal liver function tests (LFTs) are known to be associated with impaired clinical outcomes in heart failure (HF) patients. However, this implication varies with each single LFT panel. We aim to evaluate the long-term outcomes of acute HF (AHF) patients by assessing multiple LFT panels in combination. From a prospective multicenter registry in Japan, 1158 AHF patients who were successfully discharged were analyzed (mean age, 73.9 ± 13.5 years; men, 58%). LFTs (i.e., total bilirubin, aspartate aminotransferase or alanine aminotransferase, and alkaline phosphatase) at discharge were assessed; borderline and abnormal LFTs were defined as 1 and ≥2 parameter values above the normal range, respectively. The primary endpoint was composite of all-cause death or HF readmission. At the time of discharge, 28.7% and 8.6% of patients showed borderline and abnormal LFTs, respectively. There were 196 (16.9%) deaths and 298 (25.7%) HF readmissions during a median 12.4-month follow-up period. The abnormal LFTs group had a significantly higher risk of experiencing the composite outcome (adjusted hazard ratio: 1.51, 95% confidence interval: 1.08-2.12, = 0.017), whereas the borderline LFTs group was not associated with higher risk of adverse events when referenced to the normal LFTs group. Among AHF patients, the combined elevation of ≥2 LFT panels at discharge was associated with long-term adverse outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10081730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072793PMC
April 2021

Gene Amplification-Associated Overexpression of the Selenoprotein tRNA Enzyme TRIT1 Confers Sensitivity to Arsenic Trioxide in Small-Cell Lung Cancer.

Cancers (Basel) 2021 Apr 14;13(8). Epub 2021 Apr 14.

Josep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, Spain.

The alteration of RNA modification patterns is emerging as a common feature of human malignancies. If these changes affect key RNA molecules for mRNA translation, such as transfer RNA, they can have important consequences for cell transformation. TRIT1 is the enzyme responsible for the hypermodification of adenosine 37 in the anticodon region of human tRNAs containing serine and selenocysteine. Herein, we show that TRIT1 undergoes gene amplification-associated overexpression in cancer cell lines and primary samples of small-cell lung cancer. From growth and functional standpoints, the induced depletion of TRIT1 expression in amplified cells reduces their tumorigenic potential and downregulates the selenoprotein transcripts. We observed that TRIT1-amplified cells are sensitive to arsenic trioxide, a compound that regulates selenoproteins, whereas reduction of TRIT1 levels confers loss of sensitivity to the drug. Overall, our results indicate a role for TRIT1 as a small-cell lung cancer-relevant gene that, when undergoing gene amplification-associated activation, can be targeted with the differentiation agent arsenic trioxide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13081869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070726PMC
April 2021

Treatment Strategies for ARID1A-Deficient Ovarian Clear Cell Carcinoma.

Cancers (Basel) 2021 Apr 7;13(8). Epub 2021 Apr 7.

Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.

Ovarian clear cell carcinoma (OCCC) is a histological subtype of ovarian cancer that is more frequent in Asian countries (~25% of ovarian cancers) than in US/European countries (less than 10%). OCCC is refractory to conventional platinum-based chemotherapy, which is effective against high-grade serous carcinoma (HGSC), a major histological subtype of ovarian cancer. Notably, deleterious mutations in SWI/SNF chromatin remodeling genes, such as , are common in OCCC but rare in HGSC. Because this complex regulates multiple cellular processes, including transcription and DNA repair, molecularly targeted therapies that exploit the consequences of SWI/SNF deficiency may have clinical efficacy against OCCC. Three such strategies have been proposed to date: prioritizing a gemcitabine-based chemotherapeutic regimen, synthetic lethal therapy targeting vulnerabilities conferred by SWI/SNF deficiency, and immune checkpoint blockade therapy that exploits the high mutational burden of -deficient tumor. Thus, ARID1A deficiency has potential as a biomarker for precision medicine of ovarian cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13081769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068058PMC
April 2021

Long-Term Prognosis of Patients With Resected Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma of the Lung.

J Thorac Oncol 2021 08 27;16(8):1312-1320. Epub 2021 Apr 27.

Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.

Introduction: The WHO classification of lung tumors defines adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) as cancers with no or limited histologic invasive components. The probability of patients with AIS or MIA being recurrence free for 5 years postoperatively has been found to be 100%. This study aimed to analyze the prognosis of patients with AIS or MIA after more than 5 postoperative years.

