Association of immune-related adverse events with durvalumab efficacy after chemoradiotherapy in patients with unresectable Stage III non-small cell lung cancer.

BACKGROUND: Immune-related adverse events (irAEs) have been found to predict PD-L1 inhibitor efficacy in metastatic NSCLC. However, the relation of irAEs to clinical outcome for nonmetastatic NSCLC has remained unknown. METHODS: In this multicenter prospective study of Stage III NSCLC treated with PACIFIC regimen, the relation of irAEs to PFS was evaluated by 8-week landmark analysis to minimise lead-time bias as well as by multivariable analysis adjusted for baseline factors. irAEs were categorised as mild or nonmild according to whether they were treated with systemic steroid. RESULTS: Median PFS was 16.0 months, not reached, and 9.7 months for patients without (85 cases) or with mild (21 cases) or nonmild (21 cases) irAEs, respectively. Multivariable analysis indicated that nonmild irAEs were associated with poor PFS, with HRs of 3.86 (95% CI, 1.31-11.38) compared with no irAEs and 11.58 (95% CI, 2.11-63.63) compared with mild irAEs. This pattern was consistent after irAE grade, the number of durvalumab doses and immune profiles (PD-L1 score, CD8+ tumour-infiltrating lymphocyte density, and tumour mutation burden) were taken into consideration. CONCLUSIONS: The development of mild irAEs might predict a better survival outcome, whereas immunosuppressive steroid-treated irAEs were associated with a worse outcome, regardless of baseline clinical and immune profiles.

The prevalence of obstructive sleep apnea in Japanese asthma patients.

BACKGROUND: Obstructive sleep apnea (OSA) occurs more commonly in asthma patients than in the general population because these conditions share some comorbidities. In Japan, the prevalence of OSA in the general population is reported to be approximately 20%; however, few reports have described the prevalence of OSA in asthma patients. Furthermore, the characteristics of Japanese patients with OSA and asthma are not clear. METHODS: Adult asthma patients were recruited from the outpatient departments of our institution between August 31, 2017, and March 31, 2019. In all included patients, the presence and severity of OSA were evaluated by the Epworth Sleepiness Scale (ESS) and a home sleep test (HST) using portable polysomnography (PSG). The rate of coexisting OSA in asthma patients and the characteristics of those patients according to the severity of OSA were investigated. RESULTS: Fifty-three patients were included. OSA was detected in 36 (67.9%) patients (mild, n = 15; moderate, n = 14; and severe, n = 7). Patients with OSA had significantly higher body mass index, Brinkman index, apnea-hypopnea index (AHI), and 3% oxygen desaturation index (ODI) values in comparison to those without OSA, while the percentage of the predicted value of forced vital capacity (%FVC) and lowest SpO2 levels were significantly lower. As the severity of OSA increased, age, brain natriuretic peptide level, AHI, and 3%ODI increased, and in contrast, FVC, %FVC, forced expiratory volume in one second (FEV1), percentage of the predicted value of FEV1 (%FEV1), Epworth Sleepiness Scale (ESS), 3%ODI, and lowest SpO2 levels decreased. In particular, the fact that the ESS value was inversely correlated with the severity of OSA in our patients was different from the general characteristics of OSA. Moreover, the AHI value was negatively correlated with FVC, %FVC, FEV1, and %FEV1. BMI was the only independent factor for the presence of OSA, and for asthma severity (FEV1, % of predicted), there was a weak correlation with smoking history. CONCLUSIONS: This is the first report to investigate the prevalence of OSA in Japanese asthma patients, using an HST. This study suggests that an HST should be performed in addition to the sleep interview for asthma patients with refractory disease, a low pulmonary function, advanced age, and high BMI because the more severe the OSA, the lower the ESS value may be.

Multicenter, Retrospective Study to Evaluate Necitumumab Plus Cisplatin and Gemcitabine After Immune Checkpoint Inhibitors in Advanced Squamous Cell Lung Cancer in Japan: The NINJA Study.

