Unusual nuclear exchange within a germanium-containing aromatic ring that results in germanium atom transfer.

The delivery of single atoms is highly desirable for the straightforward synthesis of complex molecules, however this approach is limited by a lack of suitable atomic transfer reagents. Here, we report a germanium atom transfer reaction employing a germanium analogue of the phenyl anion. The reaction yields a germanium-substituted benzene, along with a germanium atom which can be transferred to other chemical species. The transfer of atomic germanium is demonstrated by the formation of well-defined germanium doped molecules. Furthermore, computational studies reveal that the reaction mechanism proceeds via the first example of an aromatic-to-aromatic nuclear germanium replacement reaction on the germabenzene ring. This unusual reaction pathway was further probed by the reaction of our aromatic germanium anion with a molecular silicon species, which selectively yielded the corresponding silicon-substituted benzene derivative.

Phase 2 study of first-line pembrolizumab monotherapy in elderly patients with non-small-cell lung cancer expressing high PD-L1.

BACKGROUND: Pembrolizumab is the recommended first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥50% without driver mutations. However, its efficacy and safety for patients ≥75 years have not been prospectively investigated; this was the aim of this study. METHODS: This multicenter and open-label single-arm phase II study was conducted at 12 institutions. Chemotherapy-naïve patients with advanced NSCLC and a PD-L1 TPS of ≥50% without EGFR mutations or translocation of the ALK received pembrolizumab every 3 weeks. The primary endpoint was progression-free survival (PFS) with a threshold of 4.3 months. The secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and quality of life. RESULTS: Twenty-six patients were enrolled between October 2017 and March 2020. The median PFS was 9.6 (95% confidence interval [CI] 2.1-20.6) months. The lower limit of the 95% CI did not exceed the target. The median OS was 21.6 months. The ORR and DCR were 41.7% and 70.8%, respectively. The proportion of patients with grade ≥3 treatment-related adverse events was 15.4%. The quality of life score did not change significantly during treatment. CONCLUSION: While this study showed that pembrolizumab was a tolerable treatment for elderly patients, the safety requires further confirmation in a larger study. Although the primary endpoint, the median PFS (9.6 months), was slightly shorter than that (10.3 months) of the previous phase III study (KEYNOTE-024 study), the median PFS did not achieve the expected value.

Primary advanced pulmonary synovial sarcoma treated with a multidisciplinary approach.

A 61-year-old woman was referred to our hospital due to right chest pain. A huge, 13-cm-diameter tumor was detected in the right lower lobe. For diagnostic and treatment purposes, pneumonectomy was performed, and the tumor was diagnosed as advanced pulmonary synovial sarcoma (SS) with pleural metastasis, according to immunohistochemistry analysis. Due to recurrence with brain metastases, treatment sequence composed of radiosurgery, doxorubicin, eribulin, and pazopanib was selected. The patient died after a considerably long survival of 29 months after the first visit. This case suggests that multimodal treatment may provide prolonged survival even for patients with advanced SS.

[A young case of pulmonary tuberculosis with atypical tumor shadow on chest computed tomography and its difficulty in diagnosis].

BACKGROUND: Diagnosis of pulmonary tuberculosis is usually made by diagnostic imaging such as chest X-ray or computed tomography (CT), and sputum test including smear and polymerase chain reaction (PCR) test. However there is difficulty in making diagnose when atypical imaging and negative sputum test are presented, followed by diagnostic delay. CASE: A 26-year-old man from Philippines consulted other clinic because of dry cough and was pointed out mass shadow in right upper lung field in his chest CT. He visited our office because of positive interferon gamma release assay, but repeated sputum test could not find tuberculosis. Bleeding from mass lesion failed to perform biopsy by bronchoscope, and we failed to find tuberculosis by smear and PCR test from bronchial brushing and wash. Transthoracic needle biopsy from his mass lesion revealed multiple non-caseous granuloma, and lead to make a decision about starting medication. Four weeks later sputum culture from his first visit revealed positive, and diagnosis of tuberculosis was made. DISCUSSION: For avoiding therapy delay it is important to perform invasive diagnostic procedure including histological examination and clinical decision of starting medication, when conservative diagnostic procedure such as sputum test or diagnostic imaging present atypical finding for diagnosing tuberculosis.

RASEF is a novel diagnostic biomarker and a therapeutic target for lung cancer.

