D-dimer cut-off value for predicting venous thromboembolism at the initial diagnosis in Japanese patients with advanced lung cancer.

OBJECTIVE: Cancer is a well-known risk factor for venous thromboembolism. The D-dimer level is used to predict venous thromboembolism; however, reports on an appropriate D-dimer cut-off value in Japanese patients with advanced lung cancer are lacking. Therefore, this study aimed to calculate the D-dimer cut-off value for venous thromboembolism at the time of lung cancer diagnosis. METHODS: The Rising-venous thromboembolism/NEJ037 study was a multicenter, prospective observational study. Patients with lung cancer who were contraindicated for radical resection or radiation were enrolled and followed up for 2 years. In the present study (jRCT no. 061180025), a receiver operating characteristic curve for D-dimer levels was created using the dataset of the Rising-venous thromboembolism/NEJ037 study. RESULTS: The Rising-venous thromboembolism/NEJ037 study included a total of 1008 patients, of whom 976, whose D-dimer levels had been measured at the time of cancer diagnosis, were included in the present study. At the time of lung cancer diagnosis, 62 (6.3%) and 914 (93.7%) patients presented with and without venous thromboembolism, respectively. The D-dimer values ranged from 0.1 to 180.1 µg/ml and from 0.1 to 257.2 µg/ml in patients with and without venous thromboembolism, respectively. The receiver operating characteristic curve was discriminative with a cut-off value of 3.3 µg/ml and an area under the curve of 0.794 (sensitivity, 0.742; specificity, 0.782; 95% confidence interval, 0.725-0.863). CONCLUSIONS: This is the first study to calculate the D-dimer cut-off value in Japanese patients with advanced lung cancer. Patients with D-dimer levels ≥3.3 µg/ml at the time of initial diagnosis may have coexisting venous thromboembolism.

Clinical and Diagnostic Utility of Genomic Profiling for Digestive Cancers: Real-World Evidence from Japan.

The usefulness of comprehensive genomic profiling (CGP) in the Japanese healthcare insurance system remains underexplored. Therefore, this large-scale study aimed to determine the usefulness of CGP in diagnosing digestive cancers. Patients with various cancer types recruited between March 2020 and October 2022 underwent the FoundationOne® CDx assay at the Keio PleSSision Group (19 hospitals in Japan). A scoring system was developed to identify potentially actionable genomic alterations of biological significance and actionable genomic alterations. The detection rates for potentially actionable genomic alterations, actionable genomic alterations, and alterations equivalent to companion diagnosis (CDx), as well as the signaling pathways associated with these alterations in each digestive cancer, were analyzed. Among the 1587 patients, 547 had digestive cancer. The detection rates of potentially actionable genomic alterations, actionable genomic alterations, and alterations equivalent to CDx were 99.5%, 62.5%, and 11.5%, respectively. APC, KRAS, and CDKN2A alterations were frequently observed in colorectal, pancreatic, and biliary cancers, respectively. Most digestive cancers, except esophageal cancer, were adenocarcinomas. Thus, the classification flowchart for digestive adenocarcinomas proposed in this study may facilitate precise diagnosis. CGP has clinical and diagnostic utility in digestive cancers.

Current pharmacologic treatment of brain metastasis in non-small cell lung cancer.

Lung cancer is a type of cancer that can metastasize to the lungs, brain, bones, liver, adrenal glands, and other organs; however, the occurrence of brain metastases is the most common event. Symptoms of brain metastasis include motor dysfunction, mental dysfunction, seizures, headaches, nausea, and vomiting, and significantly reduce the quality of life of cancer patients. Brain metastases are a poor prognostic factor, and controlling them is extremely important for prolonging prognosis and improving the quality of life. Currently, local surgery and radiotherapy are recommended for their treatment. However, recently, cancer treatments using molecular-targeted drugs and immune checkpoint inhibitors have been introduced, which may also be effective against brain metastases. Therefore, it is necessary to determine whether local or systemic therapy is optimal for each case. In this review, we focus on recent findings regarding drug therapy in treating brain metastases from advanced non-small cell lung cancer.

Primary lung cancer with pulmonary alveolar proteinosis treated with immune checkpoint inhibitor: A case report.

