Model of lung cancer surgery risk derived from a Japanese nationwide web-based database of 78 594 patients during 2014–2015

OBJECTIVESUsing data obtained from a Japanese nationwide annual database with web-based data entry, we developed a risk model of mortality and morbidity after lung cancer surgery.METHODSThe characteristics and operative and postoperative data from 80 095 patients who underwent lung cancer surgery were entered into the annual National Clinical Database of Japan data sets for 2014 and 2015. After excluding 1501 patients, the development data set for risk models included 38 277 patients entering in 2014 and the validation data set included 40 317 patients entering in 2015. Receiver–operating characteristic curves were generated for the outcomes of mortality and composite mortality/major morbidity. The concordance index was used to assess the discriminatory ability and validity of the model.RESULTSThe 30-day mortality and overall mortality rates, including in-hospital deaths, were 0.4% and 0.8%, respectively, in 2014, and 0.4% and 0.8%, respectively, in 2015. The rate of major morbidity was 5.6% in 2014 and 5.6% in 2015. Several risk factors were significantly associated with mortality, namely, male sex, performance status, comorbidities of interstitial pneumonia and liver cirrhosis, haemodialysis and the surgical procedure pneumonectomy. The concordance index for mortality and composite mortality/major morbidity was 0.854 (P < 0.001) and 0.718 (P < 0.001), respectively, for the development data set and 0.849 (P < 0.001) and 0.723 (P < 0.001), respectively, for the validation data set.CONCLUSIONSThis model was satisfactory for predicting surgical outcomes after pulmonary resection for lung cancer in Japan and will aid preoperative assessment and improve clinical outcomes for lung cancer surgery

Analysis of DOC and Ram for NSCLC

Background: Current clinical trials demonstrated that combination regimens comprising chemotherapy and immunotherapy lead to better patient outcomes compared to chemotherapy alone as the first line of treatment for non-small cell lung cancer (NSCLC). In addition, the combination therapy of docetaxel (Doc) and ramucirumab (Ram) was considered one of the standard treatments for advanced or relapsed NSCLC patients. However, little is known about the therapeutic responders of this combination therapy among previously treated NSCLC patients. In the present study, we aimed to identify predictive factors for therapeutic response, including programmed death-ligand 1 (PD-L1) expression in tumors, for Doc treatment in combination with Ram. Methods: We retrospectively analyzed a total of 135 advanced or relapsed NSCLC patients who were refractory to platinum-based chemotherapy at eleven institutions in Japan between July 2016 and November 2018. Results: Our observations showed that PD-L1 expression in tumors is not associated with the efficacy of combined therapy of Doc and Ram in previously treated NSCLC patients. Analysis of the patient clinical profiles indicated that prior treatment with immune checkpoint inhibitors (ICIs) is a reliable predictor for the good progression-free survival (PFS) to this combination therapy (P=0.041). Conclusions: Our retrospective study indicated that combination regimens comprising chemotherapy and ICIs followed by Doc and Ram could be an optimal therapeutic option for NSCLC patients regardless of the PD-L1 status of tumors. Further investigations are required to strengthen clinical evidence demonstrating the effectiveness of the combination therapy of Doc plus Ram in previously treated NSCLC patients

Prognostic impact of clinical factors for immune checkpoint inhibitor with or without chemotherapy in older patients with non-small cell lung cancer and PD-L1 TPS ≥ 50%

