Successful continuous nivolumab therapy for metastatic non-small cell lung cancer after local treatment of oligometastatic lesions.

The patient in this report was a 57-year-old man with metastatic non-small cell lung cancer (NSCLC). After no response to two lines of systemic chemotherapy, he was treated with nivolumab as third-line therapy, which resulted in a partial response. After 17 months of nivolumab treatment, he developed bone metastasis in his left femur which was treated with radiation therapy. Nivolumab was restarted after radiation therapy. Four months after radiation therapy, he developed another metastatic lesion in the small intestine which was surgically resected. Because there were no recurrent NSCLC lesions after surgical resection, nivolumab was restarted again. At 18 months after surgery, there were no recurrent NSCLC lesions. Immunohistochemical analysis of peritumoral T lymphocytes showed higher expression of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) and lymphocyte activation gene 3 (LAG-3) in recurrent lesions of bone and small intestine than in primary lesions. Upregulation of TIM-3 and LAG-3 could be associated with mechanisms of adaptive resistance to nivolumab in this case. Here, we report a successful case of continued nivolumab therapy with remission after local treatments consisting of radiation therapy and surgical resection for oligometastases. Continuation of immune checkpoint inhibitor (ICI) treatment may be worth considering if oligometastases can be controlled. KEY POINTS: Significant findings of the study We report a successful case of continued nivolumab treatment with remission after local treatment (radiation therapy and surgical resection) for oligometastases. What this study adds Upregulation of T cell immunoglobulin and mucin domain-containing protein 3 and lymphocyte-activation gene 3 could be associated with mechanisms of adaptive resistance to nivolumab.

Clinical outcomes in non-small cell lung cancer patients with an ultra-high expression of programmed death ligand-1 treated using pembrolizumab as a first-line therapy: A retrospective multicenter cohort study in Japan.

BACKGROUND: Pembrolizumab is currently approved as a first-line therapy for advanced non-small cell lung cancer (NSCLC) patients with a programed death ligand-1 (PD-L1) expression ≥50%. However, the association between the efficacy of pembrolizumab and PD-L1 expression levels in patients with PD-L1 expression ≥50% has not been fully elucidated. METHODS: We retrospectively analyzed patients with advanced NSCLC and a PD-L1 tumor proportion score (TPS) of ≥50% who received pembrolizumab as a first-line therapy at 11 institutions in Japan between February 2017 and January 2018. Patients were divided into TPS 50-89% and TPS 90-100% (ultra-high PD-L1 expression) cohorts. RESULTS: In total, 149 patients were included: 99 (66.4%) and 50 (33.6%) patients were in the TPS 50-89% and TPS 90-100% cohorts, respectively. Baseline characteristics were similar between the TPS 90-100% and TPS 50-89% cohorts. The objective response rates (ORR) in the TPS 90-100% and TPS 50-89% cohorts were 58.0% and 46.5%, respectively (p = 0.23). Time to treatment failure (TTF) was longer in the TPS 90-100% cohort than in the TPS 50-89% cohort (hazard ratio [HR]: 0.67, 95% confidence interval (CI): 0.42-1.07; p = 0.09). Although TTF within 120 days after the initiation of pembrolizumab therapy was comparable between both cohorts (p = 0.54), TTF after 120 days was significantly longer in the TPS 90-100% cohort than in the TPS 50-89% cohort (HR: 0.22, 95% CI: 0.06-0.87; p = 0.031). Immune related adverse events of grade 3 or more occurred in 16.0% and 19.2% of patients in the TPS 90-100% and TPS 50-89% cohorts, respectively. CONCLUSIONS: The patients with an ultra-high PD-L1 expression continued pembrolizumab therapy longer, driven by a reduced risk of treatment failure in the late phase. PD-L1 expression levels might be a predictive biomarker of a first-line immunotherapy benefit in the late phase among NSCLC patients with TPS ≥50%.

Continued administration of pembrolizumab for adenocarcinoma of the lung after the onset of fulminant type 1 diabetes mellitus as an immune-related adverse effect: A case report.

A 61-year-old woman with stage IVA lung adenocarcinoma exhibited high PD-L1 expression. Pembrolizumab was administered as second-line therapy. She developed destructive thyroiditis and her thyroid function started to decline during the administration of three to five courses. She was subsequently diagnosed with fulminant type 1 diabetes mellitus and ketoacidosis during the eighth course and insulin treatment was initiated. Pembrolizumab remained effective and was continued for 21 courses, even after the onset of diabetes mellitus. Immune-checkpoint inhibitor treatment can be continued with hormone replacement even after the development of type 1 diabetes mellitus as an immune-related adverse event.