Primary lung cancer with pulmonary alveolar proteinosis (PAP) is a rare condition. We present a case of a patient with primary lung cancer with PAP treated with an immune checkpoint inhibitor (ICI). A 62-year-old man was diagnosed with autoimmune PAP 8 years prior to current admission. Lung adenocarcinoma was found in his right lung, and platinum-based chemotherapy was administered, followed by atezolizumab. He experienced disease progression after atezolizumab treatment, whereas ICI-induced pneumonia or exacerbation of PAP did not occur. This indicates that ICI may be safely used in patients with primary lung cancer with PAP.

Risk Factors for Bleeding Events in Japanese Patients with Advanced Lung Cancer: Data from the Rising-VTE/NEJ037 Study.

Despite the occurrence of various hemorrhagic events during advanced lung cancer treatment, few researchers have reported on their risk factors. Moreover, the development of cancer-related thromboembolism indicates anticoagulant use. However, adverse events such as bleeding should be monitored. In this study, we aimed to identify factors that influence the onset of hemorrhagic events in patients with lung cancer. The Rising-VTE/NEJ037 study was a multicenter, prospective, observational study. A total of 1008 patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Multivariate analysis using a Cox proportional hazard model was performed to compare the outcomes of the time to the onset of hemorrhagic events for 2 years after registration. Hemorrhagic events occurred in 115 patients (11.4%), with 35 (30.4%) experiencing major bleeding. Significant risk factors included venous thromboembolism (VTE) (hazard ratio [HR]: 4.003, p < 0.001) and an Eastern Cooperative Oncology Group Performance Status score of 1 (HR: 2.476, p < 0.001). Factors that significantly reduced hemorrhagic event risk were female sex (HR: 0.454, p = 0.002) and M1a status (HR: 0.542, p = 0.038). VTE is a risk factor for hemorrhagic events in patients with advanced lung cancer, and risks associated with anticoagulant therapy should be considered.

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.

Impact of antimicrobial stewardship implementation on the antibiotic use and susceptibility in a Japanese long-term care hospital.

BACKGROUND: Antimicrobial use (AMU) is closely related to the emergence of antimicrobial-resistant (AMR) bacteria. Meanwhile, long-term care hospitals (LTCHs) have been pointed out to be important reservoirs for AMR. However, evidence illustrating the association between AMU and AMR in LTCHs is lacking compared to that of acute care hospitals. METHODS: We evaluated the impact of an antimicrobial stewardship (AS) program implementation, in a LTCH on AMU and antibiotic susceptibility between three periods: the pre-AS-period (pre-AS); the first period after AS implementation (post-AS 1), in which initiated recommendation the blood culture collection and definitive therapy by AS team; and the second period (post-AS 2), implementation of a balanced use of antibiotics was added. RESULTS: After the AS implementation, a significant increase in the number of blood cultures collected was observed. Conversely, the AMU of piperacillin-tazobactam (PIPC/TAZ), which has activity against Pseudomonas aeruginosa, was increased and occupied 43.0% of all injectable AMU in post-AS 1 compared with that in pre-AS (35.5%). In the post-AS 2 period, we analyzed the %AUD and recommended hospital-wide PIPC/TAZ sparing; this resulted in the significant reduction in %AUD of PIPC/TAZ, which was associated with improved susceptibility of P. aeruginosa to PIPC/TAZ. CONCLUSIONS: These results suggest that AS programs aimed at implementing antibiotic sparing may lead to improve AMR, highlighting the necessity of correcting overuse of a single class of antibiotics and usefulness of AMU monitoring in the LTCH setting.

Cytokine Release Syndrome More than Two Years after Pembrolizumab Introduction: A Case Report.

A 71-year-old man with advanced lung adenocarcinoma was treated with carboplatin, pemetrexed, and pembrolizumab in June 2020. Pemetrexed and pembrolizumab maintenance therapy were continued until November 2022. A fever and severe fatigue occurred in December 2022; however, the cause of the infection was inconclusive based on the patient's symptoms, imaging findings, and culture tests. Although the patient was administered antibiotics, his general condition worsened. Considering the possible diagnosis of immune-related cytokine release syndrome (CRS), the patient was administered prednisolone (1 mg/kg/day) and showed improvement. In conclusion, CRS can occur even long after the initial administration of immune checkpoint inhibitor therapy.

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.

Effects of single nucleotide polymorphisms of the folylpolyglutamate synthase gene on pemetrexed administration-induced nephropathy.

