Drug-induced interstitial lung disease after chemoimmunotherapy for extensive-stage small cell lung cancer.

Objectives: The combination of chemotherapy and immune checkpoint inhibitors (chemo-ICI) has become the new standard of treatment for extensive-stage small cell lung cancer (ES-SCLC). Recently, slight changes in interstitial shadows, defined as interstitial lung abnormalities (ILA), have been identified. In patients with ES-SCLC who received chemo-ICI, there are limited data on the incidence of drug-induced interstitial lung disease (D-ILD) in daily practice and the association between the development of D-ILD and ILA in the baseline computed tomography (CT). Materials and methods: A multicenter, retrospective study was conducted to investigate the incidence of D-ILD, the risk factors for developing D-ILD, progression-free survival (PFS), and overall survival (OS) in patients with ES-SCLC who received chemo-ICI between August 2019 and November 2021. Results: This study enrolled 70 patients (median age, 71 years; including 58 men) from nine institutions in Japan. There were 62 patients (89%) treated with carboplatin/etoposide/atezolizumab and 8 patients treated with carboplatin or cisplatin/etoposide/durvalumab. Twenty-nine patients (41.4%) were found to have ILA at baseline CT. Eleven patients (15.7%) developed D-ILD. The proportion of patients with ILA was significantly higher in the group who developed D-ILD than in the group who did not (9/11 (81.8%) vs. 20/59 (33.9%), respectively, P = 0.0057). In addition, the frequency of ground glass attenuation (GGA) and reticulation was higher in patients who developed D-ILD. There was no significant difference in PFS and OS between patients who developed D-ILD and those who did not (median PFS, 8.0 (95% confidence interval (CI), 5.5-9.5) months vs. 5.0 (95% CI, 4.5-5.6) months, respectively, P = 0.11 and median OS, not reached (NR) (95% CI, 8.7-NR) vs. 18.2 (95% CI, 13.2-NR) months, respectively, P = 0.20). Conclusion: The incidence of D-ILD in patients with ES-SCLC who received chemo-ICI in clinical practice was higher than that in clinical trials. Patients with pre-existing ILA were more likely to develop D-ILD.

TAPO in first-line osimertinib therapy and continuation of osimertinib.

BACKGROUND: Osimertinib is associated with a relatively high frequency of drug-induced interstitial lung disease (D-ILD), and transient asymptomatic pulmonary opacities (TAPO) have been reported to occur during osimertinib administration. The frequency of TAPO during first-line treatment and the pros and cons of osimertinib continuation is unknown. METHODS: This was a multicenter, retrospective study. The purpose of this study was to research the frequency of TAPO and to evaluate osimertinib continuation in first-line therapy. We also evaluated progression-free survival (PFS) including subgroup analysis. RESULTS: From August 2018 to December 2020, 133 patients were enrolled into the study. The median observation period was 23.2 months (0.3-48.3 months). Thirty patients (22.6%) experienced D-ILD events, including 16 patients (12.1%) with CTCAE grade 1, five patients (3.8%) with grade 2, and nine patients (6.7%) with grade 3 and above D-ILD. Among the patients with grade 1 D-ILD, 11 cases (8.3%) of TAPO were observed, and all patients succeeded in osimertinib continuation. The TAPO images were characterized by localized patchy opacities (73%). The median PFS was 22.6 months (95% confidence interval [CI]: 17.8-28.7 months). Patients with TAPO had a significantly longer PFS than patients with non-TAPO D-ILD in the multivariate analysis. CONCLUSIONS: This study showed that grade 1 D-ILD might include TAPO and that patients with TAPO might have good PFS. We need to consider the possibility of osimertinib continuation when lung opacities appear.

Surgical repair of hepatic hydrothorax caused by diaphragmatic fistula.

A 65-year-old woman visited our hospital complaining of dyspnea several days before admission. A chest X-ray showed massive right-sided pleural effusion, which was not observed 1 month previously. Although the patient had never been diagnosed with cirrhosis at regular visits, the patient was diagnosed with primary biliary cholangitis at admission. Hepatic hydrothorax was suspected because pleural effusion was transudative. A diaphragmatic fistula was confirmed and closed by thoracoscopy. Pleural effusion did not reappear after this procedure. Existence of a diaphragmatic defect should be confirmed under direct vision if pleural effusion accumulates acutely or becomes beyond control.

