Vogesella urethralis-induced aspiration pneumonia and bacteremia in an elderly man: a first case report and literature review.

BACKGROUND: Vogesella species are common aquatic Gram-negative rods that were first reported in 1997. Vogesella urethralis bacterium was first isolated from human urine in 2020. Only two cases of disease caused by Vogesella species have been reported with no case of Vogesella urethralis-caused disease being reported as yet. Herein, we report a case of aspiration pneumonia and bacteremia caused by Vogesella urethralis. CASE PRESENTATION: An 82-year-old male patient was admitted with dyspnea, increased sputum production, and hypoxia. Gram-negative rods were isolated from the blood and sputum cultures of the patient. He was diagnosed with aspiration pneumonia and bacteremia. Initially, Vogesella urethralis was wrongly identified as Comamonas testosteroni based on fully automated susceptibility testing; however, additional 16S rRNA gene sequencing identified the causative as Vogesella urethralis. The patient was treated with piperacillin and tazobactam. Unfortunately, he developed aspiration pneumonia again and died during hospitalization. CONCLUSIONS: Since no database exists for rare bacteria in traditional clinical microbiology laboratories, 16S rRNA gene sequence analysis is useful. We report the first case of Vogesella urethralis-induced aspiration pneumonia and bacteremia.

High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study.

BACKGROUND: Regimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce immunogenic cell death (ICD) and to enhance immune-regulatory genes. Some patients demonstrate an extremely long-term response to PEM. It is possible that the continued response in these patients is dependent on not only the pharmacological induction of cytotoxic cell death but also antitumor immunity. However, factors that can predict outcomes associated with long-term PEM administration using blood test results have not yet been elucidated. We investigated the clinical characteristics and predictive factors in patients with advanced NSq-NSCLC who underwent long-term PEM maintenance therapy. METHODS: In total, 504 patients with advanced NSq-NSCLC who received PEM combination therapy/monotherapy (n = 414) or paclitaxel (PTX) combination therapy (n = 90) between January 2010 and November 2019 were recruited; 381 patients were retained for the final analysis. Patients treated with PEM (n = 301) were divided into subgroups according to the total cycles of PEM (≥ 17 [n = 25] for the long-term administration group and ≤ 16 [n = 276] for the intermediate/short-term group) and compared with another population (n = 80) treated with PTX combination regimen. We investigated clinical features and predictive biomarkers, focusing on immune-regulatory factors, absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and PD-1 and PD-L1 expression, to predict long-term response to PEM. RESULTS: The long-term PEM administration group exhibited a higher ALC and a lower NLR than the shorter-term group did. Both these markers displayed greater association with progression-free survival and overall survival in the PEM combination therapy group than in the PTX combination therapy group. Increased PD-1 lymphocytes were associated with the long-term PEM response group, as PD-L1 expression in tumors was associated with a high incidence of immune-related adverse effects following ICI administration. CONCLUSIONS: ALC, NLR, and PD-1 expression are PEM-mediated predictive biomarkers that are indirectly related to tumor immunity and can provide useful predictive information on the long-term response to PEM in patients with NSq-NSCLC.

Genistein attenuates hypoxic pulmonary hypertension via enhanced nitric oxide signaling and the erythropoietin system.

