Effects of flurbiprofen on the functional regulation of serotonin transporter and its misfolded mutant.

Flurbiprofen, a nonsteroidal anti-inflammatory drug, reportedly exhibits chemical chaperone activity. Herein, we investigated the role of flurbiprofen in regulating serotonin transporter (SERT) function via membrane trafficking. We used COS-7 cells transiently expressing wild-type (WT) SERT or a C-terminus-deleted mutant of SERT (SERTΔCT), a misfolded protein. Flurbiprofen treatment reduced the expression of immaturely glycosylated SERT and enhanced the expression of maturely glycosylated SERT. In addition, we observed increased serotonin uptake in SERT-expressing cells. These results suggest that flurbiprofen modulates SERT function by promoting membrane trafficking. In SERTΔCT-expressing cells, flurbiprofen reduced the protein expression and uptake activity of SERTΔCT. Furthermore, flurbiprofen inhibited the formation of SERTΔCT aggregates. Studies using flurbiprofen enantiomers suggested that these effects of flurbiprofen on SERT were not mediated via cyclooxygenase inhibition. The levels of GRP78/BiP, an endoplasmic reticulum (ER) stress marker, were assessed to elucidate whether flurbiprofen can ameliorate SERTΔCT-induced ER stress. Interestingly, flurbiprofen induced GRP78/BiP expression only under ER stress conditions and not under steady-state conditions. In HRD1 E3 ubiquitin ligase knockdown cells, flurbiprofen affected the ER-associated degradation system. Collectively, the findings suggest that flurbiprofen may function as an inducer of molecular chaperones, in addition to functioning as a chemical chaperone.

Nintedanib administration after the onset of acute exacerbation of interstitial lung disease in the real world.

Nintedanib reduces the decline in forced vital capacity and extends the time to the first acute exacerbation of interstitial lung disease (AE-ILD). However, the effect of additional nintedanib administration after AE-ILD onset is unknown. This study aimed to investigate the efficacy and safety of nintedanib administration after AE-ILD development. We retrospectively collected the data of 33 patients who developed AE-ILD between April 2014 and January 2022. Eleven patients who received nintedanib after AE-ILD development and the remaining who did not were classified into the N and No-N groups, respectively. The survival time in the N group tended to be longer than that in the No-N group. The generalized Wilcoxson test revealed that the cumulative mortality at 90 days from AE-ILD onset was significantly lower in the N group. The time to subsequent AE-ILD development was significantly longer in the N group than that in the No-N group. The incidence of adverse gastrointestinal effects and liver dysfunction in the N group was 9-18%. Treatment without nintedanib after AE-ILD development and the ratio of arterial oxygen partial pressure to fractional inspired oxygen were significant independent prognostic factors in the multivariate analysis. Thus, nintedanib administration may be a treatment option for AE-ILD.

Mesalazine-induced airway obstruction: Utility of pulmonary function testing in drug-induced lung diseases.

Mesalazine is a standard therapeutic agent for the treatment of inflammatory bowel diseases. A rare case of mesalazine-induced airway obstruction documented by pulmonary function testing is reported herein. The patient had Crohn's disease and was treated with mesalazine; she subsequently developed a high fever, cough, and chest pain with centrilobular nodular shadows on chest computed tomography (CT). After cessation of mesalazine, the abnormal CT findings as well as the decreased forced expiratory volume in 1 second improved. Based on these findings, pulmonary function testing appears to be a useful tool, even in the acute phase, along with chest CT in drug-induced lung diseases.

Paraneoplastic Limbic Encephalitis Complicated with Small Cell Lung Cancer at the Time of Recurrence.

Paraneoplastic limbic encephalitis (PLE) is a rare neurologic disorder that can complicate various malignancies, including lung cancer. PLE is most frequently found the initial presentation of lung cancer. In this study, we reported the case of a 74-year-old Japanese woman who developed PLE after partial remission of small cell lung cancer (SCLC) by first-line systemic chemotherapy. Brain magnetic resonance imaging showed no metastatic tumor or cerebrovascular disease. Anti-glutamic acid decarboxylase (GAD) and anti-amphiphysin antibodies were detected in her serum. She was diagnosed as having PLE related to the recurrence of SCLC and received high-dose glucocorticoid, and sequentially systemic chemotherapy with amrubicin. Unfortunately, these treatments did not improve her disease progression and she died 4 months later. Although PLE rarely occurs at the time of SCLC recurrence, physicians should pay attention to PLE onset even after chemotherapy.

A case of osimertinib-resistant lung adenocarcinoma responded effectively to alternating therapy.

We report a case of initial lung adenocarcinoma in which transformation to small cell lung carcinoma (SCLC) was observed after acquired resistance to the 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and alternating treatment between chemotherapy and osimertinib was effective. A 61-year-old woman with EGFR mutation positive stage IV lung adenocarcinoma was administered 1st generation EGFR-TKI for 8 months as the first line therapy, then chemotherapy and 2nd generation EGFR-TKI after progressive disease (PD). Four years after initial diagnosis, EGFR T790M was detected in a metastatic lesion of the right thoracic wall and osimertinib was prescribed. Although partial response (PR) was achieved, a new metastatic lesion appeared in the right pleurum near the diaphragm, in which SCLC characteristics were observed with elevation of pro-gastrin-releasing peptide (pro-GRP) at the time of PD under osimertinib. Osimertinib was discontinued and carboplatin plus irinotecan chemotherapy was chosen as the next treatment, leading to PR after 2 cycles. Subsequently, the right thoracic wall tumor harboring T790M and the right pleural tumor near the diaphragm showing transformation to SCLC exhibited opposite responses to therapy alternating between osimertinib and chemotherapy. It is concluded that extended disease control can be achieved by combining appropriate treatments according to the mechanisms of resistance inferred from precise genetic and pathological examination in real time.