Introduction: Necitumumab plus gemcitabine and cisplatin (GCN) is a standard therapy for patients with advanced lung squamous cell carcinoma (LSqCC). However, the efficacy and tolerability of GCN in second-line or later treatment for patients previously treated with immune checkpoint inhibitors (ICIs) remain unknown. Methods: This multicenter, retrospective, cohort study assessed the efficacy and tolerability of GCN initiated between November 1, 2019 and March 31, 2022 as second-line to fourth-line treatment in patients with advanced LSqCC who had been pretreated with ICIs. The primary end point was progression-free survival (PFS). Results: A total of 93 patients from 35 institutions in Japan were enrolled. The median PFS, median overall survival (OS), and objective response rate were 4.4 months (95% confidence interval [CI]: 3.8-5.3), 13.3 months (95% CI: 9.6-16.5), and 27.3% (95% CI: 18.3-37.8), respectively. The median PFS, median OS, and objective response rate for second-line, third-line, and fourth-line treatment groups were 4.8 months, 3.8 months, and 4.3 months (p = 0.24); 15.7 months, 11.6 months, and 10.1 months (p = 0.06); and 31.0%, 13.6%, and 37.5% (p = 0.22), respectively. The severity of GCN-related skin disorders was associated with longer PFS (p < 0.05) and OS (p < 0.05). The frequencies of grade ≥3 skin disorders, hypomagnesemia, pneumonitis, and febrile neutropenia were 16.1%, 7.5%, 1.1%, and 4.3%, respectively. There were no treatment-related deaths. Conclusions: GCN for ICI-pretreated patients with LSqCC seems tolerable and offers promising efficacy regardless of treatment line, and ICI pretreatment might enhance GCN efficacy.

Mortality and prognostic factors for spontaneous pneumothorax in older adults.

Spontaneous pneumothorax occurs predominantly in young males and older adults, often as a secondary condition, and can be refractory and fatal. This study aimed to investigate the mortality and prognostic factors for pneumothorax in older patients. We retrospectively cohort studied patients with pneumothorax aged ≥65 years who visited our department from October 2012 to January 2019. Data on sex, age, medical history, smoking history, underlying lung disease, treatment, and prognosis were extracted from medical records. Cox proportional hazards regression analysis was used to investigate pneumothorax mortality and prognostic factors. In total, 239 patients were included. Among them, 36 (15%) died during hospitalization. Respiratory disease was the direct cause of death in 30 patients (83.3%), and 211 (88.3%) patients had underlying lung disease. The incidence of pneumonia in our hospital was 22.6% (54 cases). On admission, the mortality rate was 33% (18/54) in patients with concomitant pneumonia; univariate analysis showed significant differences in the Charlson Comorbidity Index (CCI), activities of daily living (ADL), and concomitant pneumonia. In the Cox proportional hazards analysis of ADL (p = 0.09), CCI (p = 0.05), and concomitant pneumonia on admission (p = 0.02), concomitant pneumonia on admission was found to be an independent predictor of in-hospital mortality. This study suggests that concomitant pneumonia at admission may be a mortality risk factor for pneumothorax.

Tumor Microenvironment Landscape of NSCLC Reveals Resistance Mechanisms for Programmed Death-Ligand 1 Blockade After Chemoradiotherapy: A Multicenter Prospective Biomarker Study (WJOG11518L:SUBMARINE).

INTRODUCTION: The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III NSCLC. Nevertheless, approximately half of the treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L:SUBMARINE). METHODS: A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue and flow cytometric analysis of circulating immune cells. Progression-free survival was compared on the basis of these biomarkers. RESULTS: The importance of preexisting effective adaptive immunity in tumors was revealed for treatment benefit regardless of genomic features. We also identified CD73 expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8+ tumor-infiltrating lymphocyte density and the high CD73+ cancer cells were independently associated with poor durvalumab outcome (hazard ratios = 4.05 [95% confidence interval: 1.17-14.04] for CD8+ tumor-infiltrating lymphocytes; 4.79 [95% confidence interval: 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity. CONCLUSIONS: Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC.

Analysis of nocturnal desaturation waveforms using algorithms in patients with idiopathic pulmonary fibrosis.

PURPOSE: Sleep-disordered breathing is recognized as a comorbidity in patients with idiopathic pulmonary fibrosis (IPF). Among them, nocturnal hypoxemia has been reported to be associated with poor prognosis and disease progression. We developed a diagnostic algorithm to classify nocturnal desaturation from percutaneous oxygen saturation (SpO2) waveform patterns: sustained pattern, periodic pattern, and intermittent pattern. We then investigated the prevalence of nocturnal desaturation and the association between the waveform patterns of nocturnal desaturation and clinical findings of patients with IPF. METHODS: We prospectively enrolled patients with IPF from seven general hospitals between April 2017 and March 2020 and measured nocturnal SpO2 and nasal airflow by using a home sleep apnea test. An algorithm was used to classify the types of nocturnal desaturation. We evaluated the association between sleep or clinical parameters and each waveform pattern of nocturnal desaturation. RESULTS: Among 60 patients (47 men) who met the eligibility criteria, there were 3 cases with the sustained pattern, 49 cases with the periodic pattern, and 41 cases with the intermittent pattern. Lowest SpO2 during sleep and total sleep time spent with SpO2 < 90% were associated with the sustained pattern, and apnea-hypopnea index was associated with the intermittent pattern. CONCLUSION: We demonstrated the prevalence of each waveform and association between each waveform and sleep parameters in patients with IPF. This classification algorithm may be useful to predict the degree of hypoxemia or the complication of obstructive sleep apnea.

