Clinical and Microbiological Characteristics of Bacteremia Caused by Carbapenemase-producing Enterobacterales in Minami Ibaraki Area, Japan.

Although recent propagation of carbapenemase-producing Enterobacterales (CPE) has become a problem worldwide, the picture of CPE infection in Japan has not fully been elucidated. In this study, we examined clinical and microbiological characteristics of invasive CPE infection occurring at 8 hospitals in Minami Ibaraki Area between July 2001 to June 2017. Of 7294 Enterobacterales strains isolated from independent cases of bacteremia and/or meningitis, 10 (0.14%) were CPE (8 Enterobacter cloacae-complex, 1 Escherichia coli, and 1 Edwardsiella tarda）, all of which had the blaIMP-1 gene and susceptible to gentamicin and trimethoprim/sulfamethoxazole. These strains were isolated from 7 adult and 2 infant bacteremia (1 infant patient developed CPE bacteremia twice) after 2007. The most common portal of entry was intravenous catheters. All of the adult patients were recovered, while the infant patients eventually died. Genomic analyses showed that the 8 E. cloacae-complex strains were classified into 5 groups, each of which was exclusively detected in specific facilities at intervals of up to 3 years, suggesting persistent colonization in the facilities. This study showed that invasive CPE infection in the area was rare, caused by IMP-1-type CPE having susceptibility to various antibiotics, and nonfatal among adult patients.

Extremely Poor Post-discharge Prognosis in Aspiration Pneumonia and Its Prognostic Factors: A Retrospective Cohort Study.

There is little evidence regarding the long-term prognosis of patients with aspiration pneumonia. This study aimed to investigate post-discharge survival time and prognostic factors in older patients hospitalized for aspiration pneumonia. This retrospective cohort study included patients aged ≥ 65 years hospitalized for aspiration pneumonia and discharged alive from a tertiary care hospital in Japan between April 2009 and September 2014. Candidate prognostic factors were patient's age, sex, body mass index (BMI), performance status, chronic conditions, CURB-65 score, serum albumin level, hematocrit concentration, nutritional pathway at discharge, and discharge location. Kaplan-Meier curves were determined and multivariable survival analysis using Cox regression model was performed to analyze the effect of each factor on mortality. In total, 209 patients were included in this study. The median age was 85 years, 58% of the patients were males, 33% had a performance status of 4 and 34% were discharged home. Among the patients, 65% received oral intake, 23% received tube feeding, and 21% received parenteral nutrition at discharge. During the follow-up period, 77% of the patients died, and the median post-discharge survival time was 369 days. Besides male sex and low BMI, tube feeding (adjusted hazard ratio (aHR) = 1.70, 95% confidence interval (CI) 1.11-2.59) and parenteral nutrition (aHR = 4.42, 95% CI 2.57-7.60) were strongly associated with mortality. Long-term prognosis of patients hospitalized for aspiration pneumonia was extremely poor. The nutritional pathway at discharge was a major prognostic factor. These results may be useful for future care and research.

Prognostic Implication of PD-L1 Expression on Osimertinib Treatment for EGFR-mutated Non-small Cell Lung Cancer.

BACKGROUND/AIM: Real-world data on the clinical outcomes of first-line osimertinib treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations is lacking. This study aimed to reveal the treatment outcomes and prognostic factors of osimertinib as first-line therapy in clinical practice settings. PATIENTS AND METHODS: We retrospectively evaluated clinical outcomes of patients with EGFR-mutated NSCLC treated with osimertinib as first-line therapy across 12 institutions in Japan between August 2018 and March 2020. RESULTS: Among 158 enrolled patients, the objective response rate (ORR) was 68%, and the estimated median progression-free survival (PFS) was 17.1 months [95% confidence interval (CI)=14.5-19.7]. Subgroup analysis showed that PFS in the group with high programmed death-ligand 1 (PD-L1) expression was significantly shorter than that in groups with low or no PD-L1 expression (10.1 vs. 16.1 vs. 19.0 months; p=0.03). Univariate and multivariate analyses demonstrated that high PD-L1 expression was the only independent adverse prognostic factor of osimertinib outcome related to PFS (hazard ratio=2.71; 95%CI=1.26-5.84; p=0.01). In terms of anti-tumor response, there was no statistically significant correlation between PD-L1 expression and the ORR (67% vs. 76% vs. 65%; p=0.51). No significant correlation was also found between PD-L1 and the incidence of de novo resistance to osimertinib (p=0.39). CONCLUSION: Although PD-L1 expression was not associated with either the ORR or frequency of de novo resistance, high PD-L1 expression could be an independent adverse prognostic factor related to PFS in osimertinib treatment.