Fatal Hemoptysis Due to Endobronchial Aspergilloma in the Hyperinflated Native Lung after Single-Lung Transplantation for Lymphangioleiomyomatosis: A Case Report.

Pulmonary lymphangioleiomyomatosis accounts for the majority of cadaveric lung transplantation cases. Post-transplantation management is continuingly necessary not only to prevent the progression of LAM but also to address complications. A woman with lymphangioleiomyomatosis underwent cadaveric lung transplantation. She developed post-operative native lung hyperinflation and hemoptysis with cavity shadow in the native lung on computed tomography. Isolated Aspergillus from her sputum and positive Aspergillus galactomannan antigen in the blood led to a diagnosis of aspergillosis. Despite the reduction of hemoptysis by antifungal medication, she developed fatal hemoptysis. An autopsy showed an Aspergillus fungal mass in the bronchus in the native lung whilst the lung graft was free from lymphangioleiomyomatosis lesions. Endobronchial aspergilloma was suggested to be a cause of hemoptysis. This fatal clinical course suggested that hemoptysis due to endobronchial aspergilloma in the native lung should have been considered native lung pneumonectomy as a further intervention.

Feasibility Study of Adjuvant Chemotherapy with Carboplatin and Nab-Paclitaxel for Completely Resected NSCLC.

PURPOSE: Adjuvant chemotherapy with cisplatin (CDDP) plus vinorelbine is the standard regimen for the treatment of non-small cell lung cancer (NSCLC). However, CDDP elicits severe toxic effects, including emesis, neurotoxicity, and renal damage; carboplatin (CBDCA) may be a feasible alternative for CDDP-unfit patients. CBDCA plus paclitaxel (PTX) adjuvant chemotherapy showed a survival benefit for patients with stage IB tumors >4 cm in size, while CBDCA plus nanoparticle albumin-bound (nab)-PTX showed greater efficacy and lower neurotoxicity than CBDCA plus PTX in advanced NSCLC. Here, we investigated the feasibility of using CBDCA plus nab-PTX as adjuvant chemotherapy for NSCLC. PATIENTS AND METHODS: Patients with completely resected stage II or III NSCLC, with an Eastern Cooperative Oncology Group performance status of 0-1 and adequate kidney function, received four cycles of postoperative adjuvant chemotherapy with CBDCA (AUC=5 mg/mL/min, on day 1) and nab-PTX (100 mg/m2, on days 1, 8, and 15) administered every 4 weeks within 8 weeks after surgery. The study was designed as a prospective, single-center, Phase II study. The primary endpoint was the completion rate of chemotherapy; secondary endpoints were two-year relapse-free survival (RFS) and safety. The expected completion rate was 80%, with a 50% lower limit. RESULTS: Of 21 enrolled patients, 18 (85.7%) were CDDP-unfit owing to age (≥75 years old [n=11, 52.4%]) or mild renal impairment (n=7, 33.3%). Nineteen of the 21 enrolled patients were assigned to the intervention. The most common grade 3 or 4 adverse events were neutropenia (n=15, 78.9%) and anemia (n=3, 15.8%). The completion rate for the four cycles was 63.2% (95% CI, 38.4-83.7). Two-year RFS was 56.8% (95% CI, 29.7-76.9). CONCLUSION: The completion rate for CBDCA plus nab-PTX as adjuvant chemotherapy for CDDP-unfit NSCLC patients did not reach treatment feasibility. Further dose modifications may be required in future studies.

A multi-center, Phase II trial of nab-paclitaxel and gemcitabine in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy.

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX) plus gemcitabine (GEM) significantly improved overall survival in patients with metastatic pancreatic adenocarcinoma. Anti-tumor synergy between GEM and nab-PTX was recently demonstrated in a mouse model. We planned to assess the efficacy and safety of the combination of nab-PTX + GEM in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. METHODS: Patients with advanced NSCLC with progressive disease after platinum-based chemotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and adequate kidney, liver and bone marrow function were eligible. Treatment consisted of nab-PTX (100 mg/m2) + GEM (1000 mg/m2) on days 1 and 8 of each 3-week cycle until progression disease or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS). RESULTS: Of the 28 patients enrolled, all were evaluable for response and toxicity. The median age was 68 years (range 47-79), and 23 were male and 5 female. The histologic subtypes were: adenocarcinoma in 19 patients, and squamous cell carcinoma in 9 patients. Seventeen patients had ECOG PS 1 and 11 patients had PS 0. Twenty-four patients were second line and 4 patients were third line. The median number of cycles administered was 4 (range 1-10). The overall response rate was 17.9%. The disease control rate was 67.9%. The median progression-free survival was 3.1 months (95% confidence interval [CI] =1.6-4.1). Adverse events were generally tolerable except grade 3 interstitial pneumonia with in 4 patients (14.3%). CONCLUSION: The efficacy of nab-PTX in combination with GEM in advanced second or third-line NSCLC patients was limited and the frequent occurrence of interstitial pneumonia was unacceptable.