A Need for a Diagnostic Management Protocol in Barium Aspiration.

We experienced a patient who presented with lung abscess one month after aspirating barium during a gastric cancer screening examination. The patient had no subjective symptoms suggesting a swallowing disorder. Rigorous history taking under suspicion of aspiration and a further assessment of the cause of aspiration revealed hypopharyngeal cancer. Lung abscess and hypopharyngeal cancer, both treatable but potentially fatal conditions, were not diagnosed until one month after the aspiration. This highlights the need for guidance for patients and physicians to follow in the event of barium aspiration, as it is the most common complication of a barium examination. A health checkup for one condition (gastric cancer) may also be an opportunity to diagnose another underlying condition.

Osimertinib for Lung Squamous Cell Carcinoma: A Case Report and Literature Review.

The efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in lung squamous cell carcinoma is said to be low. Thus far, only four cases of osimertinib in lung squamous cell carcinoma have been published. We experienced a case of EGFR mutant lung squamous cell carcinoma in which fifth-line treatment with osimertinib was effective after T790M EGFR mutation turned positive. Osimertinib was resumed after sixth-line chemotherapy was ineffective, showing efficacy again. Osimertinib may be a promising treatment option for EGFR mutant lung squamous cell carcinoma. This is the first report to show its effect in a case of rechallenge after intervening chemotherapy. It may therefore be important to evaluate EGFR in never-smoker lung squamous cell carcinoma patients.

Intractable pleural effusion associated with superior vena cava and upper extremity deep vein thrombosis in a patient with advanced lung cancer.

We herein report a case with intractable pleural effusion attributed to superior vena cava (SVC) and upper extremity deep vein thrombosis in a patient with lung cancer. A 62-year-old woman presented to our hospital with shortness of breath and bilateral upper extremity edema. One year ago, she was diagnosed with stage IVB lung adenocarcinoma with bilateral malignant pleural effusions. A genetic analysis of the cells from pleural effusion revealed an epidermal growth factor receptor (EGFR) point mutation at exon 21 (L858R); since then, she was treated with gefitinib. Although her lung cancer and metastatic lesions had markedly reduced and the tumor cells in the pleural effusion had disappeared, pleural effusion remained. Contrast-enhanced whole-body computed tomography (CT) revealed intravenous thrombosis extending from the SVC to the left brachiocephalic and subclavian veins, and her pleural effusion was attributed to this thrombosis. Anticoagulant therapy with intravenous heparin and oral warfarin was started, nevertheless, the thrombus remained and pleural effusion did not decrease. After the placement of a pleuroperitoneal shunt, her pleural effusion resolved and her symptoms improved. This case highlights the importance of awareness of SVC or upper extremity deep vein thrombosis as a differential diagnosis of intractable pleural effusion in lung cancer patients.

An autopsy case of ruptured liver metastases from small cell lung cancer: A case report and literature review.

A 50-year-old male presented to our hospital complaining of dry cough and slight fever. A chest CT scan showed a mass in the right upper lung lobe, pleural effusion on both sides, and multiple liver tumors. He was diagnosed with small cell lung cancer (SCLC), and then antitumor chemotherapy was started. Thereafter, his condition deteriorated rapidly, and died 2 days later. An autopsy revealed that the cause of death was ruptured liver metastases. SCLC is a highly invasive disease and often metastasizes to the liver, but the rupture of liver metastases is rare. Clinical features and imaging findings were of a great help in diagnosing ruptured hepatic metastasis. Physicians need to pay attention to this condition, especially after chemotherapy has initiated.

A familial case of Birt-Hogg-Dubé syndrome complicated with various cancers.

An 89-year-old woman with small papules on her face presented to our hospital complaining of progressive dyspnoea. Chest computed tomography (CT) showed bilateral multiple lung cysts, a nodular opacity in the right lower lobe, and bilateral pleural effusion. She was diagnosed with adenocarcinoma. Her son, a 65-year-old man, also had bilateral basally located lung cysts and a past medical history of spontaneous pneumothorax. He had multiple papules on the face and neck, which were pathologically diagnosed as fibrofolliculomas. We considered these cases to be Birt-Hogg-Dubé syndrome (BHDS). Folliculin (FLCN) gene mutations that may be tumour suppressive are suspected to be causative of this syndrome. FLCN dysfunction might lead to the development of various types of tumours other than renal tumours.

Primary Pleural Melanoma: A Case Report and Literature Review.

