Identification of risk factors for venous thromboembolism and validation of the Khorana score in patients with advanced lung cancer: based on the multicenter, prospective Rising-VTE/NEJ037 study data.

BACKGROUND: Management of cancer-associated venous thromboembolism (VTE) is essential in cancer treatment selection and prognosis. However, currently, no method exists for assessing VTE risk associated with advanced lung cancer. Therefore, we assessed VTE risk, including driver gene mutation, in advanced lung cancer and performed a Khorana score validation. METHODS: The Rising-VTE/NEJ037 study was a multicenter prospective observational study that included patients with advanced lung cancer. In the Rising-VTE/NEJ037 study, the Khorana score was calculated for enrolled patients with available data on all Khorana score components. The modified Khorana score was based on the body mass index of ≥ 25 kg/m2, according to the Japanese obesity standard. A multivariate logistic regression analysis, including patient background characteristics, was performed to evaluate the presence of VTE 2 years after the lung cancer diagnosis. RESULTS: This study included 1008 patients with lung cancer, of whom 100 (9.9%) developed VTE. From the receiver operating characteristic curve analysis, VTE risk could not be determined because both the Khorana score (0.518) and modified Khorana score (0.516) showed very low areas under the curve. The risk factors for VTE in the multivariate analysis included female sex, adenocarcinoma, performance status, N factor, lymphocyte count, platelet count, prothrombin fragment 1 + 2 and diastolic blood pressure. CONCLUSION: The Khorana score, which is widely used in cancer-VTE risk assessment, was less useful for Japanese patients with advanced lung cancer. Prothrombin fragment 1 + 2, a serum marker involved in coagulation, was more suitable for risk identification. CLINICAL TRIAL INFORMATION: jRCTs061180025.

[Patient with Breast Cancer That Developed Severe Drug-Induced Pneumonia after Administration of Trastuzumab Emtansine following Off-Label Use of Nivolumab].

Nivolumab is known to cause immune-related interstitial lung diseases. A 44-year-old woman developed multiple lung metastases 5 years after breast cancer resection. She was treated with docetaxel/trastuzumab/pertuzumab and obtained a complete response. This was a case of off-label use of nivolumab as an immune checkpoint inhibitor evaluated in a private clinic. After standard therapy with T-DM1, she developed fever and hypoxemia. Drug-induced pneumonia was suspected based on a ground-glass shadow finding in chest computed tomography. Drug-induced pneumonia may develop following molecular-targeted therapy delivered after nivolumab administration, and fatal cases have been reported. The antitumor effects of nivolumab for breast cancer have not been proven, and its off-label use may have possible adverse effects on future treatments.

Lipoid Pneumonia Caused by Esophageal Achalasia.

A 59-year-old man presented with esophageal achalasia complicated by lipoid pneumonia. Dysphagia and diffuse ground-glass shadows on computed tomography led to the diagnosis of esophageal achalasia. An analysis of bronchoalveolar lavage (BAL) revealed yellow BAL fluid, with two distinct layers. Oil droplets were observed in the upper layer. Macrophages that phagocytosed lipids were also observed. He was diagnosed with lipoid pneumonia secondary to esophageal achalasia. His lipoid pneumonia improved after peroral endoscopic myotomy because of the reduction in aspiration risk.

Usefulness of endocytoscopy in evaluating transbronchial biopsy specimens.

