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Objectives: To analyze predictors associated with viable cells in pulmonary residual lesions after chemotherapy for metastatic testicular nonseminomatous germ cell tumors and to develop models to prioritize pulmonary resection. Methods: Between 2008 and 2017, 40 patients underwent pulmonary metastasectomy after chemotherapy for nonseminomatous germ cell tumors. We evaluated these patients, and 326 pulmonary residual lesions were confirmed using computed tomography and pathological evaluations. Relationships with outcomes were analyzed using logistic regression analyses. Risk prediction models were developed, and predictive probabilities for the risk of viable cells were estimated. Results: Histological examinations showed that 73 (22%) pulmonary residual lesions contained viable cells: teratomas, 46 (14%); and cancer cells, 37 (11%). Multivariate analyses showed that the predictors associated with cancer cells in the residual lesions were elevated tumor marker levels, multiregimen chemotherapy, increased tumor size 6 months before surgery and the histological composition of the primary lesion, including yolk sac tumors. Additional predictors associated with teratomas were aspect ratio and histological composition of the primary lesion, including teratomas. Conclusions: Intratumoral heterogeneity contributes to nonseminomatous germ cell tumor chemoresistance, and primary lesion site yolk sac tumors and teratomas are associated with greater risks of viable cells. Increased residual lesion size during chemotherapy could also be a predictor. Our simple model can predict the presence of viable cells in residual lesions after chemotherapy, and it might assist in decision‐making and prioritizing pulmonary residual lesion resection. [ABSTRACT FROM AUTHOR]

Bronchiolar adenoma (BA) is a rare benign lung tumor that shows proliferation of bland bronchiolar‐type epithelium containing a continuous layer of basal cells. This tumor entity has been newly added to the recent World Health Organization (WHO) classification 5th edition. This entity encompasses a spectrum of lesions: the classic ciliated muconodular papillary tumor (CMPT) and the non‐classic CMPT. Although BA is reported to have driver mutations including BRAF V600E, EGFR, and KRAS, the molecular profile of BA is still incompletely understood. Five resected BAs at our institutions were analyzed. The BA lesions were subdivided into two groups: three proximal‐type BAs and two distal‐type BAs. NRAS codon 12/13 mutation and EML4 exon 20‐ALK exon 20 fusion were found in two of the three proximal‐types. BRAF V600E mutation was found in one of the two distal‐types. Two cases coexisted with lung adenocarcinoma, with EGFR exon 19 deletion and KRAS mutation, respectively. No recurrence was observed at a median of 12 months (range 2–84 months) of follow‐up. BA has uncommon variants of mutation seen in lung adenocarcinoma. NRAS mutation and ALK fusion partner has not been reported previously. The present cases may reinforce the distinctive biology of BA from lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

• Prognostic impact of STAS in pulmonary metastasis from colorectal cancer is unknown. • STAS was related to a poor prognosis in pulmonary metastasis from colorectal cancer. • Distance between main tumor and STAS was related to surgical margin relapse. Surgical resection for pulmonary metastases from colorectal cancer could provide long-term survival in selected patients, and it is commonly performed in practice. However, surgical margin relapse sometimes occurs and is a problematic issue to resolve. Spread through air spaces (STAS) is one of the invasion forms in primary lung cancer and is associated with local recurrence and a poor prognosis. The aim of this study was to evaluate the prognostic significance of STAS for pulmonary metastases from colorectal cancer and to assess the predictability of STAS with preoperative clinical information. A total of 96 pulmonary metastatic lesions from colorectal cancer in 37 patients who underwent metastasectomy at our institution from January 2008 to December 2013 were retrospectively analyzed. STAS was identified in 41.6 % of the 96 lesions. Surgical margin relapse was found in 8 lesions (8.3 %) from 7 patients (18.9 %). The distance of STAS was identified as an independent risk factor for surgical margin relapse on multivariable analysis (p = 0.033). The patients with STAS showed significantly worse overall survival than those without (5-year overall survival rate: 30.3 % vs. 76.9 %; p = 0.002). On multivariable analysis, patients with STAS had a significantly higher risk of death than those without (p = 0.019). An elevated pre-metastasectomy serum carcinoembryonic antigen level was independently correlated with STAS on multivariable analysis (p = 0.049). STAS was related to a poor prognosis and surgical margin relapse in pulmonary metastases from colorectal cancer. [ABSTRACT FROM AUTHOR]