Primary pleural synovial sarcoma with repeated resection leading to long-term survival.

Primary pleural synovial sarcoma is a malignant tumour and thought to be more aggressive than synovial sarcoma which occurs in extremities. Its treatment strategy has not been fully established because of its rarity. We report a primary pleural synovial sarcoma case which achieved a long-term survival with repeated surgery of recurrent pleural tumour. A 39-year-old man presented with a gradually enlarged tumour in the left hemithorax. The tumour was resected and diagnosed as primary pleural synovial sarcoma. The tumour was slowly growing and repeatedly recurrent in the left pleura. The surgical resections for the recurrent tumours were performed 6 years and 11 years after the initial surgery. Intriguingly, recurrent tumour which developed after second surgery exhibited temporally spontaneous regression. Our patient remains alive 12 years after the initial surgery. Repeated resection of metastatic lesion can achieve long survival in primary pleural synovial sarcoma.

Endobronchial metastases 20 years after prostate cancer excision.

A 78-year-old Japanese man who had undergone total prostatectomy for prostate cancer (pT3cN1M0, Gleason score 3 + 3) 20 years previously was referred to the Respiratory Medicine Department of our institution because of a 1-week history of chest pain and cough. Computed tomography showed multiple small nodules and mediastinal lymph node enlargement. Bronchoscopy revealed multiple soft polypoid masses and obstruction of the lingular segment. Prostate-specific antigen (PSA) concentrations had increased markedly from 0.48 ng/mL in 2014 to 741 ng/mL in 2018. The diagnosis of prostatic cancer metastases was confirmed by revealing the presence of PSA via immunohistological staining of a bronchoscopically obtained biopsy of one of the masses. The patient had not been attending scheduled follow-up visits for the past 4 years. Treatment with degarelix (a gonadotropin-releasing hormone) was started, and the PSA concentration decreased dramatically (29 ng/mL). Metastases from prostate cancer are rarely first diagnosed two decades after radical prostatectomy. This patient illustrates the importance of obtaining a complete medical history.

Nivolumab-induced acute-onset type 1 diabetes mellitus as an immune-related adverse event: A case report.

A 60-year-old Japanese man, with no medical or family history of diabetes, presented with acute-onset type 1 diabetes following nivolumab treatment for advanced non-small-cell lung cancer. During cycle 35 of nivolumab therapy, his glycated hemoglobin level increased from 7.6% to 9.1% in one month. Test results for islet-related and anti-thyroid peroxidase antibodies were negative. A glucagon tolerance test showed insulin dependency. Type 1 diabetes after anti-programmed death-ligand 1 antibody administration is an immune-related adverse event, and numerous reports suggest that fulminant type 1 diabetes can develop in these patients. However, there are few reports of acute-onset type 1 diabetes mellitus.

Bronchoscopy Using Virtual Navigation and Endobronchial Ultrasonography with a Guide Sheath (EBUS-GS) with or without Fluoroscopy for Peripheral Pulmonary Lesions.

OBJECTIVE: Endobronchial ultrasonography and guide sheath (EBUS-GS) technique has high diagnostic yield in lung nodules. Virtual bronchoscopic navigation (VBN) can lead bronchoscope to the target bronchi. The aim of this prospective study was to compare the diagnostic yield of two bronchoscopic procedures: bronchoscopy under EBUS-GS and VBN with or without x-ray fluoroscopy in small peripheral pulmonary lesions (PPLs, ≤30mm) with apparent CT-bronchus sign. METHODS: 31 patients with PPLs which had apparent CT-bronchus sign were randomly assigned to the X-ray or the non-X-ray groups (18 with and 13 without fluoroscopy) between September 1, 2012, and September 30, 2015. A bronchoscope was introduced into the target bronchus using the VBN system. Sites of specimen sampling were verified using EBUS-GS with or without fluoroscopy. RESULTS: The overall diagnostic yield was 83.3% in the X-ray and 69.2% in the non-X-ray group. The diagnostic yield of malignancy was 88.2% and 81.8%, respectively. The duration of the examination and time elapsed until the first EBUS visualization were similar in the X-ray and the non-X-ray group (9.0 (5.8-20.) min vs 11.0 (5.3-17.3) min, and 2.5 (1.3-14.2) min vs 4.1 (1.4-8.1) min, respectively). The fluoroscopy exposure time was 3.7 (2.9-10.56) min. The only adverse event was mild pneumothorax in a patient from the non-X-ray group, who had consequent TBB under fluoroscopy. CONCLUSIONS: There was a possibility that VBN-guided EBUS-transbronchial diagnosis without fluoroscopy might be equivalent to that under fluoroscopy. Further multi-center randomized study may be desired. (UMIN000008592).

