Clinical practice guidelines for molecular tumor marker, 2nd edition review part 2.

In recent years, rapid advancement in gene/protein analysis technology has resulted in target molecule identification that may be useful in cancer treatment. Therefore, "Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition" was published in Japan in September 2021. These guidelines were established to align the clinical usefulness of external diagnostic products with the evaluation criteria of the Pharmaceuticals and Medical Devices Agency. The guidelines were scoped for each tumor, and a clinical questionnaire was developed based on a serious clinical problem. This guideline was based on a careful review of the evidence obtained through a literature search, and recommendations were identified following the recommended grades of the Medical Information Network Distribution Services (Minds). Therefore, this guideline can be a tool for cancer treatment in clinical practice. We have already reported the review portion of "Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition" as Part 1. Here, we present the English version of each part of the Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition.

Long-Term Outcomes of Ablative Carbon-Ion Radiotherapy for Central Non-Small Cell Lung Cancer: A Single-Center, Retrospective Study.

The aim of this study is to assess the efficacy and safety of ablative carbon ion radiotherapy (CIRT) for early stage central non-small cell lung cancer (NSCLC). We retrospectively reviewed 30 patients who had received CIRT at 68.4 Gy in 12 fractions for central NSCLC in 2006-2019. The median age was 75 years, and the median Karnofsky Performance Scale score was 90%. All patients had concomitant chronic obstructive pulmonary disease, and 20 patients (67%) were considered inoperable. In DVH analysis, the median lung V5 and V20 were 15.5% and 10.4%, and the median Dmax, D0.5cc, D2cc of proximal bronchial tree was 65.6 Gy, 52.8 Gy, and 10.0 Gy, respectively. At a median follow-up of 43 months, the 3-year overall survival, disease-specific survival, and local control rates were 72.4, 75.8, and 88.7%, respectively. Two patients experienced grade 3 pneumonitis, but no grade ≥3 adverse events involving the mediastinal organs occurred. Ablative CIRT is feasible and effective for central NSCLC and could be considered as a treatment option, especially for patients who are intolerant of other curative treatments.

Safety and Efficacy of Single-Fraction Carbon-Ion Radiotherapy for Early-Stage Lung Cancer with Interstitial Pneumonia.

Patients with lung cancer complicated by interstitial pneumonia (IP) often lose treatment options early owing to acute exacerbation of IP concerns. Carbon-ion radiotherapy (CIRT) can provide superior tumor control and low toxicity at high dose concentrations. We conducted a retrospective analysis of the efficacy and tolerability of a single-fraction CIRT using 50 Gy for IP-complicated lung cancer. The study included 50 consecutive patients treated between April 2013 and September 2022, whose clinical stage of lung cancer (UICC 7th edition) was 1A:1B:2A:2B = 32:13:4:1. Of these, 32 (64%) showed usual interstitial pneumonia patterns. With a median follow-up of 23.5 months, the 3-year overall survival (OS), cause-specific survival, and local control rates were 45.0, 75.4, and 77.8%, respectively. The median lung V5 and V20 were 10.0 and 5.2%, respectively (mean lung dose, 2.6 Gy). The lung dose, especially lung V20, showed a strong association with OS (p = 0.0012). Grade ≥ 2 pneumonia was present in six patients (13%), including two (4%) with suspected grade 5. CIRT can provide a relatively safe and curative treatment for patients with IP-complicated lung cancer. However, IP increases the risk of severe radiation pneumonitis, and further studies are required to assess the appropriate indications.

Thromboxane-Prostanoid Receptor Signaling Drives Persistent Fibroblast Activation in Pulmonary Fibrosis.

