Vascular involvement in chronic thromboembolic pulmonary hypertension is associated with spirometry obstructive impairment.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension caused by persistent thromboembolism of the pulmonary arteries. In clinical practice, CTEPH patients often show obstructive ventilatory impairment, even in the absence of a smoking history. Recent reports imply a tendency for CTEPH patients to have a lower FEV1.0; however, the mechanism underlying obstructive impairment remains unknown. METHODS: We retrospectively analyzed CTEPH patients who underwent a pulmonary function test and respiratory impedance test to evaluate their exertional dyspnea during admission for right heart catheterization from January 2000 to December 2019. We excluded patients with a smoking history to rule out the effect of smoking on obstructive impairment. RESULTS: A total of 135 CTEPH patients were analyzed. The median FEV1.0/FVC was 76.0%, %FEV 1.0 had a negative correlation with the mean pulmonary artery pressure and pulmonary vascular resistance and the CT Angiogram (CTA) obstruction score. A multivariate regression analysis revealed that the CTA obstruction score was an independent factor of a lower %FEV1.0. In the 54 patients who underwent pulmonary endarterectomy, %FEV1.0 was improved in some cases and was not in some. Mean PAP largely decreased after PEA in the better %FEV1.0 improved cases, suggesting that vascular involvement in CTEPH could be associated with spirometry obstructive impairment. CONCLUSION: %FEV1.0 had a significant correlation with the CTA obstruction score. Obstructive impairment might have an etiological relationship with vascular involvement. Further investigations could shed new light on the etiology of CTEPH.

Multi­omics analysis of right ventricles in rat models of pulmonary arterial hypertension: Consideration of mitochondrial biogenesis by chrysin.

In pulmonary arterial hypertension (PAH), right ventricular failure is accompanied by metabolic alterations in cardiomyocytes, which may be due to mitochondrial dysfunction and decreased energy production. Chrysin (CH) is a phytochemical with pharmacological activity that is involved in the regulation of mitochondrial biogenesis. The present study investigated the role of CH in the right ventricle (RV) by analyzing the cardiac transcriptome and metabolome of a SU5416(a vascular endothelial growth factor receptor blocker, /hypoxia (Su/Hx) rat model of PAH. RNA­sequencing of the RV transcriptome between Su/Hx, Su/Hx with CH (Su/Hx + CH) and control groups, extracellular matrix (ECM) organization and ECM­receptor interaction­associated genes were upregulated in the RV of Su/Hx but not Su/Hx + CH rats. Furthermore, expression of mitochondrial function­, energy production­, oxidative phosphorylation­ and tricarboxylic acid (TCA) cycle­associated genes was decreased in the RV of Su/Hx rats; this was reverse by CH. Metabolomic profiling analysis of Su/Hx and Su/Hx + CH rats showed no significant changes in glycolysis, TCA cycle, glutathione, NADH or NADPH. By contrast, in the RV of Su/Hx rats, decreased adenylate energy charge was partially reversed by CH administration, suggesting that CH was involved in the improvement of mitochondrial biogenesis. Reverse transcription­quantitative PCR analysis revealed that expression of peroxisome proliferator­activated receptor γ, a master regulator of fatty acid metabolism and mitochondrial biogenesis, was increased in the RV of Su/Hx + CH rats. CH ameliorated cardiac abnormality, including cardiac fibrosis, RV hypertrophy and PH. The present study suggested that CH altered patterns of gene expression and levels of mitochondrial metabolites in cardiomyocytes, thus improving RV dysfunction in a Su/Hx PAH rat model.

Gut microbiota modification suppresses the development of pulmonary arterial hypertension in an SU5416/hypoxia rat model.

