Search

Carcinosarcoma is a rare histological type of non-small cell carcinoma (NSCLC), and its prognosis has been reported to be worse compared with other NSCLCs. Nanoparticle albumin-bound paclitaxel (nab-PTX) + carboplatin (CBDCA) achieves a favorable response rate in patients with non-small cell lung cancer (NSCLC). We administered nab-PTX + CBDCA to a 68-year-old man with postoperative recurrent carcinosarcoma with interstitial lung disease (ILD). A partial response was evident after four cycles of chemotherapy. To the best of our knowledge, the present study is the first to report the safety and efficacy of nab-PTX + CBDCA for treating carcinosarcoma with ILD. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a subtype of B-cell non-Hodgkin's lymphoma. Most cases of MCL have extranodal involvement at the time of the initial diagnosis; however, endobronchial involvement is rare. An 87-year-old man was referred to our hospital because of dyspnea on exertion. A chest CT revealed diffuse irregular wall thickening of the trachea and bilateral bronchi. A bronchoscopy revealed a diffuse irregular surface of the tracheal and bilateral bronchial mucosa and polyposis-like lesions. He was diagnosed as having MCL based on an endobronchial biopsy, and the diagnosis was confirmed using immunohistochemical staining. [ABSTRACT FROM AUTHOR]

Abstract: Afferent pathways innervating the urinary bladder consist of myelinated Aδ-fibers and unmyelinated C-fibers. Normal voiding is dependent on mechanoceptive Aδ-fiber bladder afferents that respond to bladder distention. However, the mechanisms for controlling the excitability of Aδ-fiber bladder afferents are not fully understood. We therefore used whole cell patch-clamp techniques to investigate the properties of hyperpolarization-activated, cyclic nucleotide-gated (HCN) currents (I h) in dorsal root ganglion (DRG) neurons innervating the urinary bladder of rats. The neurons were identified by axonal tracing with a fluorescent dye, Fast Blue, injected into the bladder wall. Hyperpolarizing voltage step pulses from −40 to −130 mV produced voltage- and time-dependent inward I h currents in bladder afferent neurons. The amplitude and current density of I h at a holding potential of −130 mV was significantly larger in medium-sized bladder afferent neurons (diameter: 37.8 ± 0.3 μm), a small portion (19%) of which were sensitive to capsaicin (1 μM), than in uniformly capsaicin-sensitive small-sized (27.6 ± 0.5 μm) bladder neurons. In medium-sized bladder neurons, a selective HCN channel inhibitor, ZD7288, dose-dependently inhibited I h currents. ZD7288 (10 μM) also increased the time constant of the slow depolarization phase of spike after-hyperpolarization from 91.8 to 233.0 ms. These results indicate that I h currents are predominantly expressed in medium-sized bladder afferent neurons innervating the bladder and that inhibition of I h currents delayed recovery from the spike after-hyperpolarization. Thus, it is assumed that I h currents could control excitability of mechanoceptive Aδ-fiber bladder afferent neurons, which are usually capsaicin-insensitive and larger in size than capsaicin-sensitive C-fiber bladder afferent neurons. [Copyright &y& Elsevier]