AIMS: Long-term administration of pemetrexed (PEM) in patients with lung cancer can cause renal damage, leading to treatment discontinuation. Previous reports have suggested that specific single nucleotide polymorphisms (SNPs) in the folylpolyglutamate synthase (FPGS) gene affect therapeutic efficacy; however, whether the FPGS SNPs affect renal function is unclear. Identifying SNPs related to renal damage during PEM administration may help predict the decrease in renal function caused by PEM. METHODS: We retrospectively examined age, sex, body weight, total administered PEM, combined platinum, estimated glomerular filtration rate (eGFR) and serum creatinine (SCr) levels before and after PEM administration in patients with non-small cell lung cancer and searched for the alleles of FPGS SNPs (rs1544105 and rs10106) using DNA extracted from whole blood samples of patients. RESULTS: Renal function decreased after PEM administration in 26 cases overall. The SCr and eGFR indices showed decreased renal function irrespective of concomitant cisplatin use. Based on promoter activity and miRNA binding predictions, rs1544105-C and rs10106-T were hypothesized to increase FPGS expression. Single SNP analyses showed no significant differences in renal function between groups with and without each SNP. Multiple regression analysis revealed that the most significant factors for decreased renal function were sex on SCr and the number of SNPs on eGFR. In subgroup analyses, the patients with rs10106-T showed a decline in renal function in the older group. CONCLUSIONS: The number of FPGS SNPs may contribute to PEM-induced renal impairment. Detecting FPGS SNPs may help predict PEM-induced renal damage.

Characterization of a spontaneous mouse model of mild, accelerated aging via ECM degradation in emphysematous lungs.

Emphysema limits airflow and causes irreversible progression of chronic obstructive pulmonary disease (COPD). Strain differences must be considered when selecting mouse models of COPD, owing to disease complexity. We previously reported that a novel C57BL/6JJcl substrain, the Mayumi-Emphysema (ME) mouse, exhibits spontaneous emphysema; however, the other characteristics remain unknown. We aimed to characterize the lungs of ME mice and determine their experimental availability as a model. ME mice had a lower body weight than the control C57BL/6JJcl mice, with a median survival time of ~80 weeks. ME mice developed diffused emphysema with respiratory dysfunction from 8 to 26 weeks of age, but did not develop bronchial wall thickening. Proteomic analyses revealed five extracellular matrix-related clusters in downregulated lung proteins in ME mice. Moreover, EFEMP2/fibulin-4, an essential extracellular matrix protein, was the most downregulated protein in the lungs of ME mice. Murine and human EFEMP2 were detected in the pulmonary artery. Furthermore, patients with mild COPD showed decreased EFEMP2 levels in the pulmonary artery when compared to those without COPD. The ME mouse is a model of mild, accelerated aging with low-inflammatory emphysema and respiratory dysfunction that progresses with age and pulmonary EFEMP2 decrease, similar to that observed in patients with mild COPD.

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.

Prospective Real-World Analysis of Asthma Patients With Preserved and Reduced Physical Activity.

BACKGROUND: Asthma is a highly heterogeneous airway disease, and the clinical characteristics of patients with asthma with preserved and reduced physical activity are poorly understood. OBJECTIVE: We aimed to investigate the risk factors and clinical phenotypes associated with reduced physical activity in a wide range of patients with asthma. METHODS: We conducted a prospective observational study of 138 patients with asthma, including patients with asthma without chronic obstructive pulmonary disease (COPD) (n = 104) and asthma-COPD overlap (n = 34), and 42 healthy controls. Physical activity levels were measured for 2 weeks using a triaxial accelerometer at baseline and 1 year later. RESULTS: Higher eosinophils and body mass index (BMI) were associated with reduced physical activity in patients with asthma without COPD. Cluster analysis of asthma without COPD revealed 4 asthma phenotypes. We identified a cluster with preserved physical activity (n = 43) that was characterized by good symptom control and lung function and included a high proportion of biologics users (34.9%). Multivariate regression analysis revealed that patients with late-onset eosinophilic (n = 21), high-BMI noneosinophilic (n = 14), and symptom-predominant asthma phenotypes (n = 26) had lower levels of physical activity than controls. Patients with asthma-COPD overlap also had significantly lower physical activity levels than controls. Similar trends in physical activity levels were observed in each asthma group at 1-year follow-up. CONCLUSION: This study showed the clinical features of patients with asthma with preserved and reduced physical activity. Reduced physical activity was observed in various asthma phenotypes and in asthma-COPD overlap.