• Extent of PD-L1 expression in TET was associated with histological subtype. • Type B thymoma shows higher PD-L1 expression than type A thymoma/thymic carcinoma. • WSI with cytokeratin stain appears available to analyze PD-L1 expression for thymoma. • High PD-L1 expression in TETs was associated with poor prognosis. Whether the extent of expression of programmed death-ligand 1 (PD-L1) is clinically significant remains uncertain, although immuno-oncological features have been studied in thymic epithelial cell tumors (TETs). We investigated the histological features of PD-L1 expression in TETs, and assessed PD-L1 expression using digital image analysis. Participants comprised 66 patients with TET who underwent surgical resection between 2001 and 2016. We calculated tumor cell-positive ratio as total proportion score (TPS) with immunohistochemistry using SP263 anti-PD-L1 monoclonal antibody. PD-L1 expression was also quantified using digital image analysis of whole-slide images. We evaluated the relationship between conventional visual TPS using optical microscopy (TPS-V) and TPS from digital image analysis (TPS-IA). We further classified all TETs into high or low PD-L1 expression groups and assessed the clinical significance of PD-L1 expression level using TPS-V and TPS-IA. WHO histological types were Type A (n = 8), AB (n = 18), B1 (n = 5), B2 (n = 16), B3 (n = 6), metaplastic thymoma (n = 2), and thymic carcinoma (TC) (n = 11). Median TPS-Vs were 2%, 2%, 10 %, 65 %, 90 %, 1%, and 20 %, respectively. TPS-IAs correlated with TPS-Vs in TETs overall and in thymomas, but not in TCs. PD-L1 expression levels in TETs differed significantly among histological types. Whether TPS-V or TPS-IA were used, the PD-L1high group included more cases of the more aggressive histological types. Recurrence-free survival (RFS) was shorter in the PD-L1high group than in the PD-L1low group in thymoma using TPS-IA, whereas RFS of the PD-L1high group was shorter in all TETs using TPS-V. PD-L1 expression levels depended on the histological type of TET. Extensive PD-L1 expression in TETs was associated with poor prognosis. Digital image analysis is feasible for evaluating PD-L1 expression in TETs and might offer clinically relevant features of thymomas. [ABSTRACT FROM AUTHOR]

Trousseau's syndrome is characterized as an unexpected, cancer-related thrombotic event, such as a cerebral infarction or a deep vein thrombosis/pulmonary embolism. We describe the first reported case of Trousseau's syndrome with pulmonary pleomorphic carcinoma and aggressive features. A 74 year-old man presenting with a pulmonary mass, which was identified as pleomorphic carcinoma with extensive lymph node involvement, in the left lower lobe, underwent a left lower lobectomy. Immunohistochemical analysis revealed that neoplastic cells exhibited an extensive expression of tissue factors with a mucin-producing adenocarcinoma component. Three months postoperatively, diffuse infiltration rapidly appeared in the left lung, which was identified as lymphangitic carcinomatosis via bronchoscopy. Prior to treatment for cancer recurrence, the patient presented with a left hemiplegia due to a cerebral infarction via multiple thromboses, with no evidence of atherosclerotic or cardiogenic thrombi. Elevated D-dimer and carbohydrate antigen 125 levels and the presence of a fibrin thrombus retrieved from the occluded vessel suggested Trousseau's syndrome as the etiology of the brain infarction. A hypercoagulable state associated with the aggressive recurrence of pulmonary pleomorphic carcinoma, accompanied by cancer cell production of mucin and tissue factors may be a potential mechanism for cancer-related thrombosis. [ABSTRACT FROM AUTHOR]