The pathogenesis of pulmonary arterial hypertension is closely associated with dysregulated inflammation. Recently, abnormal alterations in gut microbiome composition and function were reported in a pulmonary arterial hypertension experimental animal model. However, it remains unclear whether these alterations are a result or the cause of pulmonary arterial hypertension. The purpose of this study was to investigate whether alterations in the gut microbiome affected the hemodynamics in SU5416/hypoxia rats. We used the SU5416/hypoxia rat model in our study. SU5416/hypoxia rats were treated with a single SU5416 injection (30 mg/kg) and a three-week hypoxia exposure (10% O2). Three SU5416/hypoxia rats were treated with a combination of four antibiotics (SU5416/hypoxia + ABx group) for four weeks. Another group was exposed to hypoxia (10% O2) without the SU5416 treatment, and control rats received no treatment. Fecal samples were collected from each animal, and the gut microbiota composition was analyzed by 16S rRNA sequencing. The antibiotic treatment significantly suppressed the vascular remodeling, right ventricular hypertrophy, and increase in the right ventricular systolic pressure in SU5416/hypoxia rats. 16S rRNA sequencing analysis revealed gut microbiota modification in SU5416/hypoxia + ABx group. The Firmicutes-to-Bacteroidetes ratio in SU5416/hypoxia rats was significantly higher than that in control and hypoxia rats. Compared with the control microbiota, 14 bacterial genera, including Bacteroides and Akkermansia, increased, whereas seven bacteria, including Rothia and Prevotellaceae, decreased in abundance in SU5416/hypoxia rats. Antibiotic-induced modification of the gut microbiota suppresses the development of pulmonary arterial hypertension. Dysbiosis may play a causal role in the development and progression of pulmonary arterial hypertension.

The extent of enlarged bronchial arteries is not correlated with the development of reperfusion pulmonary edema after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension.

This study investigated whether dilated bronchial arteries are associated with reperfusion pulmonary edema in patients with chronic thromboembolic pulmonary hypertension. Results showed that the extent of enlarged bronchial arteries was not associated with the development of reperfusion pulmonary edema, whereas the residual pulmonary hypertension had a significant association.

The Safety and Efficacy of Treatment with Nab-paclitaxel and Carboplatin for Patients with Advanced Squamous Non-small Cell Lung Cancer Concurrent with Idiopathic Interstitial Pneumonias.

Objective Although lung squamous cell carcinoma (SCC) accounts for 20-30% of lung cancer cases, new treatment options are limited. The CA031 study showed that nanoparticle albumin-bound-paclitaxel (nab-PTX) plus carboplatin produced a significantly higher overall response rate (41%) than solvent-based paclitaxel plus carboplatin in patients with lung SCC. However, the safety and efficacy of combination chemotherapy of nab-PTX and carboplatin has not yet been established for patients with concurrent lung SCC and idiopathic interstitial pneumonias (IIPs). The aim of this study was to assess the safety and efficacy profiles of nab-PTX and carboplatin in patients with lung SCC and concurrent IIPs. Methods Eight patients with inoperable-stage lung SCC and IIPs were treated with nab-PTX plus carboplatin in a first-line setting between June 2013 and December 2016. One of the eight was a woman, and the median age was 77 (range=72-80) years. Their clinical outcomes, including chemotherapy-associated acute exacerbation of IIPs, were retrospectively investigated. Results The overall response rate was 50%, the median progression-free survival time was 5.6 months, and the median overall survival time was 8.1 months. No patients experienced chemotherapy-related exacerbation of IIPs in the first-line treatment with nab-PTX plus carboplatin. However, IIPs worsened in two of four patients who received second-line chemotherapy. Conclusion Combination chemotherapy of nab-PTX and carboplatin may be an effective and safe treatment option for patients with inoperable lung SCC with IIPs. To confirm this, a large-scale prospective study is needed.

A case of cerebral tuberculoma mimicking neurocysticercosis.

