A retrospective study of pulse steroid therapy for acute respiratory failure associated with tuberculosis.

BACKGROUND: Tuberculosis can cause acute respiratory failure, which is associated with a high mortality rate, even in patients receiving effective anti-tuberculosis therapy. We retrospectively analyzed patients with acute respiratory failure associated with tuberculosis who underwent pulse steroid therapy to describe the clinical characteristics and effectiveness of pulse steroid therapy in this condition. METHODS: The medical records of patients admitted to our hospital for culture-proven tuberculosis treatment from April 1, 2017, to March 31, 2022, who received pulse steroid therapy for acute respiratory failure associated with tuberculosis were reviewed. RESULTS: In total, 10 patients were included in this study. Chest computed tomography (CT) revealed diffuse ground-glass opacities and consolidation in these patients. Overall, 70% of the patients (7/10) showed an adjudicated response to pulse steroid therapy, with improved respiratory condition and radiological findings. Three patients died without response to pulse steroid therapy. One patient died of pancreatic cancer after recovering from respiratory failure. The remaining six patients were discharged without supplemental oxygen and completed anti-tuberculosis therapy. CONCLUSIONS: Pulse steroid therapy can lead to dramatic improvements in some patients with acute respiratory failure associated with tuberculosis.

Poncet's Disease (Reactive Arthritis Associated with Tuberculosis).

An 82-year-old man with miliary tuberculosis was admitted to our hospital. Approximately six weeks after starting anti-tuberculosis treatment, he complained of pain in the fingers, wrists, and ankles. A histopathological examination of the synovial biopsy revealed nonspecific chronic inflammation with no granulomas. Culture of the biopsy specimen yielded no acid-fast bacilli. Poncet's disease was diagnosed based on the clinical presentation, with no findings suggestive of other diseases. His joint pain rapidly improved with steroid therapy. Tuberculosis can cause arthritis through immune-mediated mechanisms without direct invasion in an entity known as Poncet's disease.

Abatacept for rheumatoid arthritis complicated by disseminated cryptococcosis: a case report.

A 78-year-old man developed disseminated cryptococcosis with central nervous system involvement as encapsulated yeast cells were detected in transbronchial biopsy and skin biopsy specimens, and cerebrospinal fluid. Cryptococcus neoformans was confirmed by culture. He had been treated with low-dose prednisolone and methotrexate for rheumatoid arthritis. He started receiving antifungal therapy with intravenous liposomal amphotericin B followed by oral fluconazole. Methotrexate was discontinued. Approximately 4 months after the course of intravenous liposomal amphotericin B was completed, he complained of pain and swelling of the right wrist, which suggested that rheumatoid arthritis was worsening. Abatacept therapy was initiated along with antifungal therapy, and his symptoms relieved. After 24 months of antifungal therapy, although he was still receiving oral fluconazole, he was doing well and the serum cryptococcal antigen had become negative. Disseminated cryptococcosis is an important opportunistic infection associated with low-dose methotrexate for rheumatoid arthritis. Abatacept therapy may be feasible in strictly selected patients with rheumatoid arthritis complicated with cryptococcosis concomitantly with intensive anti-fungal therapy.

Prediction of the duration needed to achieve culture negativity in patients with active pulmonary tuberculosis using convolutional neural networks and chest radiography.

BACKGROUND: We aimed to predict the duration needed to achieve culture negativity in patients with active pulmonary tuberculosis using convolutional neural networks (CNNs) and chest radiography. METHODS: Medical records were searched for eligible patients with culture-confirmed active pulmonary tuberculosis. The eligible patients were randomly assigned to the training dataset group (N = 180) and the validation dataset group (N = 59). Posteroanterior X-ray radiographs in the standing position were obtained at diagnosis. The image data were augmented by a factor of 10 by randomly shifting and rotating the original image. Thus, 1800 images (112 × 112 pixels, 8-bit grayscale) from 180 patients in the training dataset group were used for training the CNN model. The model performance was evaluated on the validation dataset. RESULTS: The values predicted by the CNN model were significantly associated with the actual values (Pearson's correlation coefficient 0.392, p = 0.002). The mean absolute error was 18.0. The visualization of the layer outputs suggested that the CNN model recognized some of the chest radiographic findings that were useful in predicting the duration needed to achieve culture negativity. CONCLUSIONS: The CNN model was useful for predicting the duration needed to achieve culture negativity in active pulmonary tuberculosis, although the accuracy was unsatisfactory. This study suggests that chest radiography findings are as important as other clinical factors for prediction and could be learned by the machine.

Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells.

Although responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) are initially positive, 30%-40% of patients with EGFR-mutant tumors do not respond well to EGFR-TKIs, and most lung cancer patients harboring EGFR mutations experience relapse with resistance. Therefore, it is necessary to identify not only the mechanisms underlying EGFR-TKI resistance, but also potentially novel therapeutic targets and/or predictive biomarkers for EGFR-mutant lung adenocarcinoma. We found that the GPI-anchored protein semaphorin 7A (SEMA7A) is highly induced by the EGFR pathway, via mTOR signaling, and that expression levels of SEMA7A in human lung adenocarcinoma specimens were correlated with mTOR activation. Investigations using cell culture and animal models demonstrated that loss or overexpression of SEMA7A made cells less or more resistant to EGFR-TKIs, respectively. The resistance was due to the inhibition of apoptosis by aberrant activation of ERK. The ERK signal was suppressed by knockdown of integrin ß1 (ITGB1). Furthermore, in patients with EGFR mutant tumors, higher SEMA7A expression in clinical samples predicted poorer response to EGFR-TKI treatment. Collectively, these data show that the SEMA7A-ITGB1 axis plays pivotal roles in EGFR-TKI resistance mediated by ERK activation and apoptosis inhibition. Moreover, our results reveal the potential utility of SEMA7A not only as a predictive biomarker, but also as a potentially novel therapeutic target in EGFR-mutant lung adenocarcinoma.

Foreign body-associated endobronchial inflammatory polyps.

Endobronchial polypoid lesions can be observed after removal of a foreign body and usually regress without treatment. Bronchial obstruction with a foreign body can cause atelectasis in nonelderly adults without history of an episode of aspiration.

Double deletion of tetraspanins CD9 and CD81 in mice leads to a syndrome resembling accelerated aging.

Chronic obstructive pulmonary disease (COPD) has been recently characterized as a disease of accelerated lung aging, but the mechanism remains unclear. Tetraspanins have emerged as key players in malignancy and inflammatory diseases. Here, we found that CD9/CD81 double knockout (DKO) mice with a COPD-like phenotype progressively developed a syndrome resembling human aging, including cataracts, hair loss, and atrophy of various organs, including thymus, muscle, and testis, resulting in shorter survival than wild-type (WT) mice. Consistent with this, DNA microarray analysis of DKO mouse lungs revealed differential expression of genes involved in cell death, inflammation, and the sirtuin-1 (SIRT1) pathway. Accordingly, expression of SIRT1 was reduced in DKO mouse lungs. Importantly, siRNA knockdown of CD9 and CD81 in lung epithelial cells additively decreased SIRT1 and Foxo3a expression, but reciprocally upregulated the expression of p21 and p53, leading to reduced cell proliferation and elevated apoptosis. Furthermore, deletion of these tetraspanins increased the expression of pro-inflammatory genes and IL-8. Hence, CD9 and CD81 might coordinately prevent senescence and inflammation, partly by maintaining SIRT1 expression. Altogether, CD9/CD81 DKO mice represent a novel model for both COPD and accelerated senescence.

A meta-analysis of laninamivir octanoate for treatment and prophylaxis of influenza.

