Nintedanib plus Chemotherapy for Small Cell Lung Cancer with Comorbid Idiopathic Pulmonary Fibrosis.

Rationale: A fatal acute exacerbation (AE) occasionally develops during chemotherapy for small cell lung cancer (SCLC) with comorbid idiopathic pulmonary fibrosis (IPF).Objectives: This study aimed to assess the safety and efficacy of carboplatin, etoposide, and nintedanib combination therapy for unresectable SCLC with comorbid IPF.Methods: The NEXT-SHIP study is a multicenter, single-arm, phase 2 trial for unresectable SCLC with IPF (Japan Registry of Clinical Trials registry number jRCTs031190119). The patients received carboplatin, etoposide, and nintedanib (150 mg twice daily). The primary endpoint was the incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy, and the sample size was set at 33 (5.0% expected, 20.0% threshold).Results: A total of 33 patients were registered; 87.9% were male, the median age was 73 years, the median percentage forced vital capacity was 85.2%, and 51.5% had honeycomb lungs. The median observation period was 10.5 months. The incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy was 3.0% (90% confidence interval [CI], 0.2-13.6). The objective response rate was 68.8% (95% CI, 50.0-83.9). The median progression-free survival and overall survival times were 4.2 months (95% CI, 4.2-5.5) and 13.4 months (95% CI, 8.1-21.6), respectively. The most common adverse event of grade 3 or higher was neutropenia (81.8%), followed by leukopenia (39.4%) and thrombocytopenia (30.3%).Conclusions: This study met its primary endpoint regarding the incidence of IPF-AEs with promising results for efficacy. Carboplatin, etoposide, and nintedanib combination therapy may be one of the standard treatment options for SCLC with comorbid IPF.Clinical trial registered with the Japan Registry of Clinical Trials (jRCTs031190119).

Mechanisms of primary and acquired resistance to immune checkpoint inhibitors in advanced non-small cell lung cancer: A multiplex immunohistochemistry-based single-cell analysis.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) have become a key therapeutic modality for advanced non-small cell lung cancer (NSCLC), but most patients experience primary or acquired resistance to these drugs. We here explored the mechanisms underlying both types of ICI resistance by analysis of the tumor immune microenvironment (TME). MATERIALS AND METHODS: Four patients who experienced a long-term response to ICI treatment (progression-free survival [PFS] of ≥12 months) followed by disease progression, after which a rebiopsy was immediately performed (cohort-A), as well as four patients who experienced early tumor progression during ICI treatment (PFS of <9 weeks, cohort-B) were enrolled in this retrospective study. The pretreatment TME was evaluated by 16- or 17-color multiplex immunohistochemistry (mIHC)-based spatial profiling at the single-cell level for both cohorts. In cohort-A, changes in the TME after disease progression during ICI treatment were also investigated by mIHC analysis and transcriptomic analysis. RESULTS: Pretreatment tumor tissue from cohort-B manifested poor infiltration of tumor-reactive CD8+ T cells characterized by CD39 and CD103 expression or by programmed cell death-1 expression, implicating insufficient recognition of tumor cells by CD8+ T cells as a mechanism of primary ICI resistance. Analysis of the paired tumor specimens from cohort-A revealed various changes in the TME associated with acquired ICI resistance, including substantial infiltration of myeloid-derived suppressor cells and M2-type tumor-associated macrophages without a marked decline in the number of tumor-reactive CD8+ T cells; a decrease in the number of tumor-reactive CD8+ T cells; and an apparent decrease in neoantigen presentation by tumor cells. CONCLUSION: The presence of intratumoral tumor-reactive CD8+ T cells may be a prerequisite for a long-term response to ICI treatment in advanced NSCLC, but it is not sufficient for cancer cell eradication. Various TME profiles are associated with acquired ICI resistance, suggesting that patient-specific strategies to overcome such resistance may be necessary.

Successful treatment of a case of hormone receptor-positive metastatic extramammary Paget disease with tamoxifen.