Upregulation of the erythropoietin (EPO)/EPO receptor (EPOR) system plays a protective role against chronic hypoxia-induced pulmonary hypertension (hypoxic PH) through enhancement of endothelial nitric oxide (NO)-mediated signaling. Genistein (Gen), a phytoestrogen, is considered to ameliorate NO-mediated signaling. We hypothesized that Gen attenuates and prevents hypoxic PH. In vivo, Sprague-Dawley rats raised in a hypobaric chamber were treated with Gen (60 mkg/kg) for 21 days. Pulmonary hemodynamics and vascular remodeling were ameliorated in Gen-treated hypoxic PH rats. Gen also restored cGMP levels and phosphorylated endothelial NO synthase (p-eNOS) at Ser(1177) and p-Akt at Ser(473) expression in the lungs. Additionally, Gen potentiated plasma EPO concentration and EPOR-positive endothelial cell counts. In experiments with hypoxic PH rats' isolated perfused lungs, Gen caused NO- and phosphatidylinositol 3-kinase (PI3K)/Akt-dependent vasodilation that reversed abnormal vasoconstriction. In vitro, a combination of EPO and Gen increased the p-eNOS and the EPOR expression in human umbilical vein endothelial cells under a hypoxic environment. Moreover, Gen potentiated the hypoxic increase in EPO production from human hepatoma cells. We conclude that Gen may be effective for the prevention of hypoxic PH through the improvement of PI3K/Akt-dependent, NO-mediated signaling in association with enhancement of the EPO/EPOR system.

Mediastinal pancreatic pseudocyst diagnosed based on black pleural effusion.

Mediastinal pancreatic pseudocysts are rare complications of pancreatitis associated with alcohol consumption. Here, we report a case of mediastinal pancreatic pseudocyst. A 61-year-old Japanese woman presented to our hospital with epigastric pain and dyspnea. A chest radiograph revealed right-sided massive pleural effusion. Thoracentesis retrieved black pleural fluid with remarkably high fluid amylase levels were. Thoracic computed tomography (CT) after drainage revealed encapsulated fluid. Magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP) were performed because abdominal CT and ultrasonography did not reveal any pancreatic problems. MRCP showed cystic masses and pancreatic tail cysts extending to the stomach and lower oesophagus. ERCP confirmed leakage of contrast medium from the pancreatic tail into the retroperitoneum. We diagnosed the patient with a pancreatic pseudocyst extending to the mediastinum. A mediastinal pancreatic pseudocyst should be considered a differential diagnosis in patients with black pleural fluid with a high amylase level.

Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is an inherited autosomal genodermatosis characterised by fibrofolliculomas of the skin, renal tumours and multiple lung cysts. Genetic studies have disclosed that the clinical picture as well as responsible germline FLCN mutations are diverse. OBJECTIVES: BHDS may be caused by a germline deletion which cannot be detected by a conventional genetic approach. Real-time quantitative polymerase chain reaction (qPCR) may be able to identify such a mutation and thus provide us with a more accurate clinical picture of BHDS. METHODS: This study analysed 36 patients with multiple lung cysts of undetermined causes. Denaturing high performance liquid chromatography (DHPLC) was applied for mutation screening. If no abnormality was detected by DHPLC, the amount of each FLCN exon in genome was quantified by qPCR. RESULTS: An FLCN germline mutation was found in 23 (63.9%) of the 36 patients by DHPLC and direct sequencing (13 unique small nucleotide alterations which included 11 novel mutations). A large genomic deletion was identified in two of the remaining 13 patients by qPCR (one patient with exon 14 deletion and one patient with a deletion encompassing exons 9 to 14). Mutations including genomic deletions were most frequently identified in the 3'-end of the FLCN gene including exons 12 and 13 (13/25=52.0%). The BHDS patients whose multiple cysts prompted the diagnosis in this study showed a very low incidence of skin and renal involvement. CONCLUSIONS: BHDS is due to large deletions as well as small nucleotide alterations. Racial differences may occur between Japanese and patients of European decent in terms of FLCN mutations and clinical manifestations.

Sex hormones alter Th1 responses and enhance granuloma formation in the lung.