BACKGROUND: Laninamivir octanoate is a recently developed inhaled neuraminidase inhibitor for treating influenza virus infection. We performed meta-analyses to clarify the efficacy of laninamivir octanoate on influenza treatment and prevention. METHODS: MEDLINE and CENTRAL were searched to identify eligible studies. The log median time to event ratios (logMRs) and log odds ratios (logORs) were combined with meta-analysis. RESULTS: Nine studies in treatment settings and three studies in prophylaxis settings were eligible for this meta-analysis. There was no significant difference between laninamivir octanoate and oseltamivir (8 studies, logMR 0.04, 95% CI [-0.05, 0.14]; P=0.36) or zanamivir (4 studies, logMR -0.01, 95% CI [-0.12, 0.11]; P=0.93) in alleviating fever. However, laninamivir octanoate was associated with significantly longer fever duration in treating H3N2 influenza as compared to oseltamivir (4 studies, logMR 0.29, 95% CI [0.00, 0.59]; P=0.047). Laninamivir octanoate was associated with significantly longer duration of fever as compared to peramivir (4 studies, logMR 0.46, 95% CI [0.14, 0.77]; P=0.004). Laninamivir octanoate significantly reduced the incidence of clinical influenza in post-exposure settings (3 studies, logOR -1.17, 95% CI [-1.72, -0.62]; P<0.001). CONCLUSIONS: Overall, the efficacy of laninamivir octanoate in treating influenza was comparable to that of oseltamivir or zanamivir, but it should be noted that laninamivir octanoate was associated with significantly longer fever duration in treating influenza H3N2 as compared to oseltamivir and oseltamivir-resistant mutations in seasonal influenza H1N1 might have affected the results. Peramivir may be superior to laninamivir in treating influenza. Laninamivir octanoate is effective in preventing influenza in post-exposure settings as compared to placebo.

Trastuzumab emtansine suppresses the growth of HER2-positive small-cell lung cancer in preclinical models.

Overcoming chemoresistance is essential for achieving better prognoses in SCLC. Previously, we reported that HER2 is upregulated when HER2-positive SCLC cells acquire chemoresistance. HER2-upregulated cisplatin- or etoposide-resistant SCLC cells were sensitive to trastuzumab-mediated ADCC. However, irinotecan-resistant SCLC cells, such as SBC-3/SN-38, were refractory to trastuzumab despite high HER2 expression. To address this issue, we examined the antitumor efficacy of trastuzumab emtansine (T-DM1) on trastuzumab-resistant HER2-positive SCLC. Treatment with T-DM1 significantly suppressed the growth of SBC-3/SN-38 xenografts in mice compared with trastuzumab (P < 0.05). Histological analysis of xenografts was performed to evaluate the therapeutic effect on apoptosis, proliferation and tumor vasculature. T-DM1 monotherapy induced apoptosis in SBC-3/SN-38 xenografts to a greater extent than trastuzumab monotherapy with the apoptotic index of 3.71 ± 1.56% vs. 0.60 ± 0.32% (P < 0.05), and also inhibited the proliferation of tumor cells compared with trastuzumab with the proliferative index of 74.30 ± 5.54% vs. 80.12 ± 4.81% (P < 0.05). On the other hand, no significant difference in micro vessel density was observed between the treatment groups. In vivo imaging using fluorescence-labeled T-DM1 showed that intravenously administered T-DM1 was rapidly delivered to xenografts and continued to accumulate for several days in a HER2-selective fashion. From these findings, delivery of the cytotoxic agent DM1 into cells via HER2-mediated internalization is expected to exert antitumor effect in such ADCC-lacking SCLC cells. Collectively, T-DM1 will be a promising option for overcoming trastuzumab-resistance in HER2-upregulated SCLC.

Phase II study of S-1 plus bevacizumab combination therapy for patients previously treated for non-squamous non-small cell lung cancer.

PURPOSE: To assess the efficacy and toxicity of S-1 and bevacizumab combination therapy for patients previously treated for advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: This was a prospective, multi-center, single-arm phase II study. Patients with non-squamous NSCLC who had experienced progression after cytotoxic chemotherapy were enrolled. Oral S-1 was administered on days 1-14 of a 21-day cycle, and bevacizumab (15 mg/kg) was given intravenously on day 1. Patients received S-1 adjusted on the basis of their creatinine clearance and body surface area. The primary endpoint was response rate (RR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: We enrolled 30 patients. One patient had never received platinum-based therapy. Five patients had activating mutations of the epidermal growth factor receptor gene, of whom four had received tyrosine kinase inhibitors before this study. The RR was 6.7% [95% confidence interval (CI) 1.8-21.3%], and the disease control rate (DCR) was 80% (95% CI 62.7-90.5%). Median PFS was 4.8 months (95% CI 2.7-6.4 months], and median OS was 13.8 months (95% CI 8.4 months-not applicable). Patients did not experience any Grade 4 toxicity or treatment-related death. Grade 3 hematologic toxicity (anemia) occurred in one patient (3.3%). The main Grade 3 non-hematologic toxicities were anorexia (10%), infection (10%), and diarrhea (6.7%). CONCLUSION: The addition of bevacizumab to S-1 was tolerable, but not beneficial for patients with previously treated non-squamous NSCLC. We do not recommend further study of this regimen.