Rationale: Although persistent fibroblast activation is a hallmark of idiopathic pulmonary fibrosis (IPF), mechanisms regulating persistent fibroblast activation in the lungs have not been fully elucidated. Objectives: On the basis of our observation that lung fibroblasts express TBXA2R (thromboxane-prostanoid receptor) during fibrosis, we investigated the role of TBXA2R signaling in fibrotic remodeling. Methods: We identified TBXA2R expression in lungs of patients with IPF and mice and studied primary mouse and human lung fibroblasts to determine the impact of TBXA2R signaling on fibroblast activation. We used TBXA2R-deficient mice and small-molecule inhibitors to investigate TBXA2R signaling in preclinical lung fibrosis models. Measurements and Main Results: TBXA2R expression was upregulated in fibroblasts in the lungs of patients with IPF and in mouse lungs during experimental lung fibrosis. Genetic deletion of TBXA2R, but not inhibition of thromboxane synthase, protected mice from bleomycin-induced lung fibrosis, thereby suggesting that an alternative ligand activates profibrotic TBXA2R signaling. In contrast to thromboxane, F2-isoprostanes, which are nonenzymatic products of arachidonic acid induced by reactive oxygen species, were persistently elevated during fibrosis. F2-isoprostanes induced TBXA2R signaling in fibroblasts and mediated a myofibroblast activation profile due, at least in part, to potentiation of TGF-ß (transforming growth factor-ß) signaling. In vivo treatment with the TBXA2R antagonist ifetroban reduced profibrotic signaling in the lungs, protected mice from lung fibrosis in three preclinical models (bleomycin, Hermansky-Pudlak mice, and radiation-induced fibrosis), and markedly enhanced fibrotic resolution after bleomycin treatment. Conclusions: TBXA2R links oxidative stress to fibroblast activation during lung fibrosis. TBXA2R antagonists could have utility in treating pulmonary fibrosis.

Coronary artery calcium score may be a novel predictor of COVID-19 prognosis: a retrospective study.

BACKGROUND: Although several studies have reported an association between atherosclerosis-related diseases and COVID-19, the relationship between COVID-19 severity and atherosclerosis progression remains unclear. The aim of this study is to determine the coronary artery calcium score (CACS) prognostic value in patients with COVID-19 using indices such as deterioration in oxygenation and CT images of the chest. METHODS: This was a single-centre retrospective study of 53 consecutive patients with COVID-19 in Narita who were admitted to our hospital between March 2020 and August 2020. CACS was calculated based on non-gated CT scans of the chest performed on admission day. The patients were divided into the following two groups based on CACS: group 1 (CACS ≥180, n=11) and group 2 (CACS <180, n=42). Following univariate analysis of the main variables, multivariate analysis of variables that may be associated with COVID-19 progression was performed. RESULTS: Multivariable logistic regression analysis of age, sex, smoking history, diabetes, hypertension, dyslipidaemia, number of days from symptom onset to hospitalisation and CACS of ≥180 was performed. It revealed that unlike CACS of <180, CACS of ≥180 is associated with exacerbation of oxygenation or CT images of the chest during hospitalisation (OR: 12.879, 95% CI: 1.399 to 380.401). Furthermore, this model of eight variables showed good calibration (Hosmer-Lemeshow p=0.119). CONCLUSION: CACS may be a prognosis marker of COVID-19 severity. Although coronary artery calcification is not typically assessed in pneumonia cases, it may provide a valuable clinical indicator for predicting severe COVID-19 outcomes.

An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression.

A majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.

Selective targeting of KRAS-driven lung tumorigenesis via unresolved ER stress.

Lung cancer with oncogenic KRAS makes up a significant proportion of lung cancers and is accompanied by a poor prognosis. Recent advances in understanding the molecular pathogenesis of lung cancer with oncogenic KRAS have enabled the development of drugs, yet mutated KRAS remains undruggable. We performed small-molecule library screening and identified verteporfin, a yes-associated protein 1 (YAP1) inhibitor; verteporfin treatment markedly reduced cell viability in KRAS-mutant lung cancer cells in vitro and suppressed KRAS-driven lung tumorigenesis in vivo. Comparative functional analysis of verteporfin treatment and YAP1 knockdown with siRNA revealed that the cytotoxic effect of verteporfin was at least partially independent of YAP1 inhibition. A whole-transcriptome approach revealed the distinct expression profiles in KRAS-mutant lung cancer cells between verteporfin treatment and YAP1 knockdown and identified the selective involvement of the ER stress pathway in the effects of verteporfin treatment in KRAS-mutant lung cancer, leading to apoptotic cell death. These data provide novel insight to uncover vulnerabilities in KRAS-driven lung tumorigenesis.