Extramammary Paget disease (EMPD) is a rare cutaneous adenocarcinoma that usually is of epidermal origin and shows glandular differentiation and that is treated by wide local excision depending on the disease extent. For widely metastatic disease, however, a standard treatment remains to be established. Similar to breast cancer, EMPD has been found to overexpress human epidermal growth factor receptor 2 (HER2) or hormone receptors (HRs). Whereas HER2-directed therapy was recently shown to be effective for HER2-positive EMPD, the potential role of endocrine therapy for HR-positive EMPD has remained unknown. We here report a case of metastatic EMPD with HR positivity that was successfully treated with the selective estrogen receptor modulator tamoxifen. This first-line treatment of systemic metastasis resulted in durable tumor regression for > 20 months without any treatment-related toxicities. This is the first report to reveal the promise of tamoxifen as a safe and effective treatment for HR-positive metastatic EMPD.

Relationship of flow-volume curve pattern on pulmonary function test with clinical and radiological features in idiopathic pulmonary fibrosis.

BACKGROUND: The flow-volume (FV) curve pattern in the pulmonary function test (PFT) for obstructive lung diseases is widely recognized. However, there are few reports on FV curve pattern in idiopathic pulmonary fibrosis (IPF). In this study, we investigated the relationship between FV curve pattern and clinical or radiological features in IPF. METHODS: The FV curves on PFTs and chest high-resolution computed tomography (HRCT) images of 130 patients with IPF were retrospectively evaluated. The FV curves were divided into four groups based on the presence or absence of the convex and concave patterns: convex/concave, non-convex/concave, convex/non-concave, and non-convex/non-concave. Using a computer-aided system, CT honeycombing area (%HA) and subtracted low attenuation area (%sLAA) were quantitatively measured. To assess the distribution of CT findings, the lung area was divided into upper, lower, central, and peripheral areas. The relationships of FV curve patterns with patient characteristics, spirometry results, and quantitative CT findings were evaluated. RESULTS: The patients with convex pattern was identified in 93 (71.5%) and concave pattern in 72 (55.4%). Among the four groups, patients with the convex/non-concave pattern had significantly lower forced vital capacity (FVC) and higher %HA of the upper/peripheral lung area (p = 0.018, and p = 0.005, respectively). The convex/non-concave pattern was a significant predictor of mortality for IPF (hazard ratio, 2.19; p = 0.032). CONCLUSIONS: Patients with convex/non-concave pattern in FV curve have lower FVC and poorer prognosis with distinct distribution of fibrosis. Hence, FV curve pattern might be a useful predictor of mortality in IPF.

Promising Effects of Benralizumab on Chronic Eosinophilic Pneumonia.

We herein report a case of refractory chronic eosinophilic pneumonia (CEP) complicated with uncontrolled bronchial asthma, in which remission was successfully induced with single dose of benralizumab, a monoclonal antibody against the alpha-chain of the interleukin-5 receptor. Resolution of the patient's symptoms and consolidation on chest X-ray were observed at 2 weeks and lasted for 8 weeks after the administration of benralizumab. Benralizumab would be a novel alternative choice of treatment for CEP patients who are at risk of potential toxicity due to long-term corticosteroid therapy.

Impact of EGFR-TKI Treatment on the Tumor Immune Microenvironment in EGFR Mutation-Positive Non-Small Cell Lung Cancer.

PURPOSE: The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear. EXPERIMENTAL DESIGN: We retrospectively identified 138 patients with EGFR-mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by IHC. Tumor mutation burden (TMB) was determined by next-generation sequencing. RESULTS: The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI (P = 0.0010). Whereas CD8+ and FOXP3+ TIL densities were significantly lower after EGFR-TKI treatment than before, CD8+ TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3→4.1 mutations/Mbp, P = 0.0508). Median progression-free survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 vs. 1.7 months, P = 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months. CONCLUSIONS: EGFR-TKI treatment was associated with changes in the TME of EGFR-mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment.

Pemetrexed-induced Interstitial Lung Disease Mimicking Hypersensitivity Pneumonia: A Pathologically Proven Case.

