We had previously demonstrated the role of CD103 integrin on lung tumor-infiltrating lymphocyte (TIL) clones in promoting specific TCR-mediated epithelial tumor cell cytotoxicity. However, the contribution of CD103 on intratumoral T cell distribution and functions and the prognosis significance of TIL subpopulations in non–small cell lung carcinoma (NSCLC) have thus far not been systematically addressed. In this study, we show that an enhanced CD103⁺ TIL subset correlates with improved early stage NSCLC patient survival and increased intraepithelial lymphocyte infiltration. Moreover, our results indicate that CD8⁺CD103⁺ TIL, freshly isolated from NSCLC specimens, display transcriptomic and phenotypic signatures characteristic of tissue-resident memory T cells and frequently express PD-1 and Tim-3 checkpoint receptors. This TIL subset also displays increased activation-induced cell death and mediates specific cytolytic activity toward autologous tumor cells upon blockade of the PD-1–PD-L1 interaction. These findings emphasize the role of CD8⁺CD103⁺ tissue-resident memory T cells in promoting intratumoral CTL responses and support the rationale for using anti–PD-1 blocking Ab to reverse tumor-induced T cell exhaustion in NSCLC patients.

Limited numbers of operated patients with chronic thromboembolic pulmonary hypertension (CTEPH) are refractory to pulmonary endarterectomy (PEA) and experience persistent pulmonary hypertension (PH).We retrospectively assessed lung histology available from nine patients with persistent PH (ineffective PEA (inPEA) group) and from eight patients transplanted for distal CTEPH inaccessible by PEA (noPEA group). Microscopically observed peculiarities were compared with the histology of a recently developed CTEPH model in piglets. Pre-interventional clinical/haemodynamic data and medical history of patients from the inPEA and noPEA groups were collected and analysed.Conspicuous remodelling of small pulmonary arteries/arterioles, septal veins and pre-septal venules, including focal capillary haemangiomatosis, as well as pronounced hypertrophy and enlargement of bronchial systemic vessels, were the predominant pattern in histology from both groups. Most findings were reproduced in our porcine CTEPH model. Ink injection experiments unmasked abundant venular involvement in so-called small vessel or microvascular disease, as well as post-capillary bronchopulmonary shunting in human and experimental CTEPH.Microvascular disease is partly due to post-capillary remodelling in human and experimental CTEPH and appears to be related to bronchial-to-pulmonary venous shunting. Further studies are needed to clinically assess the functional importance of this finding.

We report novel molecular and pathologic features of sarcomas involving the heart. Intimal sarcoma appears as the most frequent primary cardiac sarcoma within the largest described series of 100 primary cardiac sarcomas. Immunohistochemical analysis, fluorescence in situ hybridization, real-time polymerase chain reaction, and array-comparative genomic hybridization were performed on materials from 65 women and 35 men, aged 18 to 82 years (mean 50 y), retrieved from the French Departments of Pathology, between 1977 and early 2013. Right and left heart was involved in 44 and 56 cases, respectively. There were 42 intimal sarcomas, 26 angiosarcomas, 22 undifferentiated sarcomas, 7 synovial sarcomas, 2 leiomyosarcomas, and 1 peripheral neuroectodermal tumor. All but 1 angiosarcomas originated from the right heart, whereas 83% of the intimal sarcomas and 72% of the undifferentiated sarcomas were from the left heart. MDM2 overexpression was immunohistochemically observed in all intimal sarcomas, as well as in 10 of the 22 undifferentiated sarcomas and in 5 of the 26 angiosarcomas. MDM2 amplification was only demonstrated in intimal sarcomas. Genomic analysis showed a complex profile, with recurrent 12q13-14 amplicon involving MDM2, 4q12 amplicon involving KIT and PDGFRA, 7p12 gain involving EGFR, and 9p21 deletion targeting CDKN2A. Immunohistochemical detection of MDM2 overexpression can easily detect intimal sarcoma, provided that molecular aberration is proved. As resections are limited to the left atrium, this histologic subtype could benefit from therapies targeting PDGFRA or MDM2.