Bevacizumab plus cisplatin/pemetrexed then bevacizumab alone for unresectable malignant pleural mesothelioma: A Japanese safety study.

AIMS: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with poor prognosis and limited treatment options. Cisplatin plus pemetrexed is the only approved first-line treatment for patients with unresectable MPM. Recently, promising outcomes were observed with first-line bevacizumab combined with cisplatin/pemetrexed, leading to the recommendation of this regimen as a first-line treatment option for patients with MPM. Bevacizumab plus cisplatin/pemetrexed has been shown to be safe and effective in non-small cell lung cancer, however, there are no efficacy or safety data in Japanese patients with MPM treated with this regimen. We conducted a multicenter study to evaluate tolerability and safety for Japanese patients with chemotherapy-naïve, unresectable MPM. METHODS: Eligible patients (n = 7) received bevacizumab plus cisplatin/pemetrexed (up to six cycles), then single-agent bevacizumab until disease progression or onset of unacceptable adverse events (AEs), according to the 3+3 design analogy. RESULTS: One patient (14.3%) reported an AE (gastric ulcer) meeting tolerability criteria. All patients experienced gastrointestinal disorders, including nausea (grade 1/2 only, n = 6, 85.7%) and constipation (grade 1/2 only, n = 5, 71.4%). Five patients (71.4%) had grade 3 hypertension. Two patients discontinued treatment due to gastric ulcer (n = 1) and proteinuria (n = 1). At data cut-off, four patients had stable disease, two had partial response and one had non-complete response/non-progressive disease due to the absence of target lesions. CONCLUSIONS: Bevacizumab plus cisplatin/pemetrexed then bevacizumab was well tolerated in Japanese patients with MPM.

Diffuse pleural thickening and thoracic contraction: An indistinguishable case from malignant pleural mesothelioma.

The differential diagnosis of reactive mesothelial hyperplasia and mesothelioma is difficult. We present a rare case of diffuse pleural thickening with thoracic contraction that was indistinguishable from mesothelioma. A 66-year-old woman with no history of asbestos exposure visited our hospital with a complaint of dyspnea. The clinical findings included circumferential pleural thickening on chest computed tomography image and a high concentration of hyaluronic acid in the pleural fluid. Pleural biopsies obtained by thoracoscopy under local anesthesia were pathologically consistent with mesothelioma, but the patient refused to take any kind of mesothelioma treatments. Four months later, she consented to a surgical pleural biopsy under general anesthesia to obtain larger tissue samples, which included typical proliferating polygonal cells positive for CAM5.2, calretinin, WT-1, D2-40, CK5/6, epithelial membrane antigen, and glucose transporter-1 and negative for carcinoembryonic antigen, BerEP4, and MOC31. The analysis was consistent with diagnosis of epithelioid mesothelioma. Fluorescence in situ hybridization, however, showed the presence of p16 gene, and the expression of BRCA1-associated protein-1 was detected by immunohistochemistry. Our final diagnosis was diffuse pleural thickening unrelated to asbestos exposure. Differential diagnosis of diffuse pleural thickening and malignant mesothelioma is thus difficult and routine immunohistochemical examinations are often insufficient for accurate diagnosis. Multiple diagnostic methods are required for correct diagnosis in a clinically marginal case.

Feasibility and accuracy of rapid on-site evaluation of touch imprint cytology during transbronchial biopsy.