A phase II feasibility study of carboplatin and nab-paclitaxel for advanced non-small cell lung cancer patients with interstitial lung disease (YLOG0114).

BACKGROUND: A standard treatment regimen for advanced non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) has not been established since most clinical trials exclude such patients because of the high risk of acute exacerbation of ILD. This study aimed to prospectively investigate the efficacy and safety of carboplatin and nab-paclitaxel as a first-line regimen for NSCLC patients with ILD. METHODS: The enrolled patients had treatment-naïve advanced NSCLC with ILD. The patients received 4-6 cycles of carboplatin (area under the curve = 5) on day 1 and nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 every 4 weeks. The primary endpoint was the completion rate of four or more cycles. Secondary endpoints included toxicity, overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty-five patients were enrolled in this study. Nine patients had adenocarcinoma, 11 had squamous cell carcinoma, one had large cell carcinoma, and four had NSCLC, not otherwise specified. The completion rate of ≥4 cycles was 76% (95% confidence interval: 56.2%-88.8%), which met the primary endpoint. The ORR and DCR were 44% and 88%, respectively. The median PFS and OS were 5.8 months and 15.8 months, respectively. Three patients experienced grade ≥2 pneumonitis, and one patient met the acute exacerbation criteria. CONCLUSION: The 4-week modified regimen of carboplatin and nab-paclitaxel showed tolerable toxicity with favorable efficacy in NSCLC patients with ILD. This regimen may be an effective treatment option for patients in real clinical settings.

Airway disorders associated with immune checkpoint inhibitor therapy: Two case reports and a systematic review.

Immune checkpoint inhibitors (ICI) are widely used for the treatment of various malignant neoplasms. Interstitial lung disease is a well-known immune-related adverse event, however, ICI-induced airway disease remains under-recognized. Herein, we report two similar cases of pembrolizumab-induced tracheobronchitis presenting as persistent chronic cough and dyspnea. Blood tests revealed elevated C-reactive protein levels without eosinophilia. Spirometry demonstrated mild airflow obstruction. Computed tomography revealed diffuse thickening of the tracheobronchial walls and bronchiectasis predominantly in the lower lobes. Bronchoscopy revealed edematous and erythematous tracheobronchial mucosa, and bronchial biopsy tissue exhibited marked inflammation with predominant infiltration of CD8+ lymphocytes. Subsequently, pembrolizumab-induced tracheobronchitis was diagnosed in both cases. Cessation of pembrolizumab and initiation of erythromycin, inhaled corticosteroids, and long-acting beta-agonists gradually improved the symptoms, airflow obstruction, and radiographic findings. These were completely resolved in one case. The other case initially showed a poor response to systemic corticosteroids combined with the aforementioned drugs, but improved gradually and almost completely. These cases exemplify ICI-induced airway disease that is, an under-recognized manifestation of immune-related adverse events. In addition, we have systematically searched the PubMed database for articles on ICI-induced airway disease, categorized the retrieved articles as eosinophilic and non-eosinophilic airway diseases, and reviewed the differences in treatment and prognoses between these two categories.

Pulmonary tumor thrombotic microangiopathy in occult early gastric cancer that was undetectable on upper endoscopy: a case report and review of similar cases.