BACKGROUND: Endocytoscopy (ECS) provides a magnification of approximately 450× for real-time observation of lesion nuclei. Using ECS, we aimed to evaluate whether sufficient samples for diagnosis can be obtained during bronchoscopy. We also investigated whether ECS can enable two-class diagnosis of malignant or non-malignant transbronchial biopsy specimens in real-time during bronchoscopy. METHODS: This was a single-facility, prospective, observational, ex vivo study. Forty cases with localized peripheral pulmonary lesions underwent transbronchial biopsy with endobronchial ultrasonography using a guide sheath. Each biopsy specimen was immediately observed and evaluated endocytoscopically after the collection by the bronchoscopic procedure. RESULTS: Thirty-seven cases were enrolled. The diagnostic accuracy achieved by ECS was 91.9% (34/37). The agreement rate between the endocytoscopic evaluation and pathological diagnosis of each specimen (170 specimens) was 65.3% (111/170). The median time required for endocytoscopic evaluation per specimen was 70 s. When we judged a specimen to be malignant a second time on ECS evaluations of five specimens in one case, pathologically malignant specimens were collected in 26 of 27 cases (96.3%). CONCLUSIONS: ECS with methylene blue staining may aid in the two-class diagnosis of malignant or non-malignant transbronchial biopsy specimens during bronchoscopy. This may reduce the number of tissue biopsies.

A Retrospective Study of Pneumococcal Pneumonia in Hospitalized Patients Aged ≥65 Years in Izumo, Japan: 2010 to 2014.

Purpose: In Japan, both a 23-valent pneumococcal polysaccharide vaccine (PPSV23) and a 13-valent pneumococcal conjugate vaccine (PCV13) are available. Although randomized controlled trials have examined the effects of pneumococcal vaccines, few epidemiological studies have investigated the onset of pneumococcal pneumonia in general practice. In Izumo, Shimane Prefecture, Japan, a public subsidy for PPSV23 inoculation began in November 2012. Patients and Methods: The subjects were pneumonia patients aged 65 and over who were admitted to a hospital in Izumo. This retrospective study analyzed the following data extracted from medical records: pneumococcal pneumonia prevalence, pneumonia severity, mortality rate, PPSV23 vaccination rate, and length of hospital stay. The 2 years before the start of the public subsidy were defined as the early phase, and the 2 years after the subsidy initiation were defined as the late phase. We compared the two phases in terms of PPSV23 vaccination rate, prevalence and severity of pneumococcal pneumonia, and mortality rate. Results: We investigated data from a total of 1188 and 1086 patients in the early and late phases, respectively. The prevalence of pneumococcal pneumonia was 21.0% and 21.3% in the early and late phases, respectively. The mortality rate from pneumococcal pneumonia was 10.4% and 5.4% in the early and late phases, respectively (p = 0.080), indicating a 50% reduction. The PPSV23 vaccination rate (p < 0.001) and the comorbidity rates of chronic respiratory disease (p = 0.022) and chronic renal disease (p < 0.001) were significantly different between the early and late phases. Conclusion: This study showed that the rate of in-hospital deaths due to pneumococcal pneumonia was halved after the PPSV23 vaccine was subsidized. The causal relationship between the pneumococcal vaccination rate and the mortality rate of pneumococcal disease was unclear. Further investigation is deemed necessary.

Immune-related adverse events in hepatitis treated with thiopurine-based immunosuppressants: A case report.

An 82-year-old man was treated with ipilimumab and nivolumab for malignant pleural mesothelioma. Although he was previously treated with prednisolone (1 mg/kg/day) for immune-related adverse event (irAE) hepatitis by a previous doctor, he still had worsening liver function and was transferred to our hospital. Blood tests and imaging findings were negative for autoimmune and infectious hepatitis, and liver biopsy results were consistent with irAE hepatitis. Steroid pulse therapy improved liver function, but tapering to prednisolone (1 mg/kg/day) again worsened his liver function. Concomitant use of mycophenolate mofetil was initiated, but no improvement in liver function was observed, therefore azathioprine, a thiopurine immunosuppressant, was administered in combination with steroids. During the course of treatment, hepatic dysfunction due to azathioprine was suspected, and the concomitant use of mercaptopurine and prednisolone was started. Afterward, the liver function improved, and the prednisolone dose was gradually reduced to 10 mg/day. This is a rare case in which a thiopurine-based immunosuppressant was effective against irAE hepatitis, therefore thiopurine-based immunosuppressants may be effective against steroid-refractory hepatitis.

Prognosis of frail older patients treated with intubation and artificial ventilation for respiratory failure.