Case: A 42-year-old Peruvian woman residing in Japan for 11 years with a family history of neurocysticercosis presented to our intensive care unit with fever and intense headache.Computed tomography indicated multiple micronodular lesions in the brain parenchyma, and cerebral tuberculoma and neurocysticercosis were considered in the differential diagnosis. Neurocysticercosis was initially suspected, and oral praziquantel was initiated. However, because of a high adenosine deaminase level in the cerebrospinal fluid and positive peripheral blood interferon gamma release test result, cerebral tuberculoma was subsequently considered. Outcome: Antituberculous drugs with steroids were initiated on day 10, after which the symptoms gradually resolved; the patient was discharged on day 29. Gadolinium-contrast magnetic resonance imaging 8 months later showed reduced nodular shadows, confirming cerebral tuberculoma. Conclusion: Immediate diagnosis and treatment are imperative for cerebral tuberculoma, a lethal infection. Considering the recent increases in immigration worldwide, increased cases of tuberculoma mimicking neurocysticercosis are expected.

Crizotinib-induced Rectal Perforation with Abscess.

An 86-year-old Japanese man was diagnosed with stage IV lung adenocarcinoma. The patient was treated with crizotinib after echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement was detected from his pleural effusion. He subsequently developed abdominal pain and rebound tenderness in the right lower abdomen. Contrast-enhanced abdominal CT showed a low-density area in the abdominal cavity. The size of the abscess was decreased by drainage and the administration of antibiotics. Fistulography revealed a fistula from the rectum to the abscess, and a diagnosis of lower intestinal tract perforation with abscess formation was made. Crizotinib was discontinued and treatment with alectinib was initiated. The patient remains under treatment as an outpatient at our department without adverse effects.

Metastatic Recurrence of Typical Pulmonary Carcinoid Accompanied by Carcinoid Syndrome, Successfully Treated with Octreotide LAR.

We present a case of metastatic recurrence of carcinoid tumor accompanied by carcinoid syndrome in a 68-year-old Japanese man, 12 years after resection of typical pulmonary carcinoid. Histopathologic examination from percutaneous liver biopsy revealed metastatic typical carcinoid. Clinical symptoms gradually improved after administration of octreotide LAR. Two years after starting treatment, the disease remains well controlled. This case report illustrates the possibility of antiproliferative effects of octreotide LAR on typical pulmonary carcinoid.

A prospective, multicenter phase II trial of low-dose erlotinib as maintenance treatment after platinum doublet chemotherapy for advanced non-small cell lung cancer harboring EGFR mutation.

BACKGROUND: Maintenance therapy with full-dose erlotinib for patients with advanced non-small cell lung cancer (NSCLC) has demonstrated a significant overall survival (OS) benefit. However, 150 mg/day of erlotinib seems too toxic as maintenance therapy. This study aimed to evaluate the efficacy and safety of low-dose erlotinib (25 mg/day) as maintenance treatment after platinum doublet chemotherapy in NSCLC harboring epidermal growth factor receptor (EGFR) mutation. METHODS: Activated EGFR-mutation-positive NSCLC patients who did not progress after first-line platinum-doublet chemotherapy, ≥20 and ≤85 years old, with performance status (PS) 0-3 were included in this study. Low-dose erlotinib (25 mg/day) was administered until disease progression. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), OS, and safety. The required sample size was 40 patients. RESULTS: The study was stopped early, after achieving only 28% of planned enrollment, due to poor accrual. Between April 2011 and May 2014, 11 patients (male/female, 5/6; median age, 72 years; PS 0/1, 8/3; stage IV/relapse after surgery, 9/2; exon 19 deletions/L858R, 7/4) were enrolled and accessible in this study. Partial response (PR) was observed in 6 patients (56%). Median PFS was 14.9 months [95% confidence interval (CI), 2.7-27.1 months] and median OS was not calculable. Toxicities were generally mild. Only one patient developed grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation. Eight patients developed grade 1 skin rash. No treatment-related deaths were observed. Eight patients progressed, and recurrences included brain metastases (n=3), local recurrence (n=2), local recurrence plus brain metastasis (n=1), bone metastasis (n=1), and pulmonary metastasis (n=1). CONCLUSIONS: The study was stopped early due to poor accrual. However, our study suggests that maintenance therapy with low-dose erlotinib might be useful and tolerable in selected NSCLC patients harboring EGFR mutation.