UNLABELLED: Genome-wide gene expression profiling revealed that the Ras and EF-hand domain containing (RASEF) transcript was significantly transactivated in the majority of lung cancers. Using lung cancer cells, transient expression of RASEF promoted cell growth, whereas RASEF knockdown not only reduced its expression but resulted in growth suppression of the cancer cells. Immunohistochemical staining using tumor tissue microarrays consisting of 341 archived non-small cell lung cancers (NSCLC) revealed the association of strong RASEF positivity with poor prognosis (P = 0.0034 by multivariate analysis). Mechanistically, RASEF interacted with extracellular signal-regulated kinase (ERK) 1/2 and enhanced ERK1/2 signaling. Importantly, inhibiting the interaction between RASEF and ERK1/2 using a cell-permeable peptide that corresponded to the ERK1/2-interacting site of RASEF, suppressed growth of lung cancer cells. This study demonstrates that elevated RASEF promoted cell growth via enhanced ERK signaling and is associated with poor prognosis of NSCLC. IMPLICATIONS: RASEF may play an important role in lung carcinogenesis and could serve as a vaiable prognostic biomarker and target for the development of new molecular therapies.

Krebs von den Lungen-6 (KL-6) is a prognostic biomarker in patients with surgically resected nonsmall cell lung cancer.

By immunizing mice with a lung adenocarcinoma cell line, we previously established a murine IgG1 monoclonal antibody that recognizes a sialylated sugar chain designated Krebs von den Lungen-6 (KL-6). KL-6 is a high-molecular-weight glycoprotein classified as a human MUC1 mucin. The aim of this study was to determine whether KL-6 expression in tumors correlates with circulating KL-6 levels and whether circulating KL-6 has any prognostic value in patients with surgically resected non-small cell lung cancer (NSCLC). Immunohistochemical analysis of KL-6 expression was performed on 103 NSCLC tissues, and its associations with serum KL-6 levels and survival were examined. We also evaluated whether KL-6 expression patterns and/or serum KL-6 levels could predict prognosis in these NSCLC patients. Immunohistochemical analysis of KL-6 in NSCLC tissues showed that a depolarized KL-6 expression pattern was associated with a high level of circulating KL-6 and a poor prognosis in NSCLC patients who underwent curative surgery. Furthermore, a high circulating KL-6 level was associated with both poorer progression-free survival (PFS) and overall survival (OS), and multivariate analyses confirmed its independent prognostic value for both PFS and OS (p = 0.041 and 0.023, respectively). Our data suggest that preoperative serum KL-6 level reflects KL-6 expression patterns in NSCLC tissue, and can serve as a useful prognostic biomarker in NSCLC patients who undergo curative surgery.

Identification of Epstein-Barr virus-induced gene 3 as a novel serum and tissue biomarker and a therapeutic target for lung cancer.

PURPOSE: This study aims to identify novel biomarkers and therapeutic targets for lung cancer. EXPERIMENTAL DESIGN: We carried out gene expression profile analysis of 120 lung cancers to screen for genes encoding transmembrane/secretory molecules that are commonly transactivated in lung cancers. Epstein-Barr virus-induced gene 3 (EBI3), which encodes a secretory glycoprotein, was selected as a good candidate. Immunohistochemical staining using tissue microarray consisting of 414 non-small cell lung cancers was applied to examine the expression level and prognostic value of EBI3. Serum EBI3 levels in 400 individuals for training assays (274 lung cancers and 126 healthy volunteers) and those in 173 individuals for validation analysis (132 lung cancers and 41 healthy volunteers) were measured by ELISA. The role of EBI3 in cancer cell growth was examined by siRNA and cell growth assays, using cells stably expressing exogenous EBI3. RESULTS: Immunohistochemical staining of EBI3 using tissue microarrays revealed that a high level of EBI3 expression was associated with a poor prognosis of lung cancer (P = 0.0014) and multivariate analysis confirmed it to be an independent prognostic factor (P = 0.0439). Serum levels of EBI3 in the training set were found to be significantly higher in lung cancer patients than in healthy volunteers; this result was also observed in the validation set. Furthermore, reduction in EBI3 expression by siRNA suppressed cancer cell proliferation whereas induction of exogenous EBI3 conferred growth-promoting activity. CONCLUSIONS: EBI3 is a potential serum and tissue biomarker as well as therapeutic target for lung cancer.

Identification of nectin-4 oncoprotein as a diagnostic and therapeutic target for lung cancer.