BACKGROUND: Rapid on-site evaluation (ROSE) of cytologic material is widely performed because it provides clinicians with instant diagnostic information. However, the utility of ROSE of touch imprint cytology (ROSE-TIC) during transbronchial biopsy (TBB) remains unclear. The aim of this study was to evaluate the feasibility and accuracy of ROSE-TIC for TBB. METHODS: A retrospective study was performed on patients who underwent diagnostic bronchoscopy combined with ROSE-TIC. The results of ROSE-TIC, diagnosed as either positive or negative for malignancy, were compared with the histological findings and final diagnosis. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy were calculated. The success rate of molecular testing on TBB specimens was also assessed. RESULTS: Overall, 460 patients underwent bronchoscopy with ROSE-TIC. Of these, 377 cases (82.0%) were malignant and 83 cases (18.0%) were non-malignant in the final diagnosis. Compared with the histological findings, ROSE-TIC showed sensitivity, specificity, PPV, NPV, and diagnostic accuracy values of 91.1%, 90.4%, 94.8%, 84.0%, and 90.9%, respectively. Compared with the final diagnosis, ROSE-TIC showed sensitivity, specificity, PPV, NPV, and diagnostic accuracy values of 75.3%, 91.6%, 97.6%, 45.0%, and 78.3%, respectively. Seven discordant cases (1.5%) were positive on ROSE-TIC and negative on final diagnosis. The success rates for molecular analysis from TBB samples were 96.6% for EGFR mutation, 87.3% for ALK rearrangement, 93.1% for ROS1 rearrangement, and 96.2% for PD-L1 expression. CONCLUSIONS: The accuracy of ROSE-TIC is high. It can be useful for obtaining instant diagnosis, contributing to a high success rate of molecular analysis for targeted therapy.

Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype.

A majority of mesothelioma had the wild-type p53 genotype but was defective of p53 functions primarily due to a genetic defect in INK4A/ARF region. We examined a growth suppressive activity of CP-31398 which was developed to restore the p53 functions irrespective of the genotype in mesothelioma with wild-type or mutated p53. CP-31398 up-regulated p53 levels in cells with wild-type p53 genotype but induced cell growth suppression in a p53-independent manner. In contrasts, nutlin-3a, an MDM2 inhibitor, increased p53 and p21 levels in mesothelioma with the wild-type p53 genotype and produced growth suppressive effects. We investigated a combinatory effect of CP-31398 and nutlin-2a and found the combination produced synergistic growth inhibition in mesothelioma with the wild-type p53 but not with mutated p53. Western blot analysis showed that the combination increased p53 and the phosphorylation levels greater than treatments with the single agent, augmented cleavages of PARP and caspase-3, and decreased phosphorylated FAK levels. Combination of CP-31398 and defactinib, a FAK inhibitor, also achieved synergistic inhibitory effects and increased p53 with FAK dephosphorylation levels greater than the single treatment. These data indicated that a p53-activating CP-31398 achieved growth inhibitory effects in combination with a MDM2 or a FAK inhibitor and suggested a possible reciprocal pathway between p53 elevation and FAK inactivation.

Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia.

Dramatic progress in targeted therapy and immunotherapy has been changing clinical practices in lung cancer. With the accumulation of clinical practice, it has become clear that pre-existing interstitial pneumonia (IP) could be a risk factor for drug-induced lung injury, which has enhanced awareness regarding the difficulty in treating lung cancer with comorbid IP. Unfortunately, there is only low-grade evidence in the field of lung cancer with comorbid IP, because almost all clinical trials exclude such patients. There have been very few specialized clinical trials for patients with lung cancer and underlying IPs thus far. Therefore, it is necessary to treat such cases empirically or to give up on the treatment itself. Considering these circumstances, establishing how to treat lung cancer with comorbid IP is an urgent issue. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the Japanese Respiratory Society (JRS) in 2017, which attempts to approach lung cancer with comorbid IP systematically.

AMPK activation induced in pemetrexed-treated cells is associated with development of drug resistance independently of target enzyme expression.