BACKGROUND: Pulmonary tumor thrombotic microangiopathy (PTTM), a rare manifestation of metastatic cancer with poor prognosis, is characterized by subacute/acute fatal pulmonary hypertension. The main cause of PTTM is gastric cancer, and cases of early gastric cancer confirmed using autopsy have been reported. Moreover, several cases of early gastric cancer that are undetectable on endoscopy or macroscopic postmortem examination have been reported. CASE PRESENTATION: A previously healthy 50-year-old man presented with progressive dyspnea and cough for 1 month. Echocardiography suggested pulmonary hypertension. Computed tomography revealed diffuse lymphadenopathy, whereas blood work revealed an elevation in several serum tumor marker levels. Despite normal upper endoscopic findings, a presumptive diagnosis of PTTM due to gastric cancer was made based on pathological findings of cervical lymph node biopsy, which indicated signet ring cell carcinoma. Imatinib and tegafur/gimeracil/oteracil plus oxaliplatin therapy were started on day 7. The patient's condition was initially stable. However, his symptoms suddenly progressed, and the patient died on day 8. Macroscopic postmortem examination revealed no abnormal gastric wall findings. Microscopically, PTTM was confirmed, and multiple serial sections of the stomach revealed early gastric cancer. CONCLUSIONS: Despite normal endoscopic findings, micro-occult gastric cancer can lead to PTTM. Physicians should be aware of this disease presentation. Taking prompt action is needed when PTTM is suspected, even if the patient appears stable.

Pseudomembranous Tracheobronchitis With Severe Tracheal Stenosis and Masked Bronchial Obstruction.

BACKGROUND: Pseudomembranous tracheobronchitis (PMTB) is a rare condition characterized by the formation of endobronchial pseudomembranes. PMTB overlaps with necrotizing tracheobronchitis or plastic bronchitis. The reported infectious etiology mainly includes invasive aspergillosis. PMTB can cause serious airway obstruction; however, urgent tracheotomy is rarely required. CASE REPORT: A 46-year-old woman was transferred to the emergency department (ED) with a 1-week history of progressive dyspnea and cough that was preceded by fever and sore throat. She was previously healthy except for a 20-year history of mild palmoplantar pustulosis. Stridor was evident. Nasolaryngoscopy performed in the ED revealed severe tracheal stenosis caused primarily by mucosal edema and secondarily by pseudomembranes. Initially, tracheitis was considered the sole cause of dyspnea. Although she underwent urgent tracheotomy to prevent asphyxia, her respiration deteriorated progressively. Bronchoscopy revealed massive pseudomembranes obstructing the bilateral bronchi, which led to the clinical diagnosis of PMTB. Subsequent toilet bronchoscopy markedly improved her ventilation. The causative pathogen was not identified despite extensive work-up, including molecular biological testing. Histopathologic examination of the pseudomembranes revealed fibrin with abundant neutrophils, which was consistent with PMTB. Associated conditions, including immunodeficiency, were not found. Her condition improved with antibiotics and repeated toilet bronchoscopy. WHY SHOULD AN EMERGENCY PHYSICIANS BE AWARE OF THIS?: PMTB is an important differential diagnosis of airway emergencies. PMTB can present with critical edematous tracheal stenosis and masked bronchial pseudomembranous obstruction. Emergency physicians should include PMTB in the differential diagnosis in adult patients with acute central airway obstruction because it requires prompt multimodal treatment.

Pulmonary lipiodol embolism following transcatheter arterial chemoembolization.

Computed tomography of pulmonary lipiodol embolism reveals high-density areas in the lung field or intrapulmonary blood vessels. One of the risk factors of lipiodol embolism is embolization of the inferior phrenic artery.

Spontaneous remission of the micronodular pattern in cryptogenic organizing pneumonia.

Organizing pneumonia (OP) is a common interstitial lung disease, pathologically characterized by polypoid granulation tissue in the alveolar ducts and alveoli. In clinical practice, OP occasionally presents as non-resolving pneumonia. The typical radiographic pattern of OP is characterized by dense consolidation with ground-glass opacities. Diffuse micronodular pattern of OP (MNOP) is a rare radiographic manifestation that mimics non-resolving bronchiolar diseases such as pulmonary tuberculosis or hypersensitivity pneumonitis. Steroid therapy is usually effective for MNOP; however, spontaneous remission in MNOP has never been reported. Herein, we report a case of a diffuse micronodular form of cryptogenic OP (COP) that was diagnosed via transbronchial biopsy (TBB) and resolved spontaneously within a few months. Our case highlights that MNOP may resolve spontaneously similar to other forms of OP, and mild cases may be under-recognized. Furthermore, careful observation could be an option for managing MNOP with mild and non-progressive symptoms.

Real Clinical Practice in ALK-rearranged NSCLC Patients: A Retrospective Observational Study.