BACKGROUND: Older patients with severe respiratory failure have higher mortality rates and are more likely to experience impairments in activities of daily living (ADL). METHODS: We retrospectively reviewed patients (??75 years) who received intubation and artificial ventilation for respiratory failure at Shimane University Hospital between November 2014 and December 2020. We compared the outcomes of frail patients with those of self-sufficient patients. RESULTS: Thirty-two patients were included. ADL ability before respiratory failure was rated self-sufficient in 18 patients (self-sufficient group) and not self-sufficient in 14 patients (frail group). None of the patients in either group underwent advanced care planning prior to the onset of respiratory failure. In the self-sufficient and frail groups, the in-hospital mortality rates were 33% and 50%, and the incidence of bedridden patients at discharge was 6% and 43%, respectively. Most patients in the frail group (93%) died or were bedridden. The median hospitalization cost was JPY 2,984,000 for the self-sufficient group and JPY 3,008,000 for the frail group. CONCLUSION: The overall prognosis of frail older patients who underwent intubation and artificial ventilation was poor. When providing intensive care to such patients, it is important to carefully consider their suitability for the treatment. J. Med. Invest. 70 : 494-498, August, 2023.

Nontuberculous Mycobacterium-associated immune reconstitution inflammatory syndrome in a non-HIV immunosuppressed patient.

A 69-year-old woman with rheumatoid arthritis, using immunosuppressants, including etanercept-a tumour necrosis factor (TNF)-α antagonist-was referred to our hospital with fever and fatigue. Chest computed tomography revealed cavities in the left upper lobe. As Mycobacterium intracellulare infection was diagnosed, all immunosuppressants were discontinued, and treatment with anti-nontuberculous Mycobacterium drugs was initiated. However, her condition worsened paradoxically. We diagnosed immune reconstitution inflammatory syndrome (IRIS) resulting from the discontinuation of the TNF-α antagonist. Her condition improved with prednisolone treatment. IRIS is generally observed during HIV treatment, but a good understanding of immunosuppressant-related non-HIV IRIS is needed.

Deep learning-based diagnosis from endobronchial ultrasonography images of pulmonary lesions.

Endobronchial ultrasonography with a guide sheath (EBUS-GS) improves the accuracy of bronchoscopy. The possibility of differentiating benign from malignant lesions based on EBUS findings may be useful in making the correct diagnosis. The convolutional neural network (CNN) model investigated whether benign or malignant (lung cancer) lesions could be predicted based on EBUS findings. This was an observational, single-center cohort study. Using medical records, patients were divided into benign and malignant groups. We acquired EBUS data for 213 participants. A total of 2,421,360 images were extracted from the learning dataset. We trained and externally validated a CNN algorithm to predict benign or malignant lung lesions. Test was performed using 26,674 images. The dataset was interpreted by four bronchoscopists. The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the CNN model for distinguishing benign and malignant lesions were 83.4%, 95.3%, 53.6%, 83.8%, and 82.0%, respectively. For the four bronchoscopists, the accuracy rate was 68.4%, sensitivity was 80%, specificity was 39.6%, PPV was 76.8%, and NPV was 44.2%. The developed EBUS-computer-aided diagnosis system is expected to read EBUS findings that are difficult for clinicians to judge with precision and help differentiate between benign lesions and lung cancers.

Acute Exacerbation of Tracheal Obstruction and Severe Respiratory Failure after a Single Dose of 2-Gy Irradiation for Squamous Cell Lung Carcinoma: A Case Report.

The patient, a 62-year-old woman, complained chiefly of cough. We planned chemoradiotherapy for squamous nonsmall cell lung cancer. A single dose of 2-Gy irradiation and no anticancer agent administration exacerbated the airway stenosis with severe respiratory failure. Urgent tracheal intubation was performed, and a tracheal stent was implanted under extracorporeal membrane oxygenation (ECMO). Because her performance status (PS) worsened from 1 to 2, we administered radiotherapy. The tumor size decreased. There was no recurrence for the next 3 months, and her PS improved to 1. Emergency tracheal intubation and tracheal stent placement under ECMO can be effective for exacerbated airway obstruction after radiotherapy.