An 83-year-old patient with RET fusion-positive non-small cell lung cancer experiencing severe hepatic disorder due to selpercatinib administration.

An 83-year-old woman with RET fusion-positive advanced lung adenocarcinoma was administered selpercatinib 320 mg/day. Despite the shrinking of the tumour, fever, fatigue, and anorexia developed on day 17. Selpercatinib administration was interrupted. On day 21, elevated blood aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were observed. On day 28, AST and ALT levels increased to demonstrate Grade 4 in CTCAE Ver.5. The patient received a glycyrrhizin-compounding agent and steroid treatment, and AST and ALT levels gradually decreased. On day 63, selpercatinib 160 mg/day was restarted after improvement of the hepatic disorder. Since then, selpercatinib was continued without any severe adverse events. Selpercatinib is a reasonable treatment option for RET fusion-positive advanced non-small cell lung cancer even in older patients. However, old age may be a risk factor for adverse events including hepatic disorders. For safe treatment in such patients, careful follow-up is required.

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.

Comparison of Ultra-Magnifying Endocytoscopic and Hematoxylin-Eosin-Stained Images of Lung Specimens.

Endocytoscopy enables real-time observation of lesions at ultra-magnification. In the gastrointestinal and respiratory fields, endocytoscopic images are similar to hematoxylin-eosin-stained images. This study aimed to compare the nuclear features of pulmonary lesions in endocytoscopic and hematoxylin-eosin-stained images. We performed an endocytoscopy to observe resected specimens of normal lung tissue and lesions. Nuclear features were extracted using ImageJ. We analyzed five nuclear features: nuclear number per area, mean nucleus area, median circularity, coefficient of variation of roundness, and median Voronoi area. We conducted dimensionality reduction analyses for these features, followed by assessments of the inter-observer agreement among two pathologists and two pulmonologists to evaluate endocytoscopic videos. We analyzed the nuclear features of hematoxylin-eosin-stained and endocytoscopic images from 40 and 33 cases, respectively. Endocytoscopic and hematoxylin-eosin-stained images displayed a similar tendency for each feature, despite there being no correlation. Conversely, the dimensionality reduction analyses demonstrated similar distributions of normal lung and malignant clusters in both images, thus differentiating between the clusters. The diagnostic accuracy of the pathologists was 58.3% and 52.8% (κ-value 0.38, fair), and that of the pulmonologists was 50% and 47.2% (κ-value 0.33, fair). The five nuclear features of pulmonary lesions were similar in the endocytoscopic and hematoxylin-eosin-stained images.

Generation of the novel anti-FXYD5 monoclonal antibody and its application to the diagnosis of pancreatic and lung cancer.

Despite recent advances in cancer treatments, pancreatic cancer has a dismal prognosis globally. Early detection of cancer cells and effective treatments for recalcitrant tumors are required, but the innovative therapeutic tools remain in development. Cancer-specific antigens expressed only on cancer cells may help resolve these problems, and antibodies to such antigens have potential in basic research and clinical applications. To generate specific antibodies that bind to proteins expressed on the surface of pancreatic cancer cells, we immunized mice with human pancreatic cancer MIA PaCa-2 cells, and isolated a hybridoma that produces a monoclonal antibody (mAb), named 12-13.8. This antibody was applied to molecular biological experiments such as immunocytochemistry, immunoblotting, flow cytometry, and immunoprecipitation. In addition, we showed that mAb 12-13.8 could accumulate in tumors, through in vivo experiments using cancer-bearing mice. Immunohistochemical staining of pancreatic and lung tumor tissues indicated that the increase of the staining strength by mAb 12-13.8 positively and inversely correlated with the patients' cancer recurrence and survival rate, respectively. We identified the FXYD5 protein as the target protein of mAb 12-13.8, by a human protein array screening system. The FXYD5 protein is overexpressed in various types of cancer and is modified by O-linked glycosylation. We confirmed the binding of the FXYD5 protein to mAb 12-13.8 by using FXYD5-knockout MIA PaCa-2 cells, and detailed epitope mapping identified amino acid residues 45-52 as the minimal peptide sequence. Our results indicate that mAb 12-13.8 could be a valuable tool for FXYD5 studies, and useful in diagnostic and drug delivery applications for cancer patients.

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.

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.