Long response to immune checkpoint inhibitors in metastatic NSCLC despite EGFR germline mutation. A case report.

First-line therapy in advanced non-small-cell-lung-cancer (NSCLC) is based on chemotherapy except for patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab is administrated. However, patients with somatic-EGFR-mutated tumors had usually been excluded from clinical applications of immune checkpoint inhibitors (ICIs). Germline-EGFR-mutated-patients are known to not respond to EGFR-Tyrosine-Kinase-inhibitors (TKIs). But what about germline EGFR mutations and response to ICIs? Herein, we describe the case of a long response to ICIs treatment in a complex metastatic NSCLC with co-occuring EGFR germline and KRAS somatic mutations, high PD-L1 score and a smoking history.

High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC.

Significant rational is available for specific targeting of PI3K/AKT/mTOR pathway in the treatment of non-small cell lung cancer (NSCLC). However, almost all clinical trials that have evaluated Pi3K pathway-based monotherapies/combinations did not observe an improvement of patient's outcome. The aim of our study was therefore to define combination of treatment based on the determination of predictive markers of resistance to the mTORC1 inhibitor RAD001/Everolimus. An in vivo study showed high efficacy of RAD001 in NSCLC Patient-Derived Xenografts (PDXs). When looking at biomarkers of resistance by RT-PCR study, three genes were found to be highly expressed in resistant tumors, i.e., PLK1, CXCR4, and AXL. We have then focused our study on the combination of RAD001 + Volasertib, a PLK1 inhibitor, and observed a high antitumor activity of the combination in comparison to each monotherapy; similarly, a clear synergistic effect between the two compounds was found in an in vitro study. Pharmacodynamics study demonstrated that this synergy was due to (1) tumor vascularization decrease, increase of the HIF1 protein expression and decrease of the intracellular pH, and (2) decrease of the Carbonic Anhydrase 9 (CAIX) protein that could not correct intracellular acidosis. In conclusion, all these preclinical data strongly suggest that the inhibition of mTORC1 and PLK1 proteins may be a promising therapeutic approach for NSCLC patients.

Durable responses to immunotherapy of non-small cell lung cancers harboring MET exon-14-skipping mutation: A series of 6 cases.

INTRODUCTION: About 2-3% of non-small-cell lung cancers (NSCLCs) harbor MET exon-14-skipping (METex14) mutations. Efficacy of the MET-inhibitor crizotinib has been reported, but progression-free survival (PFS) was very short. Immune-checkpoint inhibitors (ICIs) have become a cornerstone of NSCLC treatment but appear to be less effective in non-smokers and against tumors exhibiting oncogenic addiction. We describe 6 remarkable (PFS exceeding 18 months) and durable responses to ICIs of NSCLCs harboring a METex14 mutation. METHODS: Each patient's clinical and biological characteristics, and tumor responses after ICIs were examined. Complete tumor-DNA sequencing was available after starting second-line ICIs, which followed first-line chemotherapy. Tumor-cell programmed cell-death protein-1 ligand-1 (PD-L1) expression on tumor cells was evaluated using antibody clone E1L3N (Cell Signaling Technology). RESULTS: Among 25 patients with METex14-mutated NSCLCs, 13 of whom were ICI-treated, 6 had prolonged responses: 5 women, 1 man; 57-80 years old; 3 never-smokers, 1 ex-smoker and 2 smokers; 5 adenocarcinomas, 1 sarcomatoid carcinoma; 5 received nivolumab, 1 pembrolizumab. No EGFR, BRAF or KRAS mutations (only 1 minority KRAS mutation), or ALK or ROS translocations were detected. No concurrent MET amplification was observed. Tumor-mutation burden was low (<10 mutations/Mb) in 3 tested tumors. Four partial and 2 complete responses were obtained during the first 3 months for 5 patients, while pseudoprogression was initially observed in 1. Tolerance was excellent, with only 1 grade-3 immune-related adverse event. Response was maintained for 18-49 months. CONCLUSION: ICIs could be considered to treat patients whose NSCLCs harbor a METex14 mutation. More biological marker data are needed to identify which patients are most likely to benefit from ICIs.

[A peculiar intra-uterine lesion: Inflammatory myofibroblastic tumor (IMT)]. / Une lésion intra-utérine atypique : tumeur myofibroblastique inflammatoire (TMI).

A 25-year-old woman presented with a spontaneous vaginal expulsion of a 4cm well-circumscribed nodule a few weeks after delivery. An inflammatory myofibroblastic tumor diagnosis was made by morphologic, immunohistochemistry and FISH analysis of the nodule.

Lung cancer in renal transplant recipients: A case-control study.