BACKGROUND/AIM: To describe real clinical outcomes when using systemic therapy to treat non-small cell lung cancer (NSCLC) patients who have anaplastic lymphoma kinase (ALK) fusion gene mutation. PATIENTS AND METHODS: We performed a retrospective chart review from April 2008 to March 2019 sourced from 16 medical institutes that cover a population of three million people. RESULTS: There were 129 ALK rearranged NSCLC patients. Among them, 103 patients including 40 recurrent disease cases received ALK-tyrosine kinase inhibitors (TKI) and chemotherapy. Our treatment results were comparable to previously reported clinical trials and clinical practice studies. First-line alectinib, treatment sequence of ALK-TKI followed by another ALK-TKI, and pemetrexed-containing chemotherapy contributed to the outcome of treatment. CONCLUSION: By arrangement of treatment such as treatment sequence of ALK-TKI and chemotherapy regimen, it might be possible to obtain a treatment outcome almost equivalent to those of clinical trials even in real clinical practice.

Characteristics of invasive Acinetobacter infection: A multicenter investigation with molecular identification of causative organisms.

We examined microbiological and clinical characteristics of invasive Acinetobacter infection occurring in four hospitals located in the Minami-Ibaraki Area. Glucose-non-fermentative Gram-negative bacilli isolated from the blood and the cerebrospinal fluid in independent cases between 2001 and 2014 were consecutively collected and those possibly to be Acinetobacter species were re-identified using molecular methods. Of 158 strains identified as Acinetobacter species, 155 were classified into 16 officially designated species, including 42 Acinetobacter pittii and 40 Acinetobacter baumannii. Imipenem non-susceptibility was detected only in 4 strains, none of which demonstrated multidrug resistance. Retrospective analyses of 154 cases for which medical records were fully available showed that the most common cause of infection was primary bloodstream infection (134 cases), of which 128 were related to intravascular catheter use. The mortality on day 28 after the onset was independently associated with cerebrovascular disease, moderate to severe renal disease, the Pitt bacteremia score, and infection other than primary bloodstream infection but not with appropriate empiric antimicrobial therapy. Isolation of A. baumannii was significantly associated with septic shock but not with the 28-day mortality. These findings, obtained in a region where drug-resistant Acinetobacter strains were much less prevailing, indicated that non-baumannii Acinetobacter species were common pathogens, that the most predominant cause of invasive Acinetobacter infection was intravascular catheter-related infection, that virulence of A. baumannii might be higher than those of other species but its association with mortality was unclear, and that administration of broad-spectrum antibiotics targeting Acinetobacter species might be deferrable in a certain situation.

The utility of ground-glass attenuation score for anticancer treatment-related acute exacerbation of interstitial lung disease among lung cancer patients with interstitial lung disease.

BACKGROUND: Acute exacerbation (AE) of interstitial lung disease (ILD) is a fatal adverse event in the treatment of lung cancer patients with ILD. The value of pre-treatment radiological findings obtained by high-resolution computed tomography for the detection of anticancer treatment-related AE of ILD has not been established. METHODS: Two medical record-based retrospective studies were performed. The chemotherapy cohort included 105 lung cancer patients with ILD who received chemotherapy at Tokyo Medical and Dental University between October 2008 and December 2017. The immune checkpoint inhibitor (ICI) cohort included 48 advanced non-small cell lung cancer patients with ILD treated with ICIs at nine institutions between January 2016 and September 2018. Variables were compared between AE-positive and -negative groups. Candidate variables were analyzed by multivariate logistic regression. A P value < 0.05 was considered statistically significant. RESULTS: Anticancer treatment-related AE of ILD occurred in 12 patients (11.4%) in the chemotherapy cohort and seven patients (14.5%) in the ICI cohort. In the multivariate logistic regression analysis, ground-glass attenuation (GGA) score was the only factor significantly associated with the development of AE of ILD in both cohorts (P = 0.037 and 0.01 in the chemotherapy and ICI cohorts, respectively). CONCLUSION: Evaluation of GGA may help predict anticancer treatment-related AE of ILD.

Chronic Brucellosis in Japan.