Pemetrexed (PEM) inhibits DNA and RNA synthesis and is currently one of the first-line agents for mesothelioma. PEM suppresses the activities of several enzymes involved in purine and pyrimidine synthesis, and elevated activity of these enzymes in tumors is often linked with resistance to PEM. The agent also stimulates AMP-activated protein kinase (AMPK) and consequently influences the mammalian target of rapamycin complex 1 (mTORC1) pathways. Nevertheless, it remains unclear whether PEM resistance is linked to the AMPK or mTORC1 pathways. Here, we established two independent PEM-resistant mesothelioma cell lines in which expression of the PEM-target enzymes was not elevated, and found that levels of phosphorylated AMPK and p70S6K and, to a lesser extent, levels of phosphorylated AKT and p53, were increased in these cells as compared with the respective parent cells. PEM stimulation also augmented phosphorylation of AMPK, p70S6K, AKT and p53 in most cases. An AMPK activator increased phosphorylation and PEM resistance in parental cells, and the inhibitor decreased the resistance of PEM-resistant cells. In contrast, inhibitors for p70S6K and AKT did not influence PEM resistance; furthermore, increased levels of endogenous p53 did not affect PEM sensitivity. These data collectively indicate that constitutive activation of AMPK is associated with PEM resistance, and that this is unconnected with elevated DNA and RNA synthesis.

Characterization of pulmonary intimal sarcoma cells isolated from a surgical specimen: In vitro and in vivo study.

Pulmonary intimal sarcoma (PIS) constitutes a rare sarcoma originating from the intimal cells of pulmonary arteries. The pathogenesis of PIS remains to be elucidated and specific treatments have not been established; therefore, prognosis is generally poor. The purpose of our study was to isolate and characterize PIS cells from a specimen resected from a patient with PIS. The surgical specimen was minced and incubated, and spindle-shaped and small cells were successfully isolated and designated as PIS-1. PIS-1 cells at passages 8-9 were used for all in vitro and in vivo experiments. Immunocytochemistry showed that PIS-1 cells were positive for vimentin, murine double minute 2, and CD44 and negative for α-smooth muscle actin, CD31, von Willebrand factor, and desmin. PIS-1 cells exhibited the hallmarks of malignant cells including the potential for autonomous proliferation, anchorage-independent growth, invasion, genetic instability, and tumorigenicity in severe combined immunodeficiency mice. The PIS-1 cells highly expressed tyrosine kinase receptors such as platelet-derived growth factor receptor, and vascular endothelial growth factor receptor 2. Pazopanib, a multi-targeted tyrosine kinase inhibitor, suppressed the proliferation of PIS-1 cells in vitro and the growth of tumors formed from xenografted PIS-1 cells. A PIS cell line was thus successfully established. The PIS-1 cells highly expressed tyrosine kinase receptors, which may be a target for treatment of PIS.

Drug library screen reveals benzimidazole derivatives as selective cytotoxic agents for KRAS-mutant lung cancer.

KRAS is one of the most frequently mutated oncogenes in human non-small cell lung cancer (NSCLC). Mutations in KRAS are detected in 30% of NSCLC cases, with most of them occurring in codons 12 and 13 and less commonly in others. Despite intense efforts to develop drugs targeting mutant KRAS, no effective therapeutic strategies have been successfully tested in clinical trials. Here, we investigated molecular targets for KRAS-activated lung cancer cells using a drug library. A total of 1271 small molecules were screened in KRAS-mutant and wild-type lung cancer cell lines. The screening identified the cytotoxic effects of benzimidazole derivatives on KRAS-mutant lung cancer cells. Treatments with two benzimidazole derivatives, methiazole and fenbendazole-both of which are structurally specific-yielded significant suppression of the RAS-related signaling pathways in KRAS-mutated cells. Moreover, combinatorial therapy with methiazole and trametinib, a MEK inhibitor, induced synergistic effects in KRAS-mutant lung cancer cells. Our study demonstrates that these benzimidazole derivatives play an important role in suppressing KRAS-mutant lung cancer cells, thus offering a novel combinatorial therapeutic approach against such cancer cells.

A p53-stabilizing agent, CP-31398, induces p21 expression with increased G2/M phase through the YY1 transcription factor in esophageal carcinoma defective of the p53 pathway.

