A Novel c-Mesenchymal-Epithelial Transition Factor Intergenic Fusion Response to Crizotinib in a Chinese Patient With Lung Adenocarcinoma: A Case Report.

BACKGROUND: The c-mesenchymal-epithelial transition factor (C-MET) is an oncogene encoding a tyrosine kinase receptor that plays an important role in tumor growth and metastasis. The National Comprehensive Cancer Network (NCCN) guidelines have approved carbatinib/crizotinib for advanced non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping. METHODS: In June 2020, the Department of Respiratory and Critical Care Medicine of Peking University People's Hospital admitted a 72-year-old male patient with lung adenocarcinoma (LADC) with a history of interstitial lung disease secondary to antineutrophil cytoplasmic antibody-associated vasculitis. Genetic examination by next-generation sequencing showed an intergenic fusion of MET, and crizotinib was administered on August 14, 2020. Follow-up showed that tumor volume was significantly reduced. However, crizotinib was discontinued in November 2020 because of the patient's worsening interstitial lung disease, and CT scans showed continued partial response (PR) for 5 months. In April 2021, right lower lobe mass progressed, and disease progression was considered. CONCLUSION: This was the first case of a patient with LADC with MET intergenic fusion who significantly benefited from crizotinib. Even after crizotinib was discontinued for 5 months, the patient continued exhibiting PR, suggesting that MET intergenic fusion may have carcinogenic activity in LADC and was sensitive to crizotinib.

Long-term bone and lung consequences associated with hospital-acquired severe acute respiratory syndrome: a 15-year follow-up from a prospective cohort study.

The most severe sequelae after rehabilitation from SARS are femoral head necrosis and pulmonary fibrosis. We performed a 15-year follow-up on the lung and bone conditions of SARS patients. We evaluated the recovery from lung damage and femoral head necrosis in an observational cohort study of SARS patients using pulmonary CT scans, hip joint MRI examinations, pulmonary function tests and hip joint function questionnaires. Eighty medical staff contracted SARS in 2003. Two patients died of SARS, and 78 were enrolled in this study from August 2003 to March 2018. Seventy-one patients completed the 15-year follow-up. The percentage of pulmonary lesions on CT scans diminished from 2003 (9.40 ± 7.83)% to 2004 (3.20 ± 4.78)% (P < 0.001) and remained stable thereafter until 2018 (4.60 ± 6.37)%. Between 2006 and 2018, the proportion of patients with interstitial changes who had improved pulmonary function was lower than that of patients without lesions, as demonstrated by the one-second ratio (FEV1/FVC%, t = 2.21, P = 0.04) and mid-flow of maximum expiration (FEF25%-75%, t = 2.76, P = 0.01). The volume of femoral head necrosis decreased significantly from 2003 (38.83 ± 21.01)% to 2005 (30.38 ± 20.23)% (P = 0.000 2), then declined slowly from 2005 to 2013 (28.99 ± 20.59)% and plateaued until 2018 (25.52 ± 15.51)%. Pulmonary interstitial damage and functional decline caused by SARS mostly recovered, with a greater extent of recovery within 2 years after rehabilitation. Femoral head necrosis induced by large doses of steroid pulse therapy in SARS patients was not progressive and was partially reversible.

Use of Monte Carlo simulation to evaluate the efficacy of tigecycline and minocycline for the treatment of pneumonia due to carbapenemase-producing Klebsiella pneumoniae.

BACKGROUND: Pneumonia caused by carbapenemase-producing Klebsiella pneumoniae (CP-KP) are increasingly encountered in hospitals worldwide, causing high mortality due to lack of treatment options. The goal of this study was to assess the efficacy of tigecycline and minocycline for CP-KP hospital-acquired pneumonia (HAP) by using Monte Carlo simulation. METHODS: A total of 164 non-duplicated CP-KP strains were collected from sputum or blood in patients with HAP. The MICs for antimicrobials were determined by the agar dilution method. A 10,000-patient Monte Carlo Simulation based on a PK/PD model incorporating the MICs and population pharmacokinetic parameters were conducted to calculate probability of target attainment (PTA) at each MIC value and total cumulative fraction of response (CFR). RESULTS: The susceptibility rate of tigecycline and minocycline were 79.9% and 41.5%, respectively. At recommended doses, an optimal PTA of 90% was obtained for treating HAP caused by CP-KP with MICs of tigecycline ≤0.5 mg/L or minocycline ≤4 mg/L. The CFR of tigecycline at the recommended dose and double dose (100 mg q12h) were 71.2% and 90.2%, respectively. The CFR of minocycline at recommended dose and double dose (200 mg q12h) was 53.4% and 77.2%, respectively. CONCLUSIONS: The findings of this study suggest that the recommended dose of tigecycline was not effective in HAP caused by CP-KP, and a higher CFR indicating a better clinical efficacy can be gained by doubling the dose (100 mg q12h). minocycline (200 mg q12h) might be a potential alternative of tigecycline to against strains with MICs ≤ 8 mg/L.