An endobronchial hamartoma observed using narrow band imaging under saline injection: A case report.

A light blue line (LBL) was observed along the edge of a lesion using narrow band imaging under saline injection during bronchoscopy in an 82-year-old patient with a lobulated mass on the left B4. The histopathological diagnosis was hamartoma with ciliated bronchial epithelium, and we speculated that LBL appeared around the ciliated bronchial epithelium.

The Association Between Cyclooxygenase-2 -1195G/A (rs689466) Gene Polymorphism and the Clinicopathology of Lung Cancer in the Japanese Population: A Case-Controlled Study.

The single nucleotide polymorphisms of COX-2 gene, also known as PTGS2, which encodes a pro-inflammatory factor cyclooxygenase-2, alter the risk of developing multiple tumors, but these findings are not consistent for lung cancer. We previously reported that the homozygous COX-2 -1195A genotype is associated with an increased risk for chronic obstructive pulmonary disease (COPD) in Japanese individuals. COPD is a significant risk factor for lung cancer due to genetic susceptibility to cigarette smoke. In this study, we investigated the association between COX-2 -1195G/A polymorphism and lung cancer susceptibility in the Japanese population. We evaluated the genotype distribution of COX-2 -1195G/A using a polymerase chain reaction-restriction fragment length polymorphism assay for 330 newly diagnosed patients with lung cancer and 162 healthy controls. Our results show that no relationship exists between the COX-2 -1195G/A polymorphism and the risk of developing lung cancer. However, compared to the control group, the homozygous COX-2 -1195A genotype increased the risk for lung squamous cell carcinoma (odds ratio = 2.902; 95% confidence interval, 1.171-7.195; p = 0.021), whereas no association is observed with the risk for adenocarcinoma. In addition, Kaplan-Meier analysis shows that the genotype distribution of homozygous COX-2 -1195A does not correlate with the overall survival of patients with lung squamous cell carcinoma. Thus, we conclude that the homozygous COX-2 -1195A genotype confers an increased risk for lung squamous cell carcinoma in Japanese individuals and could be used as a predictive factor for early detection of lung squamous cell carcinoma.

Results of 10-year mobile low-dose computed tomography screenings for lung cancer in Shimane, Japan.

BACKGROUND: Some randomized controlled trials have evaluated the effects of low-dose computed tomography (CT) screening on lung cancer mortality in heavy smokers. Based on the results of those trials, our CT screening program recommended screening for people aged ≥40 years with a history of smoking. This retrospective study aimed to verify the validity of our CT screening program and elucidate the current state of CT screening program. METHODS: We retrospectively examined lung cancer detection in 25,189 participants who underwent chest CT screening by a mobile low-dose CT screening unit in the 10-year period from April 2009 to March 2019. Participants were recruited at Japan Agricultural Cooperatives (JA) Shimane Kouseiren. Participants requested CT screening for lung cancer. CT images were read by two pulmonologists. RESULTS: Lung cancer was identified in 82 of the 25,189 participants over 10 years, an overall lung cancer detection rate (percentage of lung cancers detected among all participants) of 0.33%. Lung cancer among never smokers accounted for 54.9% of the detected cases. The lung cancer detection rate was similar for smokers versus never smokers. The stage IA detection rate (percentage of stage IA lung cancers among all lung cancers detected) was 62%, while the stage Ⅳ detection rate was 10%. CONCLUSIONS: Chest CT detected lung cancer in never smokers as well as current or former smokers. Our CT screening program was not effective for never smokers; thus, further study of the effectiveness of CT screening in never smokers is needed.

Incidence of venous thromboembolism in advanced lung cancer and efficacy and safety of direct oral anticoagulants: a multicenter, prospective, observational study (Rising-VTE/NEJ037 study).