We herein report a 45-year-old woman with lung adenocarcinoma stage IV (cT4N3M1a). She was treated with pemetrexed (PEM) monotherapy following four cycles of first-line treatment with carboplatin, paclitaxel, and veliparib. After three cycles of PEM treatment, she presented with dyspnea, and chest computed tomography showed diffuse ground-glass attenuation (GGA), suggesting hypersensitivity pneumonia (HP). Bronchoalveolar lavage revealed a marked increase in lymphocytes (90.5%), and a transbronchial lung biopsy confirmed lymphocytic alveolitis with granuloma. Because her symptoms and diffuse GGA were spontaneously resolved with PEM discontinuation alone, PEM-induced interstitial lung disease was diagnosed. Chest physicians should be aware that PEM can induce HP-type interstitial lung disease.

Anti-Ku antibody-positive desquamative interstitial pneumonia.

A 66-year-old man, an ex-smoker, was referred to our hospital for slightly progressive respiratory symptoms of cough and dyspnea on exertion and chest abnormal shadow. Chest high-resolution computed tomography showed wide-ranging ground-glass attenuation and reticulation with lower lobe predominance. Bronchoalveolar lavage (BAL) fluid revealed a marked increase in lymphocytes (53.0%), and a surgical lung biopsy revealed a pattern of desquamative interstitial pneumonia (DIP) with hyperplasia of the lymphoid follicles. His serum was positive for anti-Ku and anti-SS-A antibodies, and he had signs (such as Raynaud's phenomenon, joint pain, and mechanic's hand) suspicious of connective tissue disease (CTD) although a definitive diagnosis of CTD had not been established. On the basis of the findings in our patient obtained from the serologic domain, BAL, and pathological examination, clinicians should consider the important correlation of DIP with CTD as well as with smoking.

Clinical characteristics and early outcomes of patients newly diagnosed with pulmonary Mycobacterium avium complex disease.

BACKGROUND: The incidence of asymptomatic pulmonary Mycobacterium avium complex (MAC) disease appears to be increasing. This study aimed to determine the clinical characteristics and examine early outcomes of patients newly diagnosed with MAC disease. METHODS: We retrospectively reviewed the medical records of all 184 patients newly diagnosed with MAC disease between April 2013 and March 2015 at our hospital. Culture conversion, defined as at least two consecutive negative cultures, was used as the early outcome measure. RESULTS: Of 184 patients, 45 were male and 139 were female, with a mean age of 70 years. Abnormal chest shadow found during an annual health check-up (58 patients) or incidentally during visits for other diseases (72 patients), was the major reason for referral to hospital, typically with no symptoms. Anti-MAC IgA antibody was positive in 64.5% of patients, and the positive rate was associated with the extent of lesions. Clarithromycin-based multi-drug chemotherapy was initiated in 111 patients. Culture conversion was achieved in 61 of 82 (74.4%) patients who were able to continue multi-drug chemotherapy. Patients who achieved culture conversion were more likely to be younger, female, and have a lower smear grade and nodular-bronchiectatic type. Multivariate logistic regression analysis identified patient age and smear grade as predictive variables. CONCLUSIONS: Abnormal chest shadow found during health check-up was the major reason for hospital visits, and most were asymptomatic. Culture conversion was achieved in three-fourths of patients treated, and was associated with age and smear grade, supporting early intervention at a younger age.

The Spontaneous Regression of Grade 3 Methotrexate-related Lymphomatoid Granulomatosis: A Case Report and Literature Review.

Lymphomatoid granulomatosis (LYG) is a rare lung disorder diagnosed by radiological imaging of multiple pulmonary nodules and occasionally induced by methotrexate (MTX) use. To date, the treatment of LYG has not been standardized. We herein report the case of a patient with grade 3 MTX-related LYG who presented a bulky lung mass. Importantly, the disease condition only improved after the discontinuation of MTX and remained stable for more than 1 year. Chest physicians should be aware that LYG can develop as a single lung mass and spontaneously regress, even without aggressive chemotherapy, following the cessation of MTX.