Signet Ring Cell Carcinoma of Unknown Primary Complicated with Pulmonary Tumor Thrombotic Microangiopathy and Krukenberg Tumor.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare disease that shows hypoxia with severe pulmonary hypertension related to malignant tumor. Diagnosis is difficult due to rapid clinical progression and the need to demonstrate pathological findings from lung biopsy. A 64-year-old woman visited our hospital with hypoxia and pulmonary hypertension. Diffuse granular shadows in the centrilobular area and ground-glass shadows in both lungs and left ovarian tumor were found on radiological imaging. PTTM was suspected, but pulmonary artery blood aspiration by right cardiac catheter failed to detect cancer cells. We could not obtain lung or ovary biopsies because of hypoxia or pulmonary hypertension. The patient died due to respiratory failure. Signet ring cell carcinoma of unknown primary, PTTM, and Krukenberg tumor were diagnosed on autopsy. Since early diagnosis facilitates adequate treatment, physicians should not miss the opportunity for biopsy in cases of suspected PTTM.

Primary Pulmonary Colloid Adenocarcinoma: How Can We Obtain a Precise Diagnosis?

A 76-year-old asymptomatic man was found to have a mass in the right lower lung field. Although the presence of a mucinous component in the majority of the tumor was shown by magnetic resonance imaging, the presence of cancer cells was suspected by contrast enhancement on computed tomography (CT) and based on the partial accumulation in the marginal regions of the tumor on fluorodeoxyglucose-positron emission tomography (FDG-PET). A transbronchial lung biopsy was non-diagnostic, but resection of the mass resulted in a diagnosis of colloid adenocarcinoma. The findings from combined contrast CT and FDG-PET may raise the suspicion of colloid adenocarcinoma and prompt the consideration of surgical resection.

Current Status and Problems of T790M Detection, a Molecular Biomarker of Acquired Resistance to EGFR Tyrosine Kinase Inhibitors, with Liquid Biopsy and Re-biopsy.

BACKGROUND/AIM: The purpose of this study was to consider appropriate application of liquid and re-biopsy through analysis of current status in practice. PATIENTS AND METHODS: We performed a retrospective analysis of 22 patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer who exhibited 1st/2nd generation EGFR-tyrosine kinase inhibitors resistance. The cobas® method was used to detect T790M with re-biopsy and the mutation-biased PCR and quenched probe method was used with liquid biopsy. RESULTS: T790M detection rate was 52% with re-biopsy and 58% with liquid biopsy. The concordance between tissue and plasma was 58%. One patient who was T790M-positive with liquid biopsy showed heterogeneity among metastatic lesions in terms of osimertinib efficacy, as revealed by T790M detection with re-biopsy. CONCLUSION: Liquid biopsy reflects the whole body, whereas re-biopsy is useful for spatial diagnosis. Considering these characteristics, a combination of liquid and re-biopsy contribute to enhanced treatment.

Chemotherapy for primary mediastinal yolk sac tumor in a patient undergoing chronic hemodialysis: a case report.

BACKGROUND: The safety and efficacy of chemotherapy for patients undergoing concomitant hemodialysis have not been fully established and optimal doses of anti-cancer drugs and best timing of hemodialysis remains unclear. Although chemosensitive cancers, such as germ cell tumors, treated with chemotherapy should have sufficient dose intensity maintained to achieve the desired effect, many patients with cancer undergoing hemodialysis might be under-treated because the pharmacokinetics of anti-cancer drugs in such patients remains unknown. CASE PRESENTATION: We describe a 31-year-old Japanese man with a mediastinal yolk sac tumor treated with surgery followed by five cycles of chemotherapy containing cisplatin and etoposide while concomitantly undergoing hemodialysis. The doses of these agents used in the first cycle were 50% of the standard dose of cisplatin (10 mg/m2) and 60% of the standard dose of etoposide (60 mg/m2) on days 1 through to 5; the doses were subsequently escalated to 75% with both agents. Hemodialysis was started 1 hour after infusions of these agents. Severe hematological toxicities were observed despite successful treatment. During treatment with concurrent hemodialysis, pharmacokinetic analysis of cisplatin was performed and its relationship with adverse effects was assessed. Compared with patients with normal renal function, the maximum drug concentration was higher, and concentration increased in the interval between hemodialysis and the subsequent cisplatin infusion, resulting in a higher area under the curve despite a reduction in the dose to 75% of the standard regimen. CONCLUSIONS: Because of the altered pharmacokinetics pharmacodynamics status of patients with renal dysfunction undergoing hemodialysis, pharmacokinetics pharmacodynamics analysis is deemed to be helpful for effective and safe management of chemotherapy in patients undergoing hemodialysis.