BACKGROUND: The lung is one of the sites of granulomatous responses, which are characterized by the recruitment and organization of activated macrophages and lymphocytes. There have been several reports that have shown that some pulmonary granulomatous diseases, such as sarcoidosis and nontuberculous mycobacterial disease, are likely to be characterized by a preponderance in postmenopausal females. Although sex hormones have been shown to play an important role in the regulation of the immune system, the influence of sex hormones on pulmonary granuloma formation is still unclear. OBJECTIVES: The purpose of this study was to assess whether sex hormones are involved in granulomatous inflammation and to evaluate how sex hormones modulate this response in the lung. METHODS: Ovariectomized rats were used as an experimental postmenopausal model in which chronic pulmonary granulomatous inflammation was induced by intravenous injection of complete Freund's adjuvant. RESULTS: Histological analysis of lung tissues demonstrated enhancement of granuloma formation in the ovariectomized group. Such enhanced granuloma formation was significantly associated with generalized Th1-biased cytokine production in the bronchoalveolar lavage fluid. CONCLUSION: These results indicate that sex hormones play an important role in pulmonary granuloma formation by altering the Th1 responses.

Effects of Early Administration of Macrolides on Whooping Cough in Adolescents and Adults: A Single-center Retrospective Cohort Study.

Objective This study aimed to elucidate the effects of early macrolide administration on genetically confirmed pertussis-induced cough in adolescents and adults. Methods This single-center, retrospective cohort study examined the effects of the early administration of macrolides and antitussive agents on cough secondary to pertussis. We divided the patients into two groups based on the median duration from the beginning of the cough to the initiation of macrolide administration: early macrolide administration group (EMAG) and non-early macrolide administration group (NEMAG). The clinical improvement of cough was defined as maintaining a cough awareness score of ≤3 points for 3 consecutive days. Patients The medical records of 40 patients diagnosed with pertussis (≥12 years old) who were able to maintain a cough diary and received no other antibiotics aside from macrolides were included in the study. A diagnosis of pertussis was made using the loop-mediated isothermal amplification (LAMP) test. Results The EMAG (24 patients) showed a significantly shorter total cough period than the NEMAG [16 patients; 20.0 (95% confidence interval (CI), 16-28) vs. 30.5 (95% CI, 27-40) days; log-rank test, p=0.002]. There was no significant difference in the post-administration cough periods between the EMAG and NEMAG [11.0 (95% CI, 7-19) vs. 13.0 (95% CI, 5-23) days; log-rank test, p=0.232]. Antitussive agents did not affect the cough. Conclusion The early administration of macrolides, but not antitussive agents, is effective for treating pertussis. Therefore, macrolides should be administered as soon as possible for this disease.

EML4-ALK positive lung adenocarcinoma with skeletal muscle metastasis in the right calf which was treatable with lorlatinib after resistance to treatment with alectinib.

This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib.

Sarcoidosis with marked necrosis in enlarged lymph nodes mimics mycobacterial infection: a case report.

BACKGROUND: Sarcoidosis is pathologically characterized by the formation of non-necrotizing epithelioid cell granulomas. However, pathological findings of patients with sarcoidosis have rarely revealed necrosis. We report here on a patient with sarcoidosis which needed to be distinguished from infectious disease because of marked necrosis in the lymph nodes. CASE PRESENTATION: A 46-year-old Japanese woman was referred to our hospital due to a dry cough and appetite loss. A chest X-ray and computed tomography revealed markedly enlarged mediastinal and hilar lymph nodes and hepatosplenomegaly. Surgical biopsy of these lymph nodes was performed in order to make a diagnosis. Pathological findings revealed epithelioid cell granuloma with marked necrosis that suggested infectious etiology such as mycobacterial and fungal infections. In addition to the pathological findings, immunoglobulin A (IgA) antibody for Mycobacterium avium complex (MAC), enlargement of lymph nodes and hepatosplenomegaly indicated disseminated MAC, while sarcoidosis was considered as another important differential diagnosis according to elevated angiotensin-converting enzyme, soluble interleukin-2 receptor and uveitis. While waiting for the results of the cultures of acid-fast bacilli, the symptoms of cough and consumption had worsened, and initiation of therapy was required before the confirmed diagnosis. The therapy for MAC was initiated because it was feared that immunosuppressive therapy containing corticosteroid for sarcoidosis could worsen the patient's condition if MAC infection was the main etiology. However, the treatment for MAC was not effective, and it was clarified that no acid-fast bacilli were cultured in the liquid culture medium, so the diagnosis was corrected to sarcoidosis after reconsideration of clinical and pathological findings. Prednisolone (30 mg/day) was administered orally, and the patient's symptoms and radiological findings improved. CONCLUSION: Sarcoidosis must be considered even if pathological findings reveal marked necrosis, because rare cases of sarcoidosis exhibit extensive necrosis in lymph nodes. It is extremely important to carefully examine the clinical and pathological findings through discussion with the examining pathologist to reach the correct diagnosis.