• Anti-SP antibody titer compared after second and third doses of the BNT162b2 vaccine. • Study conducted on healthcare workers directly exposed to COVID-19 patients. • Anti-SP IgG titer decreased slowly after second dose of the vaccine. • Peak IgG titer 4.1-fold higher after the third dose than after first and second doses. • Adverse events following immunization were generally mild to moderate. Administration of three doses of Pfizer-BioNTech BNT162b2 COVID-19 mRNA vaccine was completed in Japan in the spring of 2022. This study aimed to evaluate the antibody responses, and kinetics of three doses of vaccine in healthcare workers (HCWs). We conducted a longitudinal cohort study with HCWs, who had no history of COVID-19 or serologic evidence of SARS-CoV-2 infection, from a single hospital. Immunoglobulin G (IgG) titers of anti-SARS-CoV-2 spike protein (SP) and nucleocapsid protein (NP) titers were measured using an automated chemiluminescent enzyme immunoassay system. A total of 636 HCWs participated in the study. The anti-SP IgG titers decreased slowly after the second dose of the BNT162b2 vaccine in all participants, and robust antibody response was observed after the third dose of the vaccine. The peak anti-SP IgG titer after the third dose was approximately 4.1-fold higher than that after the first and second doses, and the rate of decrease in the anti-SP IgG titer after the third dose was significantly more gradual, than that after the second dose. After the second dose of vaccine, the antibody response was weaker in older participants than in younger participants, and in males than in females respectively, whereas the response to the third dose of vaccine did not differ significantly by sex or age. Adverse events following immunization were generally mild to moderate. The third dose of the BNT162b2 vaccine induced a significant and sustained increase in anti-SP IgG titers, and was generally safe and well-tolerated. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Although nuclear factor (NF)-κB and phosphoinositide 3-kinase (PI3K)-Akt-mTOR comprise key pathways, their interrelationship in lung cancer cell survival is poorly understood and needs further analyses. Materials and methods: We examined the activation of the NF-κB and Akt-mTORC1-p70 S6 kinase (S6K) pathways and the effect of inhibitors for NF-κB, mTORC1, and Akt using fresh lung adenocarcinoma cells. Results: The cases used for this study showed constitutive NF-κB activity; however, all cases but one showed resistance to NF-κB inhibition. Further examination revealed that the resistant cases were also active in the Akt-mTORC1-S6K pathway. These cases were insensitive to mTORC1 inhibition but sensitive to Akt inhibition. Akt inhibition recovered sensitivity to NF-κB inhibition and dual inhibition showed a synergistic effect on apoptosis induction. Conclusion: These results indicate that the activation of Akt involves resistance to NF-κB inhibition and both pathways synergistically support the survival of lung adenocarcinoma cells. The results also indicate that inhibition of the mTORC1-S6K pathway does not inhibit the survival of these cells. [Copyright &y& Elsevier]

Abstract: Background: The leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5), also known as Gpr49, has been identified as a marker of crypt basal columnar stem cells along the gastrointestinal tract and of bulge stem cells in the hair follicle. The aims of this study were to immunohistochemically examine Lgr5 expression in surgically resected non-small cell lung carcinomas (NSCLC), and evaluate the relationships between Lgr5 expression and the clinicopathological parameters and prognosis of patients. Methods: Lgr5 expression was immunohistochemically studied in 266 consecutive resected NSCLCs, and its associations with clinicopathological parameters including TTF-1 and CDX-2 expressions were evaluated. Kaplan–Meier survival analysis and Cox proportional hazards models were used to estimate the effect of Lgr5 expression on survival. Results: Lgr5 was detected only in tumors with adenocarcinoma histology, and 16 cases were judged as positive. Among lung adenocarcinomas, Lgr5 expression was significantly associated with a larger tumor size (>5cm) (P =0.033), higher pathological TNM stage of the disease (stage II and III) (P =0.025), TTF-1-negative adenocarocinoma (P =0.042), and poorer prognosis (P =0.026). However, Lgr5 expression was not an independent predictor of poorer survival after controlling for clinicopathological factors. Conclusions: The present study reveals that Lgr5 is expressed in a subset of lung adenocarcinoma, and its expression is related to some clinicopathological parameters and a poorer prognosis, although further studies are required to clarify the biological function of Lgr5 in lung adenocarcinoma. [Copyright &y& Elsevier]

Abstract: Background: Large cell neuroendocrine carcinoma (LCNEC) of the lung is categorized as a high-grade neuroendocrine carcinoma with an aggressive clinical behavior. Nestin is a class VI intermediate filament protein expressed in stem/progenitor cells during central nervous system development. Recently, we reported that nestin expression is a prognostic indicator of a poorer survival probability in patients with resected NSCLC. In the present study, we aimed to determine its prognostic significance concerning survival in patients with resected LCNEC. Materials and methods: Nestin expression in tumor cells was immunohistochemically studied in 30 patients with resected LCNEC, and its associations with clinicopathologic parameters including the Ki-67 labeling index (LI) and TTF-1 expression were evaluated. Kaplan–Meier survival analysis and Cox proportional hazards models were used to estimate the effect of nestin expression on survival. Results: Nestin expression was observed in 8 of the 30 (26.7%) LCNECs. Clinicopathologically, although no significant association between nestin expression and age, gender, smoking habits, p-TNM stage, tumor size, nodal status, or TTF-1 expression was observed, nestin expression was significantly associated with a high Ki-67 LI (P =0.012). On survival analysis, nestin expression was significantly associated with a poorer prognosis in patients with LCNEC (P =0.016). The Cox proportional regression model confirmed that the crude hazard ratio (95%CI) of nestin expression was 3.40 (1.18–9.77). Conclusions: The present study suggests that nestin expression seems to be a prognostic indicator of a poorer survival probability in patients with resected LCNEC, although its prognostic significance still requires confirmation with larger patient populations. [Copyright &y& Elsevier]