Primary pleural melanoma is an extremely rare neoplasm, and to the best of our knowledge, there have been only 8 case reports of this condition in the English literature. We herein report a rare case in which the cytological and immunocytochemical analyses of pleural fluid and ultrasonography (US)-guided biopsy of a pleural lesion were useful for the diagnosis primary pleural melanoma. This case highlights the importance of careful physical examinations, cytomorphologic and immunocytochemical analyses of pleural fluid, as well as the utility of US-guided biopsy of the pleural lesions in the diagnosis of primary pleural melanoma.

Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) presenting as an endobronchial lesion: Case report and literature review.

Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) is a rare entity of lymphoma. We herein report an even rarer case of a 68-year-old male with PTCL-NOS presenting as an endobronchial lesion, and review previously published cases in the literature. Initially, he was referred to our hospital for further investigation of the right upper lobe consolidation on chest radiograph. Computed tomography and 18F-fludeoxyglucose positron emission tomography revealed a right hilar mass with obstruction of the main bronchus and submandibular, right axillary and mediastinal lymphadenopathy. Pathological examination of the biopsy specimens from of the endobronchial lesion and subcutaneous nodule revealed PTCL-NOS. Chemotherapy was started but he finally died due to septic shock after the second-line chemotherapy.

Miliary Tuberculosis in a Young Woman with Hemophagocytic Syndrome: A Case Report and Literature Review.

We herein report a rare case of miliary tuberculosis-associated hemophagocytic syndrome (HPS) complicated with respiratory failure. A 19-year-old Japanese woman with a fever, general malaise, and chest radiograph abnormalities was referred to our hospital. After admission, she developed respiratory failure with pancytopenia. A histological examination of lung and bone marrow biopsy samples revealed noncaseating granulomas without evidence of acid-fast bacilli or lymphoma. In addition, a bone marrow biopsy showed marked histiocyte hyperplasia with hemophagocytosis, and a bronchoalveolar lavage fluid culture grew Mycobacterium tuberculosis. Therefore, a diagnosis of miliary tuberculosis-associated HPS was made. The patient was successfully treated with antituberculous therapy.

Localized Pleural Metastases of Renal Cell Carcinoma After Nephrectomy: A Case Report and Literature Review.

We herein report the case of a 61-year-old Japanese male with localized pleural metastases of renal cell carcinoma. The patient was admitted to our hospital because of dyspnea on exertion and left-sided pleural effusion. He had undergone right radical nephrectomy 10 years previously. Contrast-enhanced whole-body computed tomography revealed scattered nodular thickening of the left pleura with contrast enhancement and left-sided pleural effusion. Thoracoscopy performed under local anesthesia was applied to obtain a biopsy of the pleural nodules, and the specimen was consequently diagnosed as exhibiting pleural metastasis of renal cell carcinoma, clear cell type.

Successful treatment with carboplatin and pemetrexed for multiple lymph node metastases of lymphoepithelioma-like carcinoma from an unknown primary site.

We herein report the case of an 80-year-old Japanese man with multiple lymph node metastases of lymphoepithelioma-like carcinoma (LELC) from an unknown primary site. The patient was admitted to our hospital due to hoarseness and left supraclavicular lymphadenopathy. Contrast-enhanced whole-body computed tomography revealed mediastinal, left supraclavicular, and left axillary lymphadenopathy. A left supraclavicular lymph node biopsy was performed and the specimen was consequently diagnosed as exhibting LELC. The patient's Eastern Cooperative Oncology Group performance status was 0, therefore he was started on chemotherapy with carboplatin and pemetrexed. His lymph nodes responded well to four cycles of chemotherapy without any intolerable adverse effect.

[A case of cutaneous vasculitis caused by erlotinib treatment and a review of literature].

Erlotinib is a potent drug used for treating epidermal growth factor receptor (EGFR) mutation positive lung cancer. In this study, we report a case of erlotinib induced cutaneous vasculitis. The patient was a 69-year-old woman with a history of left lower lobe resection for lung cancer. Two years after the resection, she had metastasis in the adrenal glands for which we initiated erlotinib therapy at a dose of 150 mg/day. The patient developed multiple purpurae with a partially necrotic region on both lower thighs at 8 weeks after initiating therapy. The skin biopsy results revealed cutaneous vasculitis. We stopped erlotinib therapy after this diagnosis because of this adverse effect as well as because it exacerbated the cancer. The patient's skin manifestation disappeared 2 weeks after stopping therapy, with no recurrence of any symptoms of systemic vasculitis. We reviewed the literature on drug-induced vasculitis due to oral EGFR inhibitors and found 13 such cases. In most cases, the symptoms appeared 1-2 months after initiating therapy. In all the cases, the symptoms resolved within 2-6 weeks after stopping drug therapy. Erlotinib-induced cutaneous vasculitis is rare but may cause fatal systemic vasculitis. Therefore, the skin of patients who are undergoing erlotinib therapy should be carefully examined at regular intervals during the course of therapy for drug-induced adverse effects.