Methods: We reviewed the pathologic findings of 4768 patients who underwent resection for lung cancer between 1998 and 2010. Of these, 524 patients with curative resection for AIS (207 cases, 39.5%) and MIA (317 cases, 60.5%) were included. Postoperative recurrence, survival, and development of secondary primary lung cancer (SPLC) were analyzed.

Results: Of the included patients, 342 (65.3%) were of female sex, 333 (63.5%) were nonsmokers, and 229 (43.7%) underwent sublobar resection. Average pathologic total tumor diameter was 15.2 plus or minus 5.5 mm. Median postoperative follow-up period was 100 months (range: 1-237). No recurrence of lung cancer was observed for either AIS or MIA cases. Estimated 10-year postoperative disease-specific survival rates were 100% and 100% (p = 0.72), and overall survival rates were 95.3% and 97.8% (p = 0.94) for AIS and MIA cases, respectively. Estimated incidence rates of metachronous SPLC at 10 years after surgery were 5.6% and 7.7% for AIS and MIA, respectively (p = 0.45), and these were not correlated with the EGFR mutation status.

Conclusions: Although the development of metachronous SPLC should be noted, the risk of recurrence is quite low at more than 5 years after resection of AIS and MIA. This finding strengthens the clinical value of distinguishing AIS and MIA from other adenocarcinomas of the lung.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2021.04.007DOI Listing
August 2021

Revisiting the Role of Guideline-Directed Medical Therapy for Patients with Heart Failure and Severe Functional Mitral Regurgitation.

Cardiol Clin 2021 May;39(2):255-265

Department of Cardiovascular Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 192-8508, Japan.

Patients with heart failure often have mitral regurgitation, which can generate a vicious cycle. Medical therapy remains the cornerstone of their treatment in this setting. This review revisits the role of medical therapy and its optimization for severe functional mitral regurgitation in the contemporary era.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccl.2021.01.008DOI Listing
May 2021

Factors contributing to exercise capacity in chronic thromboembolic pulmonary hypertension with near-normal hemodynamics.

J Heart Lung Transplant 2021 07 5;40(7):677-686. Epub 2021 Mar 5.

Department of Cardiovascular Medicine, Kyorin University Hospital, Tokyo, Japan.

Background: Despite improved survival for patients with chronic thromboembolic pulmonary hypertension (CTEPH) due to progressive medical and interventional treatment, impaired exercise capacity remains common due to poorly understood mechanisms. We aimed to clarify the exercise capacity of CTEPH patients with near-normal pulmonary hemodynamics and evaluate its determinants among the hemodynamic, peripheral (e.g., oxygen use by the peripheral tissues), and muscular (e.g., skeletal muscle strength) factors.

Methods: Three hundred and twenty-nine patients with CTEPH (mean age, 63 ± 12 years; men/women, 73/256) with a near-normal mean pulmonary artery pressure (≤30 mm Hg) at rest were enrolled. We assessed exercise capacity by peak oxygen consumption (peak VO) using cardiopulmonary exercise testing with a right heart catheter. We also measured the 6-minute walk distance (6MWD) and quadriceps muscle strength.

Results: The mean pulmonary artery pressure was 19 ± 4 mmHg and mean cardiac output was 4.8 ± 1.5 L/min at rest. The mean 6MWD was 444 ± 101 m, while the mean peak VO was 14.4 ± 3.9 mL/min/kg. A multivariate model that predicted 6MWD included quadriceps strength (β = 0.45, p < 0.001) and peak arterial venous oxygen difference (β = 0.29, p < 0.001). In contrast, the peak VO was best correlated with mPAP-CO slope (β = -0.30, p < 0.001), followed by quadriceps strength and peak arterial venous oxygen difference.

Conclusions: The 6MWD performance may be significantly influenced by peripheral oxygen use and muscular factors, while peak VO is influenced by hemodynamic and peripheral factors in CTEPH patients with near-normal hemodynamics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.healun.2021.03.003DOI Listing
July 2021

Comparative Analysis of Genetic Alterations, HPV-Status, and PD-L1 Expression in Neuroendocrine Carcinomas of the Cervix.

Cancers (Basel) 2021 Mar 10;13(6). Epub 2021 Mar 10.

Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

Neuroendocrine carcinoma of the cervix (NECC) is a rare and highly aggressive tumor with no efficient treatment. We examined genetic features of NECC and identified potential therapeutic targets. A total of 272 patients with cervical cancer (25 NECC, 180 squamous cell carcinoma, 53 adenocarcinoma, and 14 adenosquamous carcinoma) were enrolled. Somatic hotspot mutations in 50 cancer-related genes were detected using the Ion AmpliSeq Cancer Hotspot Panel v2. Human papillomavirus (HPV)-positivity was examined by polymerase chain reaction (PCR)-based testing and in situ hybridization assays. Programmed cell death-ligand 1 (PD-L1) expression was examined using immunohistochemistry. Somatic mutation data for 320 cases of cervical cancer from the Project GENIE database were also analyzed. NECC showed similar (, 32%; , 24%) and distinct (, 20%; , 16%; , 12%; , 12%) alterations compared with other histological types. The GENIE cohort had similar profiles and mutations in 27.6% of NECC cases. Eleven (44%) cases had at least one actionable mutation linked to molecular targeted therapies and 14 (56%) cases showed more than one combined positive score for PD-L1 expression. HPV-positivity was observed in all NECC cases with a predominance of HPV-18. We report specific gene mutation profiles for NECC, which can provide a basis for the development of novel therapeutic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13061215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001835PMC
March 2021

Final survival results for the LURET phase II study of vandetanib in previously treated patients with RET-rearranged advanced non-small cell lung cancer.

Lung Cancer 2021 05 10;155:40-45. Epub 2021 Mar 10.

Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.

Objectives: The LURET phase II study evaluated the efficacy and safety of the multikinase inhibitor vandetanib in patients with previously treatedRET-rearranged advanced non-small cell lung cancer (NSCLC). Among the eligible patients included in the primary analysis, the objective response rate met the primary endpoint (53 %, 90 % confidence interval [CI]: 31-74). Here, we report final survival outcomes of the LURET study.

Materials And Methods: Nineteen patients with previously treated RET-rearranged advanced NSCLC continuously received 300 mg of oral vandetanib daily. This final analysis provides updated data on progression-free survival (PFS), overall survival (OS) and safety. This study was registered with UMIN-CTR (number UMIN 000010095).

Results: Among the 19 patients in the intention-to-treat population, 42 % had been heavily treated with 3 or more prior chemotherapy regimens. The median PFS was 6.5 months (95 % CI, 3.9-9.3) as determined by an independent radiology review committee. The median OS was 13.5 months (95 % CI, 9.8-28.1) and the overall survival rate at 12 months was 52.6 % (95 % CI 28.7-71.9). The most common adverse events were hypertension (84.2 %), diarrhea (78.9 %), and rash acneiform (63.2 %). Overall, 11 patients (57.9 %) had adverse events leading to a dose reduction, although the safety profile was consistent with that reported in previous studies.

Conclusion: Our results indicated that vandetanib enabled a prolonged and clinically meaningful PFS and OS in patients with previously treatedRET-rearranged advanced NSCLC at the updated final analysis. The safety profile was consistent with that reported in previous studies, although most of the patients experienced off-target adverse events besides RET.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2021.03.002DOI Listing
May 2021

Activity and Immune Correlates of Programmed Death-1 Blockade Therapy in Patients With Advanced Large Cell Neuroendocrine Carcinoma.

Clin Lung Cancer 2021 07 8;22(4):282-291.e6. Epub 2021 Feb 8.

Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.

Background: The efficacy of anti-programmed death receptor 1 (PD-1) therapy in patients with large cell neuroendocrine carcinoma (LCNEC) remains unclear. We investigated the outcome of anti-PD-1 therapy and its predictive markers by evaluating the immune-related tumor microenvironment.

Patients: We retrospectively reviewed patients with advanced LCNEC treated with systemic chemotherapy. We also evaluated PD ligand 1 (PD-L1) expression (clone: 22C3), CD8-positive tumor-infiltrating lymphocytes (TILs), and the mutational profiles.

Results: Seventy patients were enrolled, and 13 of 70 patients received anti-PD-1 therapy. The progression-free survival (PFS) and objective response rate (ORR) of the anti-PD-1 therapy were 4.2 months and 39%, respectively. The overall survival of patients treated with anti-PD-1 therapy (n = 13) was significantly better than those treated without anti-PD-1 therapy (n = 57) (25.2 months vs 10.9 months; P = .02). Among the 13 patients treated with anti-PD-1 therapy, 10 patients (90%) had PD-L1-negative tumors. Patients with a high density of tumoral CD8-positive TILs (≥38/mm) had a significantly better ORR and PFS than those with a low density of tumoral CD8-positive TILs (ORR: P = .02; PFS: P = .003). Additionally, all 3 patients with TP53 mutation co-occurring with PIK3CA mutation (2 of 8 patients) or RB1 mutation (1 of 8 patients) responded to anti-PD-1 therapy.