Purpose: To investigate the safety and efficacy of concurrent vinorelbine and thoracic radiotherapy in elderly patients with locally advanced non–small-cell lung cancer (NSCLC). Methods and Materials: Eligible patients were 71 years of age or older with unresectable Stage III NSCLC. Patients were treated with thoracic radiotherapy (60 Gy) and concurrent vinorelbine (20 mg/m2 in Level 1 and 25 mg/m2 in Level 2) on Days 1 and 8 every 3 weeks for two cycles, followed by adjuvant vinorelbine (25 mg/m2) on Days 1 and 8 every 3 weeks for two cycles. Results: Four patients were enrolled at Level 1. One patient experienced Grade 3 febrile neutropenia at Level 1 and the dose was escalated to Level 2. At Level 2, 2 of 6 patients experienced dose-limiting toxicities (Grade 4 neutropenia in 1 patient and Grade 3 infection in another). Three of 6 patients developed late Grade 2 or 3 pneumonitis. Therefore, the dose was de-escalated to Level 1. An additional 6 patients were enrolled at Level 1, 4 of whom experienced dose-limiting toxicities (incomplete radiotherapy because of Grade 2 pneumonitis in 1 patient and Grade 3 infection in 1, Grade 3 febrile neutropenia in 1, and Grade 3 esophagitis in 1). Moreover, late Grade 3 pneumothorax and Grade 5 pneumonitis occurred in 1 and 1 patient, respectively. Overall, Grade 2, 3 and 5 pneumonitis occurred in 3, 3, and 1 among 16 patients, respectively. Conclusions: Concurrent vinorelbine and thoracic radiotherapy resulted in a high incidence of severe pneumonitis when the standard dose of this agent was used for elderly patients. We therefore recommend caution in the use of this regimen and schedule for elderly patients. [ABSTRACT FROM AUTHOR]

Abstract: To clarify the biological differences between small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC), we investigated the expression of two bHLH type transcription factors, human achaete-scute homolog 1 (hASH1) and hairy/enhancer of split 1 (HES1), which positively and negatively regulate the neuroendocrine differentiation of respiratory epithelial cells, respectively. Eighty-eight formalin-fixed and paraffin-embedded pulmonary carcinomas (32 SCLC, 32 LCNEC, 14 adenocarcinomas, and 10 squamous cell carcinomas) and 14 SCLC and 1 LCNEC derived cell lines were used. hASH1 and HES1 mRNA were detected using a highly sensitive in situ hybridization method with digoxigenin-labeled cRNA probes and biotinylated tyramide. The staining results were scored from 0 to 12 by multiplying the staining intensity by the percentage of positive tumor cells. The mean staining score of hASH1 mRNA was significantly higher in SCLC than in LCNEC (p <0.01); conversely, that of HES1 mRNA was lower in SCLC than in LCNEC (p <0.01). These findings reveal that SCLC more strongly expresses the neuroendocrine phenotype, while LCNEC shows characteristics more similar to the ciliated epithelium phenotype, suggesting that the biological characteristics of these two tumors are different. [Copyright &y& Elsevier]