Osteopontin is involved in the formation of malignant pleural effusion in lung cancer.

Malignant pleural effusion (MPE) is associated with advanced-stage lung cancer and is a poor prognostic sign for these patients. Osteopontin (OPN) is a multifunctional cytokine that is involved in the tumor progression and angiogenesis of lung cancer cells. The purpose of this study is to investigate and provide evidence for the role of OPN in the formation of MPE associated with lung cancer. In this study, we established an OPN knockdown murine lung cancer cell line, 3LL cells, utilizing the small interfering RNA (siRNA) technique. To reveal the effect of OPN on the formation of MPE associated with lung cancer, we directly injected OPN knockdown 3LL cells, 3LL/OPN siRNA, or control cells, 3LL/control siRNA, into the pleural space of C57BL/6 mice. OPN knockdown significantly reduced the formation of MPE, but did not inhibit in vivo tumor growth of 3LL cells in mice. Vascular endothelial growth factor (VEGF) concentration in MPE was markedly decreased in the 3LL/OPN siRNA in comparison with that of the 3LL/control siRNA. In vitro, recombinant OPN protein enhanced VEGF secretion from human umbilical vein endothelial cell (HUVEC) or human mesothelial cell line, Met5A cells, in a concentration-dependent manner. These results suggest that OPN is positively involved in the formation of MPE of lung cancer presumably by promoting VEGF secretion from vascular endothelial cells or mesothelial cells. OPN could be an effective target molecule for reducing MPE in lung cancer patients.

Cholestatic Liver Injury Induced by Pembrolizumab in a Patient with Lung Adenocarcinoma.

The anti-programmed cell death-1 protein monoclonal antibody, pembrolizumab is an immune checkpoint inhibitor. While it improves the prognoses of patients with advanced non-small-cell lung cancer, it has been reported to induce various kinds of immune-related adverse events, including hepatotoxicity. Despite the frequency of hepatotoxicity, there is only limited information available regarding the pathophysiology and treatment. We herein report a 48-year-old man with lung adenocarcinoma who was treated with pembrolizumab and developed cholestatic liver injury. In this case, the importance of evaluating the histology of hepatotoxicity and the effectiveness of ursodeoxycholic acid for cholestatic liver injury is indicated.

Borderline pulmonary hypertension associated with chronic hypercapnia in chronic pulmonary disease.

Pulmonary hypertension (PH) due to lung diseases is classified as group 3 by the Dana Point classification. Given the basic pathophysiological conditions of group 3 lung diseases and the previously well-known concept of hypercapnic pulmonary vasoconstriction, chronic hypercapnia besides alveolar hypoxia might be another causative factor to increase mean pulmonary arterial pressure (PAm). Two hundred twenty-five subjects with chronic pulmonary diseases were assessed by a right heart catheterization and blood gas parameters. The subjects were classified into the following 4 groups: Hypercapnic Hypoxia (HCHX), Hypercapnic Normoxia (HCnx), Normocapnic Hypoxia (ncHX), and Normocapnic Normoxia (ncnx). Compared with ncnx, the HCHX, HCnx and ncHX groups all showed significantly higher PAm and met the criteria of borderline PH. Multiple regression analysis showed that PaCO2, as well as SaO2, was an independent variable for PAm. Given the poor prognosis with borderline PH, the elimination of excess pulmonary carbon dioxide in hypercapnia could be a considerable treatment strategy in chronic pulmonary disease.