Gene expression profile analysis of lung cancers revealed the transactivation of an immunoglobulin-like molecule Nectin-4 in the majority of non-small cell lung cancers (NSCLC). Immunohistochemical staining of 422 NSCLCs showed that a high level of Nectin-4 expression was associated with poor prognosis for NSCLC patients (P < 0.0001), and multivariate analysis confirmed its independent prognostic value (P < 0.0001). We established an ELISA to measure serum Nectin-4 and found that serum Nectin-4 levels were significantly higher in NSCLC patients than in healthy volunteers. The proportion of the serum Nectin-4-positive cases was 88 of 164 (53.7%) NSCLCs, whereas only 3 of 131 (2.3%) healthy volunteers were falsely diagnosed as positive, which was superior to carcinoembryonic antigen (CEA) and cytokeratin 19-fragment (CYFRA21-1) in sensitivity and specificity. A combined ELISA for both Nectin-4 and CEA increased sensitivity and classified 65.0% of lung adenocarcinomas as positive with false-positive rate of 4.6%. The use of both Nectin-4 and CYFRA21-1 classified 68.3% of lung squamous cell carcinomas as positive with false-positive rate of 6.1%. Treatment of lung cancer cells with small interfering RNAs against Nectin-4 suppressed its expression and cell growth. In addition, exogenous expression of Nectin-4 increased the lamellipodia formation and the invasive ability of mammalian cells through activation of small GTPase Rac1. Nectin-4 might play a significant role in lung carcinogenesis, and it should be a new candidate serum and tissue biomarker, as well as a therapeutic target.

Usefulness of monitoring the circulating Krebs von den Lungen-6 levels to predict the clinical outcome of patients with advanced nonsmall cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors.

Krebs von den Lungen-6 (KL-6) is a high molecular weight glycoprotein classified in the category of human MUC1 mucin. KL-6 has been reported to serve as a sensitive marker for interstitial pneumonia; however, recent studies have suggested that it can also be used as a tumor marker as its origin shows. To further elucidate the clinicopathological significance of circulating KL-6 in lung cancer, we monitored the circulating KL-6 levels in advanced nonsmall cell lung cancer (NSCLC) patients and analyzed the association between these levels and the clinical outcome of EGFR-TKI treatment. The pretreatment levels of circulating KL-6 were found to be significantly higher in progressive disease (PD) patients than disease-controlled (partial response (PR) and stable disease (SD)) patients. Multivariate analyses revealed the circulating KL-6 level to be an independent prognostic factor for overall survival as well as progression-free survival. In addition to these observations, we found that changes in circulating KL-6 levels at 2 weeks after the start of EGFR-TKI treatment from the baseline could quite precisely discriminate PD cases from PR or SD patients and the clinical outcome of EGFR-TKI in NSCLC patients. These results indicate that the monitoring of circulating KL-6 levels in NSCLC patients is effective for both selecting patients to be treated with EGFR-TKI and predicting the clinical outcome of EGFR-TKI. In addition, the findings suggest that the circulating KL-6 level could be used as a clinically relevant biomarker in patients with NSCLC, particularly those who are candidates for EGFR-TKI treatment.

[Clinical study of 37 pneumonia patients in whom MRSA was identified from sputum].

When we studied the clinical aspects of 37 pneumonia patients with underlying respiratory disease in whom MRSA 1 + was identified from sputum, 43.2% of these 37 pneumonia cases were diagnosed as MRSA colonization. The whole clinical course of these pneumonia patients with MRSA colonization was average 39.5 days, on the other hand, the whole clinical course of MRSA pneumonia group was 55.3 days. We should consider that MRSA must be a cause of pneumonia, in only such cases as follows; (1) patients with unstable diabetes mellitus, or with long-term administration of steroid, (2) patients with infiltrative shadows appeared not only in the lower lobe but also the upper lobe in the chest x-ray films, (3) patients with remarkable decrease of PaO2 or patients who failed to recover within one month from MRSA isolation, (4) patients with nosocomial pneumonia or patients with poor performance status or poor prognosis, (5) patients with purulent sputum containing MRSA or other bacteria such as K. pneumoniae etc and patients who failed to respond to general antibacterial agents.

[Differences in the way of thinking about health and infectious diseases between the elderly and medical staff].

The majority of our inpatients and outpatients are senior citizens. They are in marked contrast to the majority of current medical workers who are far younger than their patients. We investigated the problems which may arise due to this age gap using a questionnaire asking about viewpoints on "health" and "infectious diseases among the elderly" Interest in general health was lower among medical workers than common citizens. Lifestyles which the public may consider to be good for health are more specific and cover a wider range than those of medical professionals. Medical staff thought home care is important for infectious diseases among the elderly. They were concerned with the appearance of resistant bacilli and considered that the type of treatment should vary in accordance with the patient's age and stamina, whereas the elderly citizens cared more strongly about the treatments result. Medical workers should understand that the general citizens have a different way of thinking about health and infectious diseases from their own.