Abstract: A phase I/II trial of TS-1 combined with gemcitabine was designed to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate the efficacy and toxicity in elderly patients with advanced non-small cell lung cancer (NSCLC). Patients older than 70 years of age received TS-1 orally b.i.d. on days 1–14 and gemcitabine intravenously on days 8 and 15 every 4 weeks. In phase I (n =22), each cohort received escalating doses of TS-1 (30–40mg/m2 b.i.d.) and gemcitabine (800–1000mg/m2); MTD was 40mg/m2 b.i.d. TS-1 and 1000mg/m2 gemcitabine; RD was 30mg/m2 b.i.d. TS-1 and 1000mg/m2 gemcitabine. Dose-limiting toxicities included a grade 3 infection, skin toxicity, and stomatitis. In phase II (n =37), the overall response rate was 27% (90% confidence interval (CI): 15–42%) and the median time to progression and overall survival were 4.2 months (90% CI: 3.2–5.7) and 12.9 months (90% CI: 10.4–14.7), respectively. The most common grade 3 or higher toxicity was neutropenia (45.9%), and thrombocytopenia was observed in 13.5% of patients. Two cases each of grade 3 pneumonitis and skin toxicity were observed, but nonhematological toxicities occurred at generally low frequencies. TS-1 with gemcitabine is a promising doublet regimen in elderly patients with advanced NSCLC with acceptable toxicities. [Copyright &y& Elsevier]

Abstract: To develop useful early and/or differential diagnostic markers for pulmonary adenocarcinomas, we generated monoclonal antibodies using A549 cells derived from pulmonary adenocarcinomas as an immunogen. Hybridoma supernatants were immunohistochemically screened for antibody production by AMeX-fixed and paraffin-embedded A549 cell preparations. Positive clones were monocloned twice by limiting dilutions. From a group of obtained antibodies, an antibody designated as KU-Lu-3 showed cytoplasmic staining. The antigen recognized by KU-Lu-3 was detected by modified two-dimensional immunoblotting, and was determined to be the receptor of activated C kinase 1 (RACK1). To evaluate the utility of KU-Lu-3, we immunohistochemically studied 184 cases of pulmonary carcinoma and paired normal lung tissues, using formalin-fixed and paraffin-embedded tissue microarray sections. The expression was significantly high and frequent in adenocarcinomas but was barely detected in a few squamous cell carcinomas and large cell carcinomas (p <0.0001). Moreover, RACK1 expression was also significantly associated with the pathological stage, tumor size and lymph node status of adenocarcinoma patients, but not with tumor differentiation, or patient age and gender. These results suggest that RACK1 may be a novel differential diagnostic marker for pulmonary adenocarcinomas. [Copyright &y& Elsevier]

Alectinib has been approved for the treatment of patients with anaplastic lymphoma kinase (ALK) gene rearrangement-positive advanced non-small cell lung cancer. In terms of adverse effects, the occurrence of a severe skin rash induced by alectinib is reportedly rare, compared with the occurrence of skin rash induced by epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). In the present case report, a 76-year-old woman with ALK - positive lung adenocarcinoma experienced disease progression after undergoing first-line chemotherapy. Subsequently, alectinib was administered as a second - line therapy. However, she discontinued alectinib therapy after 11 days because of the occurrence of an alectinib-induced skin rash. Since the skin rash improved within one week, we attempted to perform oral desensitization to alectinib. The patient has not shown any recurrence of the rash or disease progression for 7 months since the successful oral desensitization to alectinib. Here, we describe the first case of successful oral desensitization against a skin rash induced by alectinib in a patient with ALK-positive lung adenocarcinoma. Desensitization to overcome adverse effects and to enable sustained treatment with alectinib should be considered in patients who develop alectinib sensitivities. [ABSTRACT FROM AUTHOR]

A series of piperidinoalkanoyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized, and their bradycardic activities were investigated in the isolated right atria of guinea pigs and in conscious rats. These efforts identified the achiral compound 2f, which exhibited potent and long-lasting bradycardic activity with minimal effects on mean blood pressure in conscious rats. [Copyright &y& Elsevier]

A series of N-acyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and evaluated for their bradycardic activities in isolated guinea pig right atria and in urethane-anesthetized rats. These efforts resulted in identification of the compound 8a, which exhibits potent bradycardic activity with minimal influence on mean blood pressure in urethane-anesthetized rats. Oral administration of compound 8a to conscious rats revealed increased potency and prolonged duration of action when compared to Zatebradine. [Copyright &y& Elsevier]

A series of (±)-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines were prepared and their bradycardic activities were examined in isolated guinea-pigs’ right atria and in anesthetized rats. Modifications on the benzyl moiety of the parent compound, 1, led to the identification of compound 11e as a potent and specific bradycardic agent. [Copyright &y& Elsevier]