Programmed cell death protein-1 (PD-1) blockade therapy has improved outcomes in the treatment of advanced cancers. The therapy is well-tolerated, although it occasionally causes immune-related adverse events (irAEs). Thyroid dysfunction is one of the most common irAEs seen. Our aim was to clarify the clinical characteristics of thyroid dysfunction induced by PD-1 blockade and its association with the therapeutic effect of the treatment in advanced cancers. A total of 174 patients who received nivolumab or pembrolizumab for metastatic or unresectable advanced cancers were included in this retrospective study. The patients were divided into two groups: The thyroid dysfunction group and the euthyroid group. In the present study, the clinical characteristics, the association with anti-thyroid antibodies, as well as the progression-free survival (PFS) and overall survival (OS) were estimated. An adjusted Cox proportional hazard regression model was used to evaluate prognostic factors for OS and PFS. This study showed that 25 out of 150 patients (16.7%) developed immune-related thyroid dysfunction. Hypothyroidism occurred in the early stage of the clinical course (median: 12 weeks); subsequently, 9 of the 25 patients underwent a transient period of hyperthyroidism, all with mild symptoms. The presence of positive anti-thyroid antibodies at baseline was significantly higher in the thyroid dysfunction group (13/22) than in the euthyroid group (18/100, P=0.0002). Moreover, PFS (median: 66 vs. 27 weeks, hazard ratio (HR): 0.50, 95% CI: 0.26–0.89, P=0.02) and OS (median 156 vs. 59 weeks, HR: 0.34, 95% CI: 0.13–0.75, P=0.01) were significantly longer in the thyroid dysfunction group than in the euthyroid group. Multivariable analysis also revealed that thyroid dysfunction was an independent prognostic factor for OS (HR: 0.42, 95% CI: 0.16–0.97, P=0.04). These findings may enable the early recognition and appropriate management of thyroid dysfunction, and help in maximizing the therapeutic effect of PD-1 blockade. [ABSTRACT FROM AUTHOR]

Background: The mechanism by which tumors escape the immune system has been actively investigated and is partly explained by the programmed death-1 (PD-1) and its ligand (PD-L1) pathway. This study is aimed at clarifying the prognostic significance of PD-L1 expression in patients with surgically resected pulmonary metastases of head and neck squamous cell carcinoma (HNSCC). Patients and methods: A retrospective review was conducted of 26 HNSCC patients who underwent complete resection of pulmonary metastases. PD-L1 expression in both the primary and metastatic tumors was evaluated using immunohistochemistry (anti-PD-L1 antibody, clone SP263). High PD-L1 expression was defined as ≥50% of tumor cells with positive staining. Survival and prognostic impacts following pulmonary metastasectomy were analyzed based on the PD-L1 expression level. Results: The patients included 23 men and 3 women, with a median age of 65 years. Six (23%) of the pulmonary metastatic cases showed high PD-L1 expression, while their corresponding primary lesions had low PD-L1 expression. The 5-year overall survival rate after pulmonary metastasectomy was 57.6% in all cases. The 5-year overall survival rates were 72.5% and 16.7% in the low and high PD-L1 groups, respectively (p < 0.001). Multivariate analysis demonstrated that high PD-L1 expression and older age (>65 years) correlated independently with a shorter overall survival (p < 0.001). Conclusions: High PD-L1 expression in pulmonary metastases could be an independent predictor of poor outcome in HNSCC patients undergoing pulmonary metastasectomy. This is the first report evaluating the prognostic implication of PD-L1 expression in metastatic HNSCC. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to identify the factors associated with prolonged air leak (PAL) following pulmonary lobectomy for lung cancer. Methods: The data of 146 patients who underwent pulmonary lobectomy for lung cancer between August 2010 and July 2015 were retrospectively reviewed. Air leaks were assessed daily by a visual evaluation and were categorized as follows: forced expiratory only (Grade 1), expiratory only (Grade 2), or continuous (Grade 3). Logistic regression analyses were performed to identify the predictors of PAL (>5 days). Results: PAL occurred in 23 patients (16%). An air leak at rest (Grade ≥ 2) was detected on postoperative day (POD) 1 in 48% of the patients with PAL and 7% of the patients without PAL. A univariate analysis demonstrated that PAL was significantly associated with male sex, a smoking history of ≥ 40 pack years, a serum albumin level of ≤4.0 mg/dL, and an air leak on POD1 (Grade ≥ 2). A multivariate analysis demonstrated that a serum albumin level of ≤4.0 mg/dL ( p = 0.027) and an air leak on POD1 ( p = 0.006) were independent predictors of PAL. PAL occurred in 75% of the patients with these two risk factors. Conclusions: The preoperative serum albumin level and the presence of a visually evaluated air leak on POD1 may be useful indicators for the perioperative management of air leaks. [ABSTRACT FROM AUTHOR]

Anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) monotherapies have shown promising clinical activity in advanced cancers. Many studies of immune-related adverse events (irAEs) have been reported. Although, the safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting positive antinuclear antibodies (ANA) and autoimmune disease (AD) remains unclear. Methods: 216 patients who received nivolumab, pembrolizumab, atezolizumab or durvalumab for unresectable advanced cancers between September 2014 and December 2018 were retrospectively identified. The patients were divided into the positive (ANA titers≥1:80) and negative (titers≤1:40) ANA groups. Development and characteristics of irAEs, the response rate (RR) and disease control rate (DCR) were estimated. We also focused on the patients with preexisting AD and assessed their clinical courses. Results: 17 out of 190 patients had positive ANA. 8 patients developed irAEs of any grade in the positive ANA group while 65 developed in the negative group, which showed no significant difference among the two groups. No significant differences were shown in the development of endocrine, pulmonary and cutaneous irAEs, while the presence of positive ANA was significantly higher in patients who developed colitis (3/17) than in patients who did not (2/173, P < 0.0001). No statistically significant differences were found in RR and DCR between the positive and negative ANA groups. Besides, 8 patients had preexisting AD and one had a flare after induction of PD-L1 blockade, requiring increasement of prednisolone and discontinuation of PD-L1 blockade. Conclusion: No correlation was shown between the preexisting positive ANA and the development of irAEs in total. Positive ANA showed a trend of developing colitis, although there were manageable. Careful consideration is needed for induction of PD-1/PD-L1 blockade therapy in patients with preexisting AD. [ABSTRACT FROM AUTHOR]

The number of elderly patients with cancer has increased due to aging of the population. However, safety of programmed cell death-1 (PD-1) or programed cell death ligand 1 (PD-L1) inhibitors in elderly patients remains controversial, and limited information exists in frail patients. The present study retrospectively identified 197 patients treated with nivolumab, pembrolizumab or atezolizumab for unresectable advanced cancer between September 2014 and December 2018. Patients were divided into the elderly (age, ≥75 years) and non-elderly (age, <75 years) groups. The detailed immune-related adverse events (irAE) profile and development of critical complications were evaluated. To assess tolerability, the proportion of patients who continued PD-1/PD-L1 inhibitor for >6 months was analyzed. In the two groups, a three-element frailty score, including performance status, Charlson Comorbidity Index and neutrophil-lymphocyte ratio, was estimated, and patients were divided into the low-, intermediate- and high-frailty subgroups. Safety and tolerability were evaluated using the aforementioned items. A total of 58 patients (29.4%) were aged ≥75 years. No significant difference was found in the development of irAEs, hospitalization and treatment discontinuation due to irAEs between the two groups. However, the occurrence of unexpected critical complications was significantly higher in the elderly group (P=0.03). Among the elderly patients with high frailty, more critical complications and fatal irAE (hepatitis) were observed. In this population, 33.3% were able to continue treatment for >6 months without disease progression. The present analysis based on real world data showed similar safety and tolerability of PD-1/PD-L1 inhibitors in elderly patients with advanced malignancies. However, the impact of irAE in elderly patients, especially those with frailty, was occasionally greater compared with that in younger and fit patients. [ABSTRACT FROM AUTHOR]

Introduction Anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) monotherapies have shown promising clinical activity in advanced cancers. Many studies of immune-related adverse events (irAEs) have been reported. Although, the safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting positive antinuclear antibodies (ANA) and autoimmune disease (AD) remains unclear. Methods: 216 patients who received nivolumab, pembrolizumab, atezolizumab or durvalumab for unresectable advanced cancers between September 2014 and December 2018 were retrospectively identified. The patients were divided into the positive (ANA titers≥1:80) and negative (titers≤1:40) ANA groups. Development and characteristics of irAEs, the response rate (RR) and disease control rate (DCR) were estimated. We also focused on the patients with preexisting AD and assessed their clinical courses. Results: 17 out of 190 patients had positive ANA. 8 patients developed irAEs of any grade in the positive ANA group while 65 developed in the negative group, which showed no significant difference among the two groups. No significant differences were shown in the development of endocrine, pulmonary and cutaneous irAEs, while the presence of positive ANA was significantly higher in patients who developed colitis (3/17) than in patients who did not (2/173, P < 0.0001). No statistically significant differences were found in RR and DCR between the positive and negative ANA groups. Besides, 8 patients had preexisting AD and one had a flare after induction of PD-L1 blockade, requiring increasement of prednisolone and discontinuation of PD-L1 blockade. Conclusion: No correlation was shown between the preexisting positive ANA and the development of irAEs in total. Positive ANA showed a trend of developing colitis, although there were manageable. Careful consideration is needed for induction of PD-1/PD-L1 blockade therapy in patients with preexisting AD. [ABSTRACT FROM AUTHOR]