Three Cases of Idiopathic Diffuse Pulmonary Ossification.

Diffuse pulmonary ossification (DPO) is an uncommon diffuse lung disease characterized by metaplastic bone formation in the lung parenchyma and is rarely diagnosed in life. While DPO usually occurs as a secondary disease, idiopathic cases are extremely rare. We describe three cases of idiopathic DPO, two of which were definitively diagnosed by surgical lung biopsy. One case was observed in a 43-year-old man with a history of recurrent pneumothorax who developed pneumothorax after the surgical biopsy. Few reports have described cases of DPO with recurrent pneumothorax; however, pneumothorax should be considered as a potential complication when such patients are encountered.

Improvement of exertional dyspnea and breathing pattern of inspiration to expiration after bronchial thermoplasty.

BACKGROUND: Bronchial thermoplasty (BT) is a bronchoscopic treatment that can ameliorate the symptoms of severe asthma. However, little is known about the mechanism by which BT improves exertional dyspnea without significantly changing the resting pulmonary function in asthmatics. To understand the mechanism, cardiopulmonary variables were investigated using cardiopulmonary exercise testing (CPET) in a patient with severe asthma before and after BT. CASE PRESENTATION: A 57-year-old Japanese man visited our hospital for consultation of the intractable asthma, which we managed with three treatment sessions of BT. Comparison of the findings pre-BT and at 1 year after BT demonstrated that (1) the resting tests for respiration showed no improvement in forced expiratory volume in 1 s, but the forced oscillation technique showed decreases in both inhalation and exhalation respiratory resistance values, and (2) the CPET results showed (i) improvement in exertional dyspnea, exercise endurance, and arterial oxygen saturation at the end of exercise; (ii) that the expiratory tidal volume exceeded the inspiratory tidal volume during exercise, which implied that a sufficient exhalation enabled longer inspiratory time and adequate oxygen absorption; and (iii) that an increase in respiratory frequency could be prevented throughout exercise. CONCLUSIONS: This case report described a novel mechanism of BT in improving exertional dyspnea and exercise duration, which was brought about by ventilatory improvements related to the breathing pattern of inspiration to expiration.

Post-progression survival after cessation of treatment with nivolumab for advanced non-small cell lung cancer: A retrospective study.

OBJECTIVES: The effectiveness of treatment after cessation of nivolumab in patients with advanced non-small cell lung cancer (NSCLC) has not been well investigated. The aim of the present study was to clarify the clinical benefit of post-nivolumab treatment in such patients. MATERIALS AND METHODS: A retrospective review was conducted on patients who received treatment after cessation of nivolumab due to disease progression or adverse events at the Toneyama National Hospital between January 2016 and April 2017. RESULTS: Among 64 patients treated with nivolumab, 26 patients received treatment after cessation of nivolumab due to disease progression (n = 21) or adverse events (n = 5). The median age of the patients was 68 years and 19 patients were male. Nineteen patients had performance status (PS) 1 or less at initiation of post-nivolumab treatment. Four, 20, and 2 patients were treated with platinum doublets, a single agent, and molecular targeting agents, respectively. Response rate, disease control rate, and median progression-free survival of first-line post-nivolumab treatment were 34.6% (9 patients), 73.1% (19 patients), and 2.8 months (95% confidence interval [CI]: 1.7-5.2), respectively. Adverse events (≥ grade 3) and treatment cessation were observed in 57.7% (15 patients) and 19.2% (5 patients), respectively. There were no statistically significant differences for the majority of patient characteristics between the groups with (n = 26) and without post-nivolumab treatment. However, PS at cessation of nivolumab and post-progression survival (PPS) after cessation of nivolumab (median PPS: 12.6 vs. 1.4 months, 95% CI: 3.8-14.7 vs. 0.4-2.2) were significantly different between the groups. A multivariate Cox regression analysis showed significant correlation of PS at cessation of nivolumab (hazard ratio [HR]: 0.34, 95% CI: 0.13-0.87) and post-nivolumab treatment (HR: 0.19, 95% CI: 0.08-0.43) with prolonged PPS after nivolumab. CONCLUSION: Median post-progression survival in patients with advanced NSCLC who received post-nivolumab treatment was approximately 1 year.