[Value of cerebral spinal fluid measurement of hypocretin-1 in the diagnosis of Chinese patients with narcolepsy].

OBJECTIVE: To evaluate the diagnostic value of cerebral spinal fluid (CSF) measurement of hypocretin-1 (hcrt-1) in Chinese patients with narcolepsy. METHODS: A total of 139 narcoleptic patients, including 111 narcolepsy with typical cataplexy (NC) and 28 narcolepsy without cataplexy (NWC), were diagnosed at the sleep centre of Peking University People's Hospital from April 2003 to March 2012. And 64 non-narcoleptic controls were recruited. CSF hcrt-1 levels were measured in all subjects.Receiver operating characteristic curve (ROC) was applied to determine the cutoff value of hcrt-1 for Chinese narcoleptic patients. The diagnostic utility of hcrt-1 ≤ 110.0 ng/L and hcrt-1 ≤ 30% of mean normal level defined by International Classification of Sleep Disorders-II and the new Chinese cutoff value were evaluated respectively. RESULTS: The level of hcrt-1 in narcolepsy patients was significantly lower than that of normal controls and the NC group was even lower than NWC group (20 (13, 36) vs 319 (244, 379) and 36 (15, 114) ng/L) (all P < 0.01).Using the international criteria of CSF hcrt-1 ≤ 110.0 ng/L or a level of 1/3 of mean normal control values, a specificity of 100% and sensitivity of 90.6% were generated.ROC curve indicated that CSF hcrt-1 level of 138.0 ng/L was the best cutoff value for the diagnosis of narcolepsy in Chinese narcoleptic patients. There were a specificity of 100%, a sensitivity of 92.8% and the area under the ROC curve of 0.98. CONCLUSIONS: CSF hcrt-1 measurement with high specificity and sensitivity is a useful diagnostic tool for Chinese narcoleptics. And the level of 138.0 ng/L may be the optimal cutoff for the diagnosis of narcolepsy in this group of patients.

Treatment responses of procaterol and CD38 inhibitors in an ozone-induced airway hyperresponsiveness mice model.

Airway hyperresponsiveness (AHR) and airway inflammation are key pathophysiological features of many respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). To evaluate the treatment responses of procaterol and CD38 inhibitors in an ozone-induced AHR mice model, we hypothesized that procaterol and two synthetic CD38 inhibitors (Compounds T and H) might have therapeutic effects on the ozone-induced AHR mice model, and the nuclear factor-kappaB (NF-κB) pathway and the CD38 enzymatic activity might be involved in the mechanisms. With the exception of the Control group, ozone exposure was used to establish an AHR model. Male Kunming mice in the Procaterol and CD38 inhibitors groups were treated with an emulsifier of procaterol hydrochloride, Compound T or H. Results indicated that (1) no drug showed severe toxicity in this study; (2) ozone exposure induced airway inflammation and AHR; (3) intragastric treatment with procaterol and Compound T achieved potent therapeutic effects, but Compound H did not show any therapeutic effect; (4) the NF-κB pathway was involved in both the pathogenic mechanisms of ozone and therapeutic mechanisms of procaterol and Compound T; (5) however, the in vivo effect of Compound T was not caused by its inhibitory activity on CD38. Taken together, procaterol and Compound T are potentially good drugs to treat asthma and COPD complicated with ozone exposure.

Pandemic response lessons from influenza H1N1 2009 in Asia.

During April 2009, a novel H1N1 influenza A virus strain was identified in Mexico and the USA. Within weeks the virus had spread globally and the first pandemic of the 21st Century had been declared. It is unlikely to be the last and it is crucial that real lessons are learned from the experience. Asia is considered a hot spot for the emergence of new pathogens including past influenza pandemics. On this occasion while preparing for an avian, highly virulent influenza virus (H5N1 like) originating in Asia in fact the pandemic originated from swine, and was less virulent. This discrepancy between what was planned for and what emerged created its own challenges. The H1N1 pandemic has tested national health-care infrastructures and exposed shortcomings in our preparedness as a region. Key health challenges include communication throughout the region, surge capacity, access to reliable information and access to quality care, health-care worker skills, quality, density and distribution, access to essential medicines and lack of organizational infrastructure for emergency response. Despite years of preparation the public health and clinical research community were not ready to respond and opportunities for an immediate research response were missed. Despite warm words and pledges efforts to engage the international community to ensure equitable sharing of limited resources such as antivirals and vaccines fell short and stockpiles in the main remained in the rich world. This manuscript with authors from across the region describes some of the major challenges faced by Asia in response to the pandemic and draws lessons for the future.