Clarifying the biological significance of the CHK2 K373E somatic mutation discovered in The Cancer Genome Atlas database.

We identified CHK2 K373E as a recurrent mutation in The Cancer Genome Atlas (TCGA) database. In this study, we demonstrate that the K373E mutation disrupts CHK2 autophosphorylation as well as kinase activity, thus leading to impairment of CHK2 functions in suppressing cell proliferation and promoting cell survival after ionizing radiation. We propose that K373E impairs p53-independent induction of p21WAF1/CIP1 by CHK2. Our data implicate the K373E mutation of CHK2 in tumorigenesis.

Dapsone hypersensitivity syndrome-related lung injury without eosinophilia in the bronchoalveolar lavage fluid.

A 73-year-old man was admitted in respiratory failure that had subacutely progressed after five weeks of dapsone treatment for a skin rash. He also presented with fever, systemic erythroderma and liver dysfunction. Chest computed tomography showed diffuse reticular shadows with ground-glass opacity and bilateral mediastinal lymphadenopathy. Lymphocytes, but not eosinophils, were increased in the bronchoalveolar lavage fluid. Moreover, reactivation of human herpes virus-6 was confirmed on a paired serum test. Finally, we diagnosed the patient with dapsone hypersensitivity syndrome (DHS), a rare adverse event of this drug. Lung injury unaccompanied by eosinophilia in the bronchoalveolar lavage fluid is even more rare as a DHS-related lung manifestation.

Favorable response to trastuzumab plus irinotecan combination therapy in two patients with HER2-positive relapsed small-cell lung cancer.

Small-cell lung cancer (SCLC) easily recurs with multidrug resistance phenotype. However, standard therapeutic strategies for relapsed-SCLC remain unestablished. Human epidermal growth factor receptor 2 (HER2) expression correlates with poor prognosis in extensive disease-SCLC. We have reported previously that HER2 expression is upregulated when HER2-positive SCLC cells acquire chemoresistance, and also demonstrated that trastuzumab exerts significant antitumor activity toward HER2-upregulated chemoresistant SCLC, mainly via antibody-dependent cell-mediated cytotoxicity mechanism. Based on these preclinical data, we treated two patients with HER2-positive SCLC by combination of trastuzumab (6 mg/kg, day 1) and irinotecan (80 mg/m(2), days 1 and 8) every 21 days as the third-line chemotherapy following two prior regimens, first-line carboplatin plus etoposide and second-line amrubicin. One patient achieved partial response after the first cycle and received 6 cycles in total without disease progression for 4.5 months. The other also received 4 cycles and kept stable disease for 3.5 months. This treatment can be continued safely at an outpatient clinic without any severe adverse event. In conclusion, trastuzumab plus irinotecan chemotherapy is promising and feasible against HER2-positive relapsed SCLC. Further clinical studies are encouraged to confirm the antitumor efficacy of trastuzumab in SCLC.

A retrospective study of prognostic factors in patients with interstitial pneumonia receiving long-term oxygen therapy.

PURPOSE: We retrospectively analyzed patients with clinically diagnosed interstitial pneumonia to investigate the factors which contribute to the difference in prognosis from the initiation of long-term oxygen therapy (LTOT) among subtypes. METHODS: Seventy-six patients with clinically diagnosed idiopathic interstitial pneumonia (IIP; n = 49) or interstitial pneumonia associated with collagen vascular disease (CVD-IP; n = 27) in whom LTOT was initiated in our facility from January 1999 to December 2012 were analyzed. RESULTS: Patients with CVD-IP had significantly longer survival time from the initiation of LTOT than those with IIP with the median survival of 51.7 months versus 18.8 months, respectively. The 1-year survival rate was 92.4% for patients with CVD-IP versus 76.5% for those with IIP, and 2-year survival was 88.6 versus 36.0%, respectively. The patterns classified with high-resolution computed tomography (HRCT) were not associated with prognosis. The association between pulmonary hypertension and prognosis was unclear. In results of the multivariate Cox analysis which included factors demonstrating p < 0.1 in the univariate Cox analysis, male gender, low body mass index, and the absence of collagen vascular disease (CVD) were significantly associated with poor prognosis. CONCLUSIONS: After the initiation of LTOT, patients with IIP had poor prognosis regardless of the patterns classified with HRCT, while those with CVD-IP survived longer. Male gender, low body mass index, and the absence of CVD were the independent negative prognostic factors in patients with interstitial pneumonia receiving LTOT.