Background: Venous thromboembolism (VTE) is a well-known type of cancer-associated thrombosis and a common complication of malignancy. However, the incidence of VTE associated with lung cancer and the effectiveness of direct oral anticoagulants remain unclear. This study aimed to identify the incidence of VTE associated with lung cancer at the time of diagnosis or during treatment, the efficacy and safety of edoxaban, and associated risk factors. Methods: The Rising-VTE/NEJ037 study was a multicenter prospective observational study. Altogether, 1021 patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Patients with VTE at the time of lung cancer diagnosis started treatment with edoxaban. The primary endpoint of this trial was the rate of newly diagnosed VTE after enrollment or recurrence rate 6 months after treatment initiation. Results: Data were available for 1008 patients. The median age was 70 years (range: 30-94 years), and 70.8% were men. Sixty-two patients had VTE at the time of lung cancer diagnosis, and 38 (9.9%) developed VTE at follow-up. No cases of VTE recurrence were recorded 6 months after treatment initiation with edoxaban. Major and clinically relevant non-major bleeding events occurred in 4.9% of patients and increased to 22.7% in the edoxaban treatment group. Conclusions: VTE occurrence should be monitored during lung cancer treatment. Although treatment with edoxaban was highly effective in preventing VTE recurrence, its administration should be cautiously considered because of the high bleeding rate. Trial registration: jRCTs061180025.

A new risk-assessment tool for venous thromboembolism in advanced lung cancer: a prospective, observational study.

Management of cancer-associated venous thromboembolism (VTE) is essential in treatment selection and cancer prognosis. However, to date, there is no method to assess the risk of VTE specifically associated with advanced lung cancer. Our aim was to create a new risk assessment scoring system that can predict the concomitant or incidence of VTE in advanced lung cancer. We used the dataset of 1008 patients with lung cancer in the Rising-VTE/NEJ037 study, of which 100 (9.9%) developed VTE. The items extracted in the multivariate analysis included female sex, adenocarcinoma, performance status, N factor, lymphocyte count, platelet count, prothrombin fragment 1 + 2, and diastolic blood pressure. This model had a maximum score of 8 points, with ≥ 5 points indicating a high risk of VTE. This simple risk-assessment model for VTE complications with advanced lung cancer could help identify cases that required monitoring for VTE.

Use of saline to evaluate a cavity due to Mycobacterium kansasii infection during ultrathin bronchoscopy and endobronchial ultrasonography.

A 28-year-old man had a cavitary lesion in the upper right lobe with a tree-in-bud appearance on chest computed tomography (CT). Diagnostic bronchoscopy was performed. An ultrathin bronchoscope in the right B2aiißxyy reached the cavity. We filled the cavity with saline under direct bronchoscopic visualization. We suspected a blood vessel was present in the cavity wall based on narrow-band imaging. Bronchial lavage of the cavity was performed. Next, endobronchial ultrasonography (EBUS) using a guide sheath was performed with a thin bronchoscope. EBUS showed a pulsating blood vessel in the cavity wall. Bronchial lavage collected with ultrathin and thin bronchoscopy revealed Mycobacterium kansasii. Observation of vessels in the wall of a cavitary lesion with ultrathin bronchoscopy and EBUS may be useful for avoiding severe bleeding associated with biopsy of a cavitary lesion.

Comparative Analysis of the Attitudes toward Palliative Care between Medical Oncologists and Pulmonologists.

Objective In Japan, both medical oncologists and pulmonologists treat lung cancer patients; however, the difference in their attitude toward palliative care referral is unknown. Thus, we retrospectively investigated the difference in attitudes toward palliative care referral between medical oncologists and pulmonologists in Japan. Methods We retrospectively reviewed the charts of patients with thoracic malignancy who died at Shimane University Hospital between June 2011 and October 2015. We compared the patients' demographics and medical history according to their doctor's specialty (i.e., medical oncologist or pulmonologist). Results We identified 182 patients, among whom 90 were treated by medical oncologists and 56 by pulmonologists at the outpatient clinic. Thirty-six patients did not undergo outpatient clinic treatment. Out of 59 patients, 22 (37.3%) referred by medical oncologists, and 7 out of 36 patients (19.4%) referred by pulmonologists, were referred to palliative care specialists in the outpatient setting (p=0.107, Fisher's exact test). The median survival time after admission to PCU was 21 (95% CI: 13-32) and 9 (95% CI: 5-15) days among the patients treated by medical oncologists and pulmonologists, respectively (p=0.128). Conclusion Medical oncologists are more likely to refer their patients to palliative care in the outpatient setting, thus enabling patients to receive longer end of life care in the PCU. Bridging the research gap regarding differences between the physicians' attitudes toward palliative care referral may lead to patients receiving more quality palliative care.