[Case of pulmonary carcinosarcoma and a summary of 17 cases reported in Japan].

The patient was a 69-year-old man who complained of dyspnea and severe general fatigue. Chest CT showed a large tumor (6 x 5 cm) in the left S3 together with left pleural effusion. Despite pleurodesis and chemotherapy, he died 1.5 months after admission. At autopsy, a final diagnosis of pulmonary carcinosarcoma was obtained. We have summarized 17 cases of pulmonary carcinosarcoma reported in Japan. All patients were men, and had an average age of 68 years. The majority of the patients were heavy smokers. Death was reported in 70% of cases, the median survival period being 5 months, whereas the patients reported as living had operable cases of T2 tumor without distant metastatic lesions.

Legionella micdadei pneumonia diagnosed by culture isolation and DNA-dNA hybridization from bronchial lavage fluid.

An 80-year-old man was admitted because of dyspnea on effort. We suspected an acute exacerbation of chronic heart failure and idiopathic interstitial pneumonia caused by right-sided pneumonia. A nodular shadow in right upper lobe spread and consolidated into the airspace, and it failed to improve despite administration of meropenem trihydrate, vancomycin hydrochloride and clindamycin. A definitive diagnosis of Legionella micdadei pneumonia was made on the basis of this organism being isolated in culture from bronchial lavage fluid and subsequent identification of Legionella micdadei using DNA-DNA hybridization. The airspace consolidation gradually improved following treatment with intravenous erythromycin and minocycline hydrochloride.

[A case of primary pulmonary leiomyosarcoma with history of pneumonia 5 years before].

A 35-year-old woman with past history of pneumonia in the right lung field 5 years before was admitted to our hospital because of fever and cough. Chest radiographs showed a pulmonary tumor with atelectasis of the right lower lung. Chest CT also revealed a round clear-edged tumor at the right S6 with atelectasis of the right lower lung lobe. Bronchoscopic findings showed a yellowish endobronchial tumor in the right truncus intermedius, which proved to be leiomyosarcoma. We could not find any other malignant lesion, and therefore, on a diagnosis of primary pulmonary leiomyosarcoma, right middle and lower lobectomy was performed with lymph node excision. Retrospective examination of the chest radiographs revealed not only that the original region of the leiomyosarcoma seemed to be near the site of the earlier pneumonia, but also that the atelectasis-like findings 2 years before were similar to the findings on this admission. It was reported that, if an operation could not be performed at an early stage, the prognosis might be poor. In the follow-up of the abnormal chest radiographic findings, the clinic physician should observe the symptoms from the same viewpoint as hospital doctors. It is important to keep an active relationship between clinic and hospital. We might have reached our final diagnosis earlier if we had been more active in seeking an examination for abnormal chest radiographic findings, without attaching too much importance to the patient's age.

[Detection of MRSA with antimicrobial susceptibility by using chemiluminescent assay].

Chemiluminescent assay can give the result of the detection of MRSA about 13 hours more rapidly than conventional broth microdilution method. In order to apply chemiluminescent assay to detection of MRSA, we compared MIC and antimicrobial susceptibility to MPIPC in using chemiluminescent assay with these in using broth microdilution method. In MSSA, rate of concordance of MIC and antimicrobial susceptibility to MPIPC obtained by both methods was 87%, but all MICs come to be agreed by modifying the concentration of bacterial liquid. In MRSA, all MICs and susceptibility to MPIPC are agreed in both methods. Although we have used chemiluminescent assay to detect MRSA for one year, no trouble has been reported by clinical side. The chemiluminescent assay is evaluated to be good in detecting MRSA.

[A case of severe pneumoconiosis with synchronous triple lung cancer].

A 70-year-old man who had worked in a stonepit for about fifty years was admitted to our hospital for detailed examination of the signs of pneumoconiosis (3/3, q) and a nodular shadow in the right upper lung field. Under a clinical diagnosis of lung cancer complicated with pneumoconiosis, right upper lobectomy with a right S6 resection was performed. Pathological examination revealed moderately differentiated adenocarcinoma of the right S2, well-differentiated adenocarcinoma of the right S6, and a squamous cell carcinoma of the right S1 which was not detected by chest CT. In addition to the difficulty of diagnosing lung cancer in a patient with severe pneumoconiosis, treatment for lung cancer may be limited by the poor pulmonary function that results from pneumoconiosis. Although the labor administration's decision that lung cancer patients with concomitant pneumoconiosis deserve compensation can be evaluated as a good one, the study of the relationship between pneumoconiosis and lung cancer needs further study through follow-up examination of pneumoconiosis cases.