Restoration of p53 functions is one of the therapeutic strategies for esophageal carcinoma which is often defective of the p53 pathway. We examined effects of CP-31398 which potentially increased expression of wild-type p53 or converted mutated p53 to the wild-type. We used 9 kinds of human squamous esophageal carcinoma cells with different p53 genotypes and examined expression of p53 and the related molecules in CP-31398-treated cells. Cisplatin, a DNA damaging agent, induced cleavages of PARP and caspase-3 without increase of p53 levels, indicating that the p53 down-stream pathway was disrupted in these cells. CP-31398 induced growth retardation but the cytotoxic effects were irrelevant to p53 genotype. CP-31398 influenced expression of p53 and the downstream molecules in a cell-dependent manner, but constantly increased p21 expression at the transcriptional level with decreased YY1 expression. Knockdown experiments with siRNA demonstrated that the CP-31398-mediated p21 up-regulation was unrelated with p53 expression but was associated with YY1 expression. We also showed that CP-31398-induced cell cycle changes including increase of G2/M populations was attributable to the up-regulated p21. These data collectively indicated that CP-31398 augmented endogenous p21 levels and induced cell cycle changes through regulation of YY1, and that YY1 was a novel target of CP-31398 in p53 dysfunctional cells.

Safety of diagnostic flexible bronchoscopy in patients with echocardiographic evidence of pulmonary hypertension.

BACKGROUND: The presence of pulmonary hypertension (PH) and treatment with anticoagulant agents could potentially increase the risk for bleeding/hemodynamic complications associated with bronchoscopic procedures. The aim of this study was to assess the safety of diagnostic flexible bronchoscopy (FB) in patients with PH. METHODS: A retrospective review of clinical records of patients with echocardiographic evidence of PH (right ventricular systolic pressure [RVSP] > 40 mm Hg) who underwent diagnostic FB between 2004 and 2016 at a single facility in Japan was conducted. Patients with no clinical evidence suggestive of PH who underwent FB during the same period were enrolled as a pairwise-matched control group; factors used in matching included age, sex, and performed procedures. RESULTS: Overall, there were 45 patients in the PH group and 90 patients in the control group. Six (13%) patients in the PH group had severe PH (RVSP > 61 mm Hg). Forceps biopsies and transbronchial needle aspirations were performed in 62% and 13% of patients, respectively, in the PH group, and 58% and 13% of patients, respectively, in the control group. The total incidence of bleeding during FB was not significantly different between the two groups (18% versus 16%; p = 0.742). Vital signs recorded 2 h after FB were also not significantly different between the two groups. There were no episodes of cardiac arrhythmias or deaths associated with the FB procedures. CONCLUSIONS: The data suggest that diagnostic FB procedures can be performed safely in patients with echocardiographic evidence of PH.

Identification of factors during bronchoscopy that affect patient reluctance to undergo repeat examination: Questionnaire analysis after initial bronchoscopy.

BACKGROUND: Re-biopsy by bronchoscopy is an important part of treatment for patients with relapsed lung cancer; however, some patients refuse to undergo a re-examination due to discomfort during their first bronchoscopy. The aim of the present study was to determine factors causing discomfort during bronchoscopy and to identify the factors that affect patients' reluctance to undergo repeat examinations via a questionnaire administered immediately after the initial bronchoscopy. METHODS AND FINDINGS: We evaluated 283 patients who underwent bronchoscopy at Chiba University Hospital between September 2015 and March 2017. Following bronchoscopy, the patients answered a questionnaire regarding the procedure. We identified patient characteristics and factors related to bronchoscopy that were associated with patients' reluctance to undergo re-examination. Two hundred nine patients were ultimately enrolled in the study. The factors affecting patient tolerance for re-examination were female sex (odds ratio [OR], 2.81; 95% confidence interval [CI], 1.43-5.53), discomfort during the examination (OR, 1.70; 95% CI, 1.13-2.56), and unexpectedness of discomfort during the examination (OR, 1.83; 95% CI, 1.19-2.81). Patients experienced discomfort most frequently owing to throat anesthesia (n = 50 [24%]). CONCLUSIONS: Comfort during bronchoscopy is an important factor influencing patient tolerance for re-examination. Expectations of discomfort during bronchoscopy, as indicated by instructions provided before examination, and throat anesthesia are also important factors. Detailed explanations about bronchoscopy and improvement of the methods of throat anesthesia could decrease patient discomfort and may help decrease patients' reluctance to undergo re-examinations.