Exercise tolerance and balance of inspiratory-to-expiratory muscle strength in relation to breathing timing in patients with chronic obstructive pulmonary disease.

RATIONALE: Little is known about the applicability of respiratory muscle training based on exertional pathophysiological conditions in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the relationship between breathing timing and exertional responses, as well as whether exertional changes in the inspiratory duty cycle (Ti/Ttot) affect pathophysiological conditions, including respiratory muscles. METHODS: Forty-five stable COPD patients (mean age: 71.2 years, severe and very severe COPD: 80%) were evaluated based on exertional cardiopulmonary function and respiratory muscle strength. To compare exertional responses and the balance of inspiratory-to-expiratory muscle strength, the patients were divided into two groups according to whether the Ti/Ttot increased (Ti/Ttot-increased group: resting Ti/Ttot ≤ peak Ti/Ttot, n = 21) or decreased during exercise (Ti/Ttot-decreased group: resting Ti/Ttot > peak Ti/Ttot, n = 24). RESULTS: At peak exercise, the Ti/Ttot was positively correlated with minute ventilation ([Formula: see text] E), and oxygen uptake ([Formula: see text]) in all patients. No significant differences were seen in breathing frequency, tidal volume, or [Formula: see text] E at peak exercise between the two groups. Compared with the Ti/Ttot-increased group, the Ti/Ttot-decreased group had significantly lower mean values of [Formula: see text] and ΔFO2 (the inspired minus expired oxygen concentration) at peak exercise, and significantly higher mean values of the absolute ratio of maximal inspiratory pressure/maximal expiratory pressure. CONCLUSIONS: The exertional change of breathing timing affected exercise tolerance and the balance of inspiratory-to-expiratory muscle strength; this finding might be helpful in making the contradictory choice of managing COPD patients with inspiratory or expiratory muscle training.

Two cases of response to pembrolizumab in epidermal growth factor receptor mutated lung adenocarcinoma patients with programmed death-ligand 1 overexpression.

Recently, the immune checkpoint inhibitor (ICI) pembrolizumab was demonstrated to be superior to platinum doublet chemotherapy in the first-line setting in patients with tumor programmed death-ligand 1 (PD-L1) expression of at least 50%. However, because patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements were not included in that study, the efficacy of pembrolizumab in lung cancers carrying EGFR mutations could not be determined. Here we describe two cases of response to pembrolizumab in EGFR mutated lung adenocarcinoma patients with PD-L1 overexpression. These cases indicate that ICI is an effective treatment for EGFR mutated lung adenocarcinoma patients with PD-L1 overexpression.

Oxidative stress-inducible truncated serine/arginine-rich splicing factor 3 regulates interleukin-8 production in human colon cancer cells.

Serine/arginine-rich splicing factor 3 (SRSF3) is a member of the SR protein family and plays wide-ranging roles in gene expression. The human SRSF3 gene generates two alternative splice transcripts, a major mRNA isoform (SRSF3-FL) encoding functional full-length protein and a premature termination codon (PTC)-containing isoform (SRSF3-PTC). The latter is degraded through nonsense-mediated mRNA decay (NMD). Treatment of a human colon cancer cell line (HCT116) with 100 µM sodium arsenite increased SRSF3-PTC mRNA levels without changing SRSF3-FL mRNA levels. A chemiluminescence-based NMD reporter assay system demonstrated that arsenite treatment inhibited NMD activity and increased SRSF3-PTC mRNA levels in the cytoplasm, facilitating translation of a truncated SRSF3 protein (SRSF3-TR) from SRSF3-PTC mRNA. SRSF3-TR lacked two-thirds of the Arg/Ser-rich (RS) domain whose phosphorylation state is known to be crucial for subcellular distribution. SRSF3-FL was localized in the nucleus, while overexpressed SRSF3-TR was diffusely distributed in the cytoplasm and the nucleus. A part of SRSF3-TR was also associated with stress granules in the cytoplasm. Interestingly, treatment of HCT116 cells with a small interference RNA specifically targeting SRSF3-PTC mRNA significantly attenuated arsenite-stimulated induction of c-JUN protein, its binding activity to the AP-1 binding site (-126 to 120 bp) in the interleukin (IL)-8 gene promoter, and AP-1 promoter activity, resulting in significant reduction of arsenite-stimulated IL-8 production. Our results suggest that SRSF3-TR may function as a positive regulator of oxidative stress-initiated inflammatory responses in colon cancer cells.