Human brucellosis, one of the most common zoonoses worldwide, rarely occurs in Japan, and only a few chronic cases have been reported. We herein report the case of a 39-year-old Japanese woman with chronic human brucellosis, considered a Brucella canis infection, that persisted for 19 years. Her medical history and fever pattern suggested chronic brucellosis, and the diagnosis was made based on the results of a serum tube agglutination test (SAT). After undergoing combination therapy with streptomycin and doxycycline, she achieved symptomatic relief and showed negative SAT results. Even in non-endemic areas, chronic brucellosis is an important differential diagnosis in patients with long-term persistent fatigue or a fever.

Erythema multiforme like reaction to santos rosewood (Machaerium scleroxylon) and Torreya nucifera.

Erythema multiforme is a skin disorder characterised by target epithelial eruption, which is mainly caused by infection or drugs. In this case, we report an erythema multiforme like reaction caused by contact dermatitis against wood, especially santos rosewood. During the hospitalisation, we performed a patch test with lumber used in the patient's workplace, and recognised a positive response to multiple woods and a simultaneous recurring eruption (flare up) outside of the test site. The findings from this case of contact dermatitis caused by frequently used industrial wood type is important for the management of occupational environments. A review of the literature on erythema multiforme like reaction due to contact dermatitis, including past case reports, has also been provided.

Cellulitis Complicated with Bacteremia Due to Sphingobacterium Species: A Report of Two Cases and a Literature Review.

Sphingobacterium species rarely cause human infection. We herein report two cases of cellulitis complicated with bacteremia due to this genus. The patients, both in their 70s and receiving corticosteroid therapy for their underlying diseases, had antecedent skin injuries in their affected limbs. The patients' symptoms improved promptly and completely with the administration of cefazolin, which did not inhibit the growth of isolated organisms at a concentration of 4 µg/mL.

Treatment of asthma in smokers: A questionnaire survey in Japanese clinical practice.

BACKGROUND: Cigarette smoking in patients with asthma leads to poor symptom control. As patients who are current smokers have been excluded from enrollment in many clinical trials on asthma, there are few reports on the treatment in current smokers with asthma. In this study, we aimed to assess how respiratory physicians manage asthma in current smokers in Japan. METHODS: Respiratory physicians in 16 Japanese hospitals answered a questionnaire on treatment for patients with asthma between December 2014 and February 2015. Medical records were reviewed for 1756 patients with asthma. RESULTS: The mean patient age was 61.1 years, and 62.9% of the patients were female. A total of 102 patients (5.8%) were current smokers, and 546 patients (31.1%) were former smokers. Long-acting muscarinic antagonists (LAMA) were prescribed more frequently for current smokers with asthma than for former smokers and never smokers with asthma (10.8% vs 4.6%, p = 0.01, 10.8% vs 3.8%, p < 0.01). In contrast, macrolides were prescribed more frequently for former smokers and never smokers with asthma than for current smokers with asthma (7.7% vs 1.0%, p = 0.01, 6.4% vs 1.0%, p = 0.03). Triple therapy, i.e., inhaled corticosteroids, long-acting beta agonists, and LAMA concomitantly, was prescribed for current smokers with asthma more frequently than for former smokers and never smokers with asthma (9.8% vs 4.0%, p = 0.01, 9.8% vs 3.3%, p < 0.01). CONCLUSIONS: According to this survey, current smokers with asthma received more intensive therapy, including LAMA, than did former smokers with asthma.

Real Clinical Practice of Using Afatinib Therapy in NSCLC Patients with an Acquired EGFR T790M Mutation.

BACKGROUND/AIM: To describe real clinical outcomes when using afatinib therapy to treat non-small cell lung cancer patients who have an acquired EGFR T790M mutation. MATERIALS AND METHODS: A retrospective chart review was conducted from January 2013 to November 2017 sourced from 15 medical institutes that cover a population of three million people. RESULTS: There were 74 patients who met the above-mentioned criteria. Treatment outcomes with afatinib, in patients with or without tyrosine kinase inhibitor (TKI) therapy prior to afatinib, were similar to previously reported clinical trials. Stratification of patients by the presence or absence of TKI pretreatment before afatinib, and the presence or absence of an acquired T790M mutation found no statistical difference in overall survival. CONCLUSION: This population-based study found that the disadvantages of pretreatment before afatinib, and absence of an acquired T790M EGFR mutation, could be overcome by an appropriate treatment strategy in clinical practice.