Overcoming chemoresistance of small-cell lung cancer through stepwise HER2-targeted antibody-dependent cell-mediated cytotoxicity and VEGF-targeted antiangiogenesis.

Small-cell lung cancer (SCLC) easily recurs with a multidrug resistant phenotype. However, standard therapeutic strategies for relapsed SCLC remain unestablished. We found that human epidermal growth factor receptor 2 (HER2) is not only expressed in pretreated human SCLC specimens, but is also upregulated when HER2-positive SCLC cells acquire chemoresistance. Trastuzumab induced differential levels of antibody-dependent cell-mediated cytotoxicity (ADCC) to HER2-positive SCLC cells. Furthermore, as a mechanism of the differential levels of ADCC, we have revealed that coexpression of intracellular adhesion molecule (ICAM)-1 on SCLC cells is essential to facilitate and accelerate the trastuzumab-mediated ADCC. Although SN-38-resistant SCLC cells lacking ICAM-1 expression were still refractory to trastuzumab, their in vivo growth was significantly suppressed by bevacizumab treatment due to dependence on their distinctive and abundant production of vascular endothelial growth factor. Collectively, stepwise treatment with trastuzumab and bevacizumab is promising for the treatment of chemoresistant SCLC.

Long-term amrubicin chemotherapy for small-cell lung cancer.

BACKGROUND: Amrubicin is an active agent for the treatment of small-cell lung cancer (SCLC). However, there have been no reports of long-term amrubicin use. PATIENTS AND METHODS: Twelve patients with SCLC who were treated with eight or more cycles of amrubicin chemotherapy were retrospectively reviewed. RESULTS: The median number of cycles of amrubicin chemotherapy received by the patients was 12 (range=8-20), and the median cumulative dose of amrubicin was 2076 mg (range=1200-2856 mg). The median survival time of the study patients was 1104 days (range=459-1997 days). The main adverse events observed during amrubicin chemotherapy were leukopenia and neutropenia. The cardiothoracic ratio (CTR), expressed as the mean (standard deviation) of the values measured at the initiation and termination of amrubicin chemotherapy was 46.2 (4.0), and 46.1 (5.1), respectively. The change in CTR did not reach statistical significance (p=0.92). CONCLUSION: Long-term amrubicin chemotherapy is a safe and effective treatment that is associated with a good survival prognosis in properly selected patients.

A retrospective study of chemotherapy with and without pemetrexed in malignant pleural mesothelioma.

BACKGROUND: The current standard first-line chemotherapy for malignant pleural mesothelioma (MPM) is pemetrexed and cisplatin. However, other regimens, with or without a platinum agent, are reported to be effective in the treatment of MPM. PATIENTS AND METHODS: Patients who were diagnosed with MPM and treated with chemotherapy between January 1999 and June 2010 at the Osaka Prefectural Medical Center for Respiratory and Allergic Diseases were studied, and the outcomes of these patients were retrospectively analyzed in relation to therapy. RESULTS: In total, 48 patients with MPM (42 men and 6 women) treated with chemotherapy were included in the current analysis. The median survival time (MST) and one-year survival rate in the pemetrexed-containing group were 541 days and 63.2%, respectively. The MST and one-year survival rate in the non-pemetrexed group were 516 days and 66.7%, respectively. Overall survival did not differ significantly with respect to the pemetrexed-containing regimen. CONCLUSION: The superiority of pemetrexed-containing regimens is equivocal. Non-pemetrexed-containing regimens may be potent alternatives.