IntroductionThe proportion of older patients diagnosed with advanced-stage non-small cell lung cancer (NSCLC) has been increasing. Immune checkpoint inhibitor (ICI) monotherapy (MONO) and combination therapy of ICI and chemotherapy (COMBO) are standard treatments for patients with NSCLC and programmed cell death ligand-1 (PD-L1) tumor proportion scores (TPS) ≥ 50%. However, evidence from the clinical trials specifically for older patients is limited. Thus, it is unclear which older patients benefit more from COMBO than MONO.MethodsWe retrospectively analyzed 199 older NSCLC patients of Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and PD-L1 TPS ≥ 50% who were treated with MONO or COMBO. We analyzed the association between treatment outcomes and baseline patient characteristics in each group, using propensity score matching.ResultsOf the 199 patients, 131 received MONO, and 68 received COMBO. The median overall survival (OS; MONO: 25.2 vs. COMBO: 42.2 months, P = 0.116) and median progression-free survival (PFS; 10.9 vs. 11.8 months, P = 0.231) did not significantly differ between MONO and COMBO group. In the MONO group, OS was significantly shorter in patients without smoking history compared to those with smoking history [HR for smoking history against non-smoking history: 0.36 (95% CI: 0.16-0.78), P = 0.010]. In the COMBO group, OS was significantly shorter in patients with PS 1 than those with PS 0 [HR for PS 0 against PS 1: 3.84 (95% CI: 1.44-10.20), P = 0.007] and for patients with squamous cell carcinoma (SQ) compared to non-squamous cell carcinoma (non-SQ) [HR for SQ against non-SQ: 0.17 (95% CI: 0.06-0.44), P &lt; 0.001]. For patients with ECOG PS 0 (OS: 26.1 months vs. not reached, P = 0.0031, PFS: 6.5 vs. 21.7 months, P = 0.0436) or non-SQ (OS: 23.8 months vs. not reached, P = 0.0038, PFS: 10.9 vs. 17.3 months, P = 0.0383), PFS and OS were significantly longer in the COMBO group.ConclusionsECOG PS and histological type should be considered when choosing MONO or COMBO treatment in older patients with NSCLC and PD-L1 TPS ≥ 50%

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

Successful treatment of late onset empyema after extrapleural pneumonectomy: A case report

Treatment of post-extrapleural pneumonectomy empyema (PEPPE) is more difficult than that for post-pneumonectomy empyema for two reasons: first, a large infectious dead space remains after extrapleural pneumonectomy (EPP); and second, defects of the pericardium and diaphragm are reconstructed with artificial materials, which ideally should be removed for treatment of infection. Here, we report the case of a 56-year-old male with PEPPE that occurred long after EPP for mesothelioma. The patient was treated successfully by minimally invasive procedures of irrigation, instillation of urokinase and antibiotics, and surgical debridement without peeling off artificial materials. Keywords: Late onset empyema, Minimally invasive surgery, Extrapleural pneumonectomy, Malignant mesotheliom

Impact of relative dose intensity in gemcitabine–cisplatin chemotherapy for metastatic urothelial carcinoma

Objectives: To evaluate the impact of relative dose intensity for gemcitabine–cisplatin chemotherapy in patients with metastatic urothelial carcinoma. Methods: We retrospectively reviewed the medical records of 18 patients with metastatic urothelial carcinoma, who received gemcitabine–cisplatin regimen as the first-line chemotherapy between 2009 and 2015. The doses of gemcitabine and cisplatin were reduced or the intervals between treatment cycles were prolonged according to the treatment efficacy and adverse events during the first and second cycles. The individually optimal relative dose intensity was set as the actual dose per the standard dose in the first and second cycles. From the third course onward, patients received the gemcitabine–cisplatin chemotherapy with the same relative dose intensity. Overall survival was compared with the groups according to the value of relative dose intensity. Results: The median age was 72.5 (range, 56–79) years and 15 men and 3 women were enrolled in the study. The median number of cycles of first-line gemcitabine–cisplatin chemotherapy was 8 (range, 2–17), and the median survival time from initiation of first-line chemotherapy was 20.1 (range, 3.5–32.8) months. The total median relative dose intensity of gemcitabine–cisplatin chemotherapy was 56.1%. The median survival time of 10 patients in the group with the relative dose intensity of less than 60% was significantly longer than that of 8 patients in the group with the relative dose intensity of more than 60% (19.2 and 11.0 months, respectively, p = 0.04). Conclusion: Individual low relative dose intensity management in the first-line gemcitabine–cisplatin chemotherapy may be an acceptable option for patients with metastatic urothelial carcinoma

Pulmonary mucosa-associated lymphoid tissue lymphoma forming a reversed halo sign from ground-glass opacity

The reversed halo sign (RHS) has been associated with various pulmonary diseases. We report a rare case of pulmonary mucosa-associated lymphoid tissue lymphoma forming a RHS from a ground-glass opacity (GGO). A 73-year-old man was followed-up for the GGO on his computed tomography images, which gradually extended peripherally. During the fourth year of follow-up, the GGO significantly evolved into a well-demarcated, oval lesion, with interlobular and intralobular septal thickenings, and multiple air spaces were surrounded by a well-defined thin consolidative rim, called the RHS. A pathologic study of the specimen via transbronchoscopic biopsy revealed pulmonary mucosa-associated lymphoid tissue lymphoma