Vinorelbine is effective for the malignant pleural effusion associated with lung cancer in mice.

Malignant pleural effusion (MPE) is associated with advanced-stage lung cancer. Vinorelbine (VNR) is a semisynthetic vinca alkaloid with strong antitumor activity in non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the effect of VNR on the production of MPE associated with lung cancer. To investigate the therapeutic efficacy of VNR in the production of MPE in mice, cells of the murine lung cancer cell line, 3LL, were injected into the pleural space of mice, and VNR was administered once intravenously. Treatment with VNR almost completely inhibited tumor growth and MPE production. In addition, immunohistochemical staining revealed that neovascularization and vascular endothelial growth factor (VEGF) expression were markedly decreased in VNR-treated tumors compared with those of the control tumors. Treatment of 3LL cells with high concentrations of VNR (5 or 10 nM) significantly inhibited cell proliferation in vitro. Interestingly, low concentrations of VNR (1 or 2.5 nM) did not affect 3LL cell proliferation, but markedly reduced VEGF expression in these cells. These results suggest that VNR may be effective for the treatment of MPE associated with lung cancer not only by its cytotoxic effect but also through down-regulation of VEGF expression in lung cancer cells.

ERC/mesothelin as a marker for chemotherapeutic response in patients with mesothelioma.

BACKGROUND: It has been recently reported that soluble mesothelin-related protein (SMRP), serum mesothelin, and osteopontin (OPN) are considered as relevant biomarkers for the diagnosis of mesothelioma. The aim of this study was to investigate whether serum N-ERC/mesothelin, an NH3-terminal fragment of mesothelin, and plasma OPN reflect chemotherapeutic effect in patients with mesothelioma. MATERIALS AND METHODS: Serum N-ERC/mesothelin and plasma osteopontin were determined with a sandwich enzyme-linked immunosorbent assay (ELISA) system. RESULTS: The average N-ERC ratio, determined by dividing the N-ERC levels following chemotherapy by those prior to chemotherapy, in the partial response (PR) group was significantly lower than that of the stable disease (SD)/progressive disease (PD) group. In contrast, the average OPN ratio, determined by dividing the OPN levels following chemotherapy by those prior to chemotherapy, in the PR group was not statistically different from that of the SD/PD group. CONCLUSION: N-ERC/mesothelin is considered as relevant in monitoring chemotherapeutic response in patients with mesothelioma.

Hydrocarbon pneumonitis caused by the inhalation of wood preservative.

A 69-year-old man was admitted to our hospital with acute dyspnoea, which developed after using a wood-preserving agent in an enclosed space. Burn injuries were evident on his face, neck, chest, and both upper arms. Bronchoalveolar lavage was carried out. The collected fluid resembled wood preservative. Subsequently, it was established that kerosene was a major component of the wood preservative. A diagnosis of hydrocarbon pneumonitis was established. The patient's respiratory and general findings improved with intensive care, which included mechanical ventilation. Corticosteroid was not required to aid his recovery. Aspiration and/or inhalation of hydrocarbon compounds, such as kerosene, turpentine, and gasoline, can cause acute and fatal pneumonitis. In managing cases of hydrocarbon pneumonitis, a prompt diagnosis and appropriate supportive care are important to achieve a good outcome.

The diagnostic yield using ultrasound-guided needle-aspiration for subpleural primary lung cancer is not affected by the radiological properties of the lesions resulting from computed tomography.