Conclusions: Anti-PD-1 therapy was effective regardless of PD-L1 positivity in patients with advanced LCNEC. Our investigation might suggest that the density of tumoral CD8-positive TILs and the presence of co-occurring mutations are predictors of the efficacy of anti-PD-1 therapy in patients with advanced LCNEC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cllc.2021.02.003DOI Listing
July 2021

Frequent nightmares and its associations with psychological and sleep disturbances in hospitalized patients with cardiovascular diseases.

Eur J Cardiovasc Nurs 2021 Jun;20(5):421-427

Division of Cardiology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

Aims: Frequent nightmares can pose a serious clinical problem, especially in association with sleep and psychological disturbances, in the general population. However, this association has not been investigated in inpatients with cardiovascular (CV) diseases. Furthermore, whether CV medications could induce iatrogenic nightmares remains unknown. In a cross-sectional designed study, we evaluated the prevalence and determinants of frequent nightmares and its association with sleep and psychological disturbances among hospitalized CV patients.

Methods And Results: A total of 1233 patients (mean age, 64 ± 15 years; 25.1% female) hospitalized for various CV diseases in a single university hospital were enrolled. We assessed nightmares and sleep characteristics using the Pittsburgh Sleep Quality Index (PSQI), sleep-disordered breathing (SDB) using nocturnal pulse oximetry, and psychological disturbances using Hospital Anxiety and Depression Scale (HADS). Overall, 14.8% and 3.6% of the patients had at least one nightmare per month and per week (frequent nightmares), respectively. In this cohort, 45.9% had insomnia (modified PSQI > 5), 28.0% had SDB (3% oxygen desaturation index > 15), 18.5% had depression (HADS-depression ≥ 8), and 16.9% had anxiety (HADS-anxiety ≥ 8). Frequent nightmares were not associated with CV medications and SDB but were associated with depression [odds ratio (OR) = 4.61, 95% confidence interval (CI) = 2.03-10.48], anxiety (OR = 5.32, 95% CI = 2.36-12.01), and insomnia (OR = 7.15, 95% CI = 2.41-21.22).

Conclusions: Frequent nightmares were not uncommon in patients hospitalized for CV diseases. Although the cause-effect relationship is unclear, frequent nightmares were associated with psychological disturbances and insomnia, but not iatrogenic factors, among hospitalized CV patients. Cardiologists should be more conscientious to nightmare complaints with respect to screening for psychological disturbances and insomnia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurjcn/zvaa016DOI Listing
June 2021

HSP90 inhibition overcomes EGFR amplification-induced resistance to third-generation EGFR-TKIs.

Thorac Cancer 2021 03 20;12(5):631-642. Epub 2021 Jan 20.

Division of Cancer Immunology, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan.

Background: Patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are sensitive to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) but inevitably develop resistance to the inhibitors mostly through acquisition of the secondary T790M mutation. Although third-generation EGFR-TKIs overcome this resistance by selectively inhibiting EGFR with EGFR-TKI-sensitizing and T790M mutations, acquired resistance to third-generation EGFR-TKIs invariably develops.

Methods: Next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) analysis were performed in an EGFR T790M-mutated NSCLC patient who had progressed after a third-generation EGFR-TKI, TAS-121. EGFR-mutated cell lines were subjected to a cell proliferation assay and western blotting analysis with EGFR-TKIs and a heat shock protein 90 (HSP90) inhibitor.

Results: NGS and FISH analysis revealed EGFR amplification in the resistant cancer cells. While EGFR L858R/T90M-mutated cell line was sensitive to osimertinib or TAS-121 in vitro, EGFR-overexpressing cell lines displayed resistance to these EGFR-TKIs. Western blot analysis showed that EGFR phosphorylation and overexpression of EGFR in cell lines was not suppressed by third-generation EGFR-TKIs. In contrast, an HSP90 inhibitor reduced total and phosphorylated EGFR and inhibited the proliferation of resistant cell lines.

Conclusions: EGFR amplification confers resistance to third-generation EGFR-TKIs which can be overcome by HSP90 inhibition. The results provide a preclinical rationale for the use of HSP90 inhibitors to overcome EGFR amplification-mediated resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1759-7714.13839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919131PMC
March 2021
-->