Synergistic effects of pemetrexed and amrubicin in non-small cell lung cancer cell lines: Potential for combination therapy.

The purpose is to examine the synergistic effect of pemetrexed (PEM) and amrubicin (AMR) on the proliferation of lung cancer cell lines. In vitro, dose-dependent synergistic effects of concurrent PEM and AMRol, which is an active metabolite of AMR were observed in A549 and H460 cells. In real-time RT-qPCR analysis and western blotting, expression of the target enzymes of PEM were suppressed in cells treated with amrubicinol alone. In vivo, AMR/PEM treatment also showed synergistic antitumor activity both in A549-bearing and H520-bearing mice. PEM and AMR work synergistically to inhibit the proliferation of several different lung cancer cell lines.

Long-term outcome after multidisciplinary approach for leptomeningeal carcinomatosis in a non-small cell lung cancer patient with poor performance status.

The present study describes a case of a 60-year-old Japanese man who was histologically diagnosed with lung adenocarcinoma harboring L858R mutation of epidermal growth factor receptor. He was successfully treated with gefitinib, but eventually developed leptomeningeal carcinomatosis. He underwent ventriculoperitoneal shunting for hydrocephalus and received erlotinib in place of gefitinib with concurrent whole brain radiotherapy; this resulted in dramatic improvement in his symptoms and performance status from four to one and he survived for as long as 13.6 months after the initiation of erlotinib therapy. This multidisciplinary approach may be particularly useful in terms of increasing survival and improving quality of life.

A metabolomic approach to lung cancer.

Lung cancer is one of the most common cancers in the world, but no good clinical markers that can be used to diagnose the disease at an early stage and predict its prognosis have been found. Therefore, the discovery of novel clinical markers is required. In this study, metabolomic analysis of lung cancer patients was performed using gas chromatography mass spectrometry. Serum samples from 29 healthy volunteers and 33 lung cancer patients with adenocarcinoma (n=12), squamous cell carcinoma (n=11), or small cell carcinoma (n=10) ranging from stage I to stage IV disease and lung tissue samples from 7 lung cancer patients including the tumor tissue and its surrounding normal tissue were used. A total of 58 metabolites (57 individual metabolites) were detected in serum, and 71 metabolites were detected in the lung tissue. The levels of 23 of the 58 serum metabolites were significantly changed in all lung cancer patients compared with healthy volunteers, and the levels of 48 of the 71 metabolites were significantly changed in the tumor tissue compared with the non-tumor tissue. Partial least squares discriminant analysis, which is a form of multiple classification analysis, was performed using the serum sample data, and metabolites that had characteristic alterations in each histological subtype and disease stage were determined. Our results demonstrate that changes in metabolite pattern are useful for assessing the clinical characteristics of lung cancer. Our results will hopefully lead to the establishment of novel diagnostic tools.

Successful erlotinib treatment for a patient with gefitinib-related hepatotoxicity and lung adenocarcinoma refractory to intermittently administered gefitinib.

A 73-year-old Japanese man was histologically diagnosed with lung adenocarcinoma harboring an exon 19 deletion in the epidermal growth factor receptor. The patient was treated with gefitinib for 6 weeks until he developed substantially elevated hepatic enzyme levels that resulted in the discontinuation of gefitinib. Gefitinib was reintroduced with an intermittent treatment schedule after the transaminase levels normalized, but the patient's enzyme levels rose again, and the cancer progressed. Gefitinib was eventually replaced with erlotinib. There was stable disease for 7 weeks without any signs of liver toxicity. Thus, erlotinib may be a beneficial and well-tolerated treatment option for patients with gefitinib-related hepatotoxicity.