Over the last few years, the routine testing of gene mutations involving epidermal growth factor receptor (EGFR) has led to dramatic therapeutic advances in non–small-cell lung cancer. Indeed, such mutations allow the use of targeted therapies by EGFR tyrosine kinase inhibitor (TKI) with durable response and improved survival.¹ x 1 Pao, W and Miller, VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol. 2005; 23: 2556–2568 Crossref | PubMed | Scopus (501) | Google Scholar See all References ^{, 2} x 2 Lynch, TJ, Bell, DW, Sordella, R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004; 350: 2129–2139 Crossref | PubMed | Scopus (8312) | Google Scholar See all References ^{, 3} x 3 Paez, JG, Jänne, PA, Lee, JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004; 304: 1497–1500 Crossref | PubMed | Scopus (7067) | Google Scholar See all References However, acquired drug resistances usually emerge. Transformation into small-cell lung carcinoma (SCLC) has been described as one of the mechanisms of acquired resistance in a series of treated mutated lung adenocarcinomas.⁴ x 4 Sequist, LV, Waltman, BA, Dias-Santagata, D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011; 3: 75ra26 Crossref | PubMed | Scopus (1612) | Google Scholar See all References Several other cases of lung adenocarcinoma harboring EGFR mutation, which evolved into metastatic SCLC under TKI, have also been reported.⁵ x 5 Okamoto, I, Araki, J, Suto, R, Shimada, M, Nakagawa, K, and Fukuoka, M. EGFR mutation in gefitinib-responsive small-cell lung cancer. Ann Oncol. 2006; 17: 1028–1029 Crossref | PubMed | Scopus (78) | Google Scholar See all References ^{, 6} x 6 Zakowski, MF, Ladanyi, M, and Kris, MG. Memorial Sloan-Kettering Cancer Center Lung Cancer OncoGenome Group. EGFR mutations in small-cell lung cancers in patients who have never smoked. N Engl J Med. 2006; 355: 213–215 Crossref | PubMed | Scopus (132) | Google Scholar See all References ^{, 7} x 7 Morinaga, R, Okamoto, I, Furuta, K et al. Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation. Lung Cancer. 2007; 58: 411–413 Abstract | Full Text | Full Text PDF | PubMed | Scopus (71) | Google Scholar See all References ^{, 8} x 8 Alam, N, Gustafson, KS, Ladanyi, M et al. Small-cell carcinoma with an epidermal growth factor receptor mutation in a never-smoker with gefitinib-responsive adenocarcinoma of the lung. Clin Lung Cancer. 2010; 11: E1–E4 Abstract | Full Text | Full Text PDF | PubMed | Scopus (40) | Google Scholar See all References ^{, 9} x 9 Popat, S, Wotherspoon, A, Nutting, CM, Gonzalez, D, Nicholson, AG, and O'Brien, M. Transformation to “high grade” neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant lung adenocarcinoma. Lung Cancer. 2013; 80: 1–4 Abstract | Full Text | Full Text PDF | PubMed | Scopus (45) | Google Scholar See all References ^{, 10} x 10 Ma, AT, Chan, WK, Ma, ES, Cheng, T, and Cheng, PN. Small cell lung cancer with an epidermal growth factor receptor mutation in primary gefitinib-resistant adenocarcinoma of the lung. Acta Oncol. 2012; 51: 557–559 Crossref | PubMed | Scopus (8) | Google Scholar See all References ^{, 11} x 11 van Riel, S, Thunnissen, E, Heideman, D, Smit, EF, and Biesma, B. A patient with simultaneously appearing adenocarcinoma and small-cell lung carcinoma harbouring an identical EGFR exon 19 mutation. Ann Oncol. 2012; 23: 3188–3189 Crossref | PubMed | Scopus (16) | Google Scholar See all References In all cases, the same two EGFR mutations were found in both adenocarcinoma and SCLC components: exon 19 deletion⁴ x 4 Sequist, LV, Waltman, BA, Dias-Santagata, D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011; 3: 75ra26 Crossref | PubMed | Scopus (1612) | Google Scholar See all References ^{, 5} x 5 Okamoto, I, Araki, J, Suto, R, Shimada, M, Nakagawa, K, and Fukuoka, M. EGFR mutation in gefitinib-responsive small-cell lung cancer. Ann Oncol. 2006; 17: 1028–1029 Crossref | PubMed | Scopus (78) | Google Scholar See all References ^{, 6} x 6 Zakowski, MF, Ladanyi, M, and Kris, MG. Memorial Sloan-Kettering Cancer Center Lung Cancer OncoGenome Group. EGFR mutations in small-cell lung cancers in patients who have never smoked. N Engl J Med. 2006; 355: 213–215 Crossref | PubMed | Scopus (132) | Google Scholar See all References ^{, 7} x 7 Morinaga, R, Okamoto, I, Furuta, K et al. Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation. Lung Cancer. 2007; 58: 411–413 Abstract | Full Text | Full Text PDF | PubMed | Scopus (71) | Google Scholar See all References ,⁹ x 9 Popat, S, Wotherspoon, A, Nutting, CM, Gonzalez, D, Nicholson, AG, and O'Brien, M. Transformation to “high grade” neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant lung adenocarcinoma. Lung Cancer. 2013; 80: 1–4 Abstract | Full Text | Full Text PDF | PubMed | Scopus (45) | Google Scholar See all References ,¹¹ x 11 van Riel, S, Thunnissen, E, Heideman, D, Smit, EF, and Biesma, B. A patient with simultaneously appearing adenocarcinoma and small-cell lung carcinoma harbouring an identical EGFR exon 19 mutation. Ann Oncol. 2012; 23: 3188–3189 Crossref | PubMed | Scopus (16) | Google Scholar See all References or the mutation L858R in exon 21.⁴ x 4 Sequist, LV, Waltman, BA, Dias-Santagata, D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011; 3: 75ra26 Crossref | PubMed | Scopus (1612) | Google Scholar See all References ,⁸ x 8 Alam, N, Gustafson, KS, Ladanyi, M et al. Small-cell carcinoma with an epidermal growth factor receptor mutation in a never-smoker with gefitinib-responsive adenocarcinoma of the lung. Clin Lung Cancer. 2010; 11: E1–E4 Abstract | Full Text | Full Text PDF | PubMed | Scopus (40) | Google Scholar See all References ,¹⁰ x 10 Ma, AT, Chan, WK, Ma, ES, Cheng, T, and Cheng, PN. Small cell lung cancer with an epidermal growth factor receptor mutation in primary gefitinib-resistant adenocarcinoma of the lung. Acta Oncol. 2012; 51: 557–559 Crossref | PubMed | Scopus (8) | Google Scholar See all References