Clinical Management of Asthma by Respiratory Specialists versus General Practitioners: Questionnaire Survey Results Over 6 Years.

BACKGROUND: In Japan, the Ministry of Health, Labour and Welfare population dynamics investigation showed a decrease in the number of deaths related to asthma in recent years. In 2016, the mortality rate was 1.2 deaths per 100,000 population. There were regional differences; Shimane Prefecture had a higher mortality rate (1.6 deaths per 100,000 population in 2016) than other prefectures. In this study, to clarify problems in asthma treatment, we evaluated the status of asthma treatment in Shimane Prefecture. METHODS: We performed three cross-sectional questionnaire surveys, in October 2006, February 2009, and February 2012. We received responses from 78 clinics and hospitals. Subjects were patients with bronchial asthma over 14 years of age who regularly visited an outpatient clinic. Survey items included smoking status, control status assessed using the Asthma Control Test (ACT), treatment, and medication adherence. Doctors board-certified by the Japanese Respiratory Society were defined as respiratory specialists (RSs) and other doctors were defined as general practitioners (GPs). We compared various factors between the RS and GP groups. RESULTS: Clinical data of 2159 patients were available for analysis. The proportion of patients with ACT score ≥ 20 points increased significantly between 2006 and 2012 in the GP group. The rate of inhaled corticosteroid use increased in the GP group from 63.6% to 76.4%. CONCLUSION: It was suggested that asthma control and the rate of inhaled corticosteroid use were related. We should continue educating GPs about asthma treatment.

A Novel Model-Based Questionnaire Based on Low-Dose CT Screening Data for Chronic Obstructive Pulmonary Disease Diagnosis in Shimane, Japan.

Purpose: Although there have been many reports on the use of respiratory function tests and questionnaires for creating chronic obstructive pulmonary disease (COPD) questionnaires, there have been no reports on the effectiveness of questionnaires using computed tomography (CT) screening data. We aimed to validate the International Primary Care Airways Group (IPAG) questionnaire and to propose a novel COPD screening questionnaire based on the CT screening data of Japanese participants. Patients and Methods: Low-dose CT screening was performed for early detection of lung cancer and COPD since 2009 in Shimane, Japan, and clinical information was collected using an original questionnaire that included all the IPAG questionnaire items and eight additional items (for eg, on dyspnea) during CT screening. Participants with emphysema, smoking history, and respiratory symptoms were instructed to undergo a respiratory function test. The participants with the forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) <0.7 on the respiratory function test were diagnosed with COPD, and 11,458 participants underwent CT screening from 2013 to 2016 and were enrolled and filtered using <22.5 pack-years. Data from 3252 participants were selected for the final analysis. The receiver operating characteristic curve determined the best cutoff points for discriminating patients with COPD. The efficacy of the questionnaire items was determined using logistic regression analysis. Results: The best cutoff point for the Japanese IPAG questionnaire was 23. The logistic regression analysis revealed significant differences in the question items of "age", "pack-year", "cough", "phlegm", and "feeling of dyspnea". COPD-CT questionnaire was developed based on the CT screening data. The COPD predicted value was determined using the regression model obtained in this study. Conclusion: The IPAG questionnaire had low specificity for discriminating COPD in Japanese patients. A novel questionnaire (COPD-CT) and the COPD predicted value based on the CT screening data was developed.