BACKGROUND: It is well known that ultrasound-guided needle-aspiration (USGNA) for intrapulmonary subpleural lesion in contact with the pleura is useful and safe, and its diagnostic yield is high. However, reports concerned with the analyses of cases with intrapulmonary subpleural lesion which could not be diagnosed using USGNA are limited. The objective of this study is to clarify the radiological properties of subpleural primary lung cancer which obstruct diagnosis by USGNA. METHODS: The consecutive cases with subpleural primary lung cancer whose radiological properties could be confirmed by thoracic computed tomography (CT) without contrast enhancement (CE), and examined by USGNA at our hospital between January 1999 and December 2014 have been analyzed. All cases were given pathological diagnoses of primary lung cancer. The diagnostic yield by USGNA was calculated, and the properties of the lesions of the subjects were analyzed by means of thoracic CT without CE images and pathological findings. RESULTS: 87 consecutive cases (41-86 year olds, 75 males, 12 females) were analyzed. The overall diagnostic yield by USGNA was 86.2%. There was no statistically significant difference regarding the diagnostic yield concerning radiological properties such as cavities, small airspaces and low density areas in the lesions and their sizes. However, the diagnostic yield for the cases with squamous cell carcinoma was statistically significantly low (p=0.02). CONCLUSION: Although the diagnostic yield of USGNA is not distorted by the radiological properties of lesions, it is statistically significantly low in cases with squamous cell carcinoma.

[A case of exogenous lipoid pneumonia with marked elevation of serum KL-6 and interstitial lung shadows due to aspiration of liquid paraffin].

A 64-year-old man who ingested liquid paraffin as a laxative for over two years, was admitted to our hospital with a persistent interstitial lung shadow and marked elevation of serum KL-6. He had no overt symptoms although his chest radiograph revealed ground glass opacities in the left lower lung field and right middle and lower lung fields. We performed fiberoptic bronchoscopy. Exogenous lipoid pneumonia was diagnosed based on microscopic analysis of the bronchoalveolar lavage fluid that revealed the presence of lipid-laden alveolar macrophages. We instructed the patient to discontinue liquid paraffin ingestion and observed his clinical course. The chest radiograph and thoracic computed tomography revealed a tendency to improve and serum KL-6 decreased with time. Serum KL-6 may be an important index of the severity of exogenous lipoid pneumonia.

[Case of Heerfordt's syndrome with prolonged peripheral nerve involvement].

A 28-year-old man complaining of myiodesopsia was given a diagnosis of uveitis. Subsequently he complained facial nerve palsy and enlargement of parotid gland. Heerfordt's syndrome was diagnosed based on the results of several examinations. Facial nerve palsy, enlargement of the parotid gland and uveitis were improved by systemic corticosteroid therapy. At present he is receiving systemic corticosteroid therapy, but numbness in the mouth, thought to be the involvement of the trigeminal nerve, remains. Systemic corticosteroid therapy is usually effective for most cases with Heerford's syndrome. On the other hand, there are some cases with the prolonged peripheral nerve involvement despite systemic corticosteroid therapy, as seen in this case. If peripheral nerve involvement is prolonged, it is necessary to consider small-fibre neuropathy as one possible cause.

Carcinomatous pleuritis and pericarditis accompanied by pulmonary tuberculosis.

Although both lung cancer and pulmonary tuberculosis (TB) commonly occur in clinical practice, little attention has been paid to their coexistence. A 62-year-old female was admitted with acute dyspnoea secondary to cardiac tamponade. During her admission, a mass lesion harbouring air bronchograms in the right upper lobe rapidly increased in size. Surgical lung, pericardial, and pleural specimens yielded TB from a nodule in the right upper lobe and lung adenocarcinoma from the pericardium and pleura. Anti-tuberculous therapy was administered and gefitinib was subsequently started after the positive identification of epidermal growth factor receptor (EGFR) mutation (exon 19 deletion). The patient's general condition gradually improved with the anti-tuberculous and the EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment. Dual pathology is important to consider in patients with atypical radiological appearances. In those with proven EGFR mutation positive for lung cancer and pulmonary TB, sequential anti-tuberculous medication followed by EGFR-TKI treatment is advised.