Heat shock protein 90 inhibitors augment endogenous wild-type p53 expression but down-regulate the adenovirally-induced expression by inhibiting a proteasome activity.

Heat shock protein 90 (HSP90) inhibitors suppressed MDM4 functions which mediated p53 ubiquitination, and blocked a chaperon function which influenced expression of the client proteins. We examined cytotoxic effects of the inhibitors, 17-allylamino-17-demetheoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG), on mesothelioma and investigated combinatory effects of the inhibitors and adenoviruses expressing the wild-type p53 gene (Ad-p53). A majority of mesothelioma lacks p14 and p16 expression, which leads to defective p53 pathway despite bearing the wild-type p53 genotype. The HSP90 inhibitors up-regulated endogenous wild-type p53 expression and induced cell death. Furthermore, the inhibitors increased the endogenous p53 levels that were induced by cisplatin. Nevertheless, the HSP90 inhibitors suppressed Ad-p53-induced exogenous p53 expression primarily at a posttranscriptional level and inhibited the Ad-p53-mediated cell death. HSP90 inhibitors suppressed ubiquitination processes which were involved in p53 degradation, but a proteasome inhibitor, MG-132, prevented the HSP90 inhibitors-induced p53 down-regulation. In contrast, an inhibitor for HSP70 with a chaperon function, pifithrin-µ, did not produce the p53 down-regulation. The HSP90 inhibitors did not suppress expression of Ad receptor molecules but rather increased expression of green fluorescence protein transduced by the same Ad vector. These data collectively indicated that an HSP90 inhibitor possessed a divalent action on p53 expression, as an activator for endogenous wild-type p53 through inhibited ubiquitination and a negative regulator of exogenously over-expressed p53 through the proteasome pathway.

Efficacy of End-Tidal Capnography Monitoring during Flexible Bronchoscopy in Nonintubated Patients under Sedation: A Randomized Controlled Study.

BACKGROUND: Although appropriate sedation is recommended during flexible bronchoscopy (FB), patients are at risk for hypoventilation due to inadvertent oversedation. End-tidal capnography is expected as an additional useful monitor for these patients during FB. OBJECTIVES: The aim of this study was to evaluate the benefit of additional end-tidal capnography monitoring in reducing the incidence of hypoxemia during FB in patients under sedation. METHODS: Patients undergoing FB under moderate sedation without tracheal intubation were randomly assigned to receive standard monitoring including pulse oximetry or additional capnography monitoring. Bronchoscopy examiners for the only capnography group were informed of apnea events by alarms and display of the capnography monitor. RESULTS: A total of 185 patients were enrolled. Patient characteristics were well balanced between the two groups. Hypoxemia (at least one episode of pulse oximeter oxygen saturation [SpO2] < 90%) was observed in 27 out of 94 patients in the capnography group (29%) and in 42 out of 91 patients in the control group (46%; p = 0.014), resulting in an absolute risk difference of -17.4% (95% confidence interval, -31.1 to -3.7). In the capnography group, hypoxemia duration was shorter (20.4 vs. 41.7 s, p = 0.029), severe hypoxemic events (SpO2 < 85%) were observed less frequently (16 [17%] vs. 29 [32%], p = 0.019), and the mean lowest SpO2 value was higher (90.5 vs. 87.6%, p = 0.002). CONCLUSION: End-tidal capnography monitoring can reduce the incidence and duration of hypoxemia during FB in nonintubated patients under sedation.