INTRODUCTION: Solid organ transplant patients are at heightened risk of several cancers compared to the general population. Secondary to a higher number of procedures and better survival after transplantation, cancer is a rising health concern in this situation. Limited data exist for lung cancer (LC) after renal transplantation. We report here the most important series of renal transplant recipients with lung cancer. METHODS: Retrospective study of all cases of LC diagnosed in three French Renal Transplant Units from 2003 to 2012. A control group consisted of non-transplant patients with LC matched with the cases for age (<30; 30-50; 50-65; >65 years), gender and diagnosis date. We recruited two controls for each case. RESULTS: Thirty patients (median age 60 years; range 29-85; male/female ratio 80/20%) with LC were analysed. LC incidence was 1.89/1000 person-years over the period 2008-2012. All patients were former or active smokers (median 30 pack-years). Transplanted patients had significantly more comorbidities, mainly cardiovascular disease. The median interval of time from kidney transplantation (KT) to diagnosis of LC was 7 years (range 0.5-47 years). LC was incidentally diagnosed in 40%. Most patients (70%) had advanced LC (stage III or IV) disease. Stage of LC at diagnosis was similar in cases and controls. Surgery and chemotherapy were proposed to the same proportion of patients. In cases, mortality was cancer related in 87% and median survival time after diagnosis was 24 months. Survival was not significantly different between the 2 groups. CONCLUSION: Despite frequent medical and radiological examinations, diagnosis of LC is usually made at an advanced stage and the overall prognosis remains poor.

[A hybrid lesion: Low-grade fibromyxoid sarcoma (LGFMS) and sclerosing epithelioid fibrosarcoma (SEF)]. / Une lésion hybride : sarcome fibromyxoïde de bas grade (SFBG) et fibrosarcome épithélioïde sclérosant (FES).

We report the case of a 34-year-old woman presenting a 10cm axillary mass diagnosed as hybrid tumor low-grade fibromyxoid sarcoma/sclerosing epithelioid fibrosarcoma. Microbiopsy for morphological and immunohistochemical analyses was associated with molecular analysis (FISH and PCR) to confirm the diagnosis.

Giant basal cell carcinoma with regional lymph node and distant lung metastasis.

The prevalence of metastatic basal cell carcinoma (MBCC) varies between 0.0028% and 0.55% of all cases. In total, more than 300 MBCC have been reported in the literature. We report the case of a 72 year old lady, who presented in September 2009 with a 10-year history of a progressively growing, giant, facial basal cell carcinoma (BCC). Clinical and imaging evaluations identified large local invasion with bone and meningeal involvement. Treatment consisted of an extensive surgery including left eye exenteration and meningeal resection followed by radiotherapy. A solitary lung metastasis was identified five months after the primary tumor resection. As the lesion remained solitary but had increased in size five months later, the patient finally accepted a surgical resection. A right upper-lobe pneumonectomy was performed and pathologic examination confirmed the metastasis as a MBCC.

[Myocardial involvement in invasive aspergillosis]. / Myocardite aspergillaire.

We report the case of a 48-year-old female patient who had a Crohn's disease treated by corticosteroids. The patient developed severe cardiac failure, which was refractory to treatment with inotropic agents. At necropsy, examination of the heart revealed myocardial abscesses. On microscopic study, we diagnosed an aspergillar myocarditis. Aspergillar myocarditis is a rare and fatal localisation in disseminated aspergillosis. Diagnosis is difficult and treatment, usually initiated late, is ineffective.

Small-cell lung carcinoma of recipient origin after bilateral lung transplantation for cystic fibrosis.

Bronchial carcinoma, usually of the non-small-cell type, is uncommon after lung transplantation and occurs predominantly in single-lung transplant ex-smoker recipients on their native lung. Bronchial carcinoma of donor origin is much rarer. We report the case of a small-cell lung carcinoma of recipient origin that occurred 12 months after a bilateral lung transplantation for cystic fibrosis in a 25-year-old woman who was a non-smoker. The tumor was of recipient origin, due to a gender mismatch between donor and recipient. This unusual observation corroborates the hypothesis of chimerism of the bronchial epithelium after lung transplantation.

Endocardial location of familial myofibromatosis revealed by cerebral embolization: cardiac counterpart of the frequent intravascular growth of the disease?

Myofibromatosis is a rare infantile benign neoplasia, which may involve the heart in the rare and usually fatal generalized form of the disease. Diagnosis of endocardial myofibromas was made on two surgically excised lesions of the mitral valve that were reveled by a cerebral embolization in a 12-month-old female infant. Surprisingly, the patient had no other obvious lesion of myofibromatosis. However, her father had a histologically proven neonatal history of myofibromatosis. This case confirms the likely autosomal dominant mode of inheritance of myofibromatosis. It highlights the embolization risk of the previously unreported endocardial location. We suggest that these clinically isolated non-invasive endocardial myofibromas did not represent a true visceral form of myofibromatosis. They were, rather, similar to the frequent intravascular growth of the disease.

[Thymoma with epithelial micronodules and lymphoid hyperplasia: six cases of a rare and equivocal subtype]. / Thymome avec micronodules épithéliaux et hyperplasie lymphoïde: à propos de six cas d'un sous-type rare équivoque

Thymomas with the characteristic pattern of small epithelial nodules separated by an abundant lymphoid tissue have been recently described with divergent interpretations. These thymomas are not specified in currently used classification systems. We present six such thymomas, including three that represented 1.38% of a series of 217 consecutive cases. These thymomas were totally encapsulated (Masaoka stage I, n=1) or minimally invasive (stage II, n=5). The epithelial cells of the nodules were oval and bland-appearing. In one case, these cells formed rosettes. Cysts, that were present in four cases, showed a strong linear expression of EMA and were associated with foci of glandular differentiation. The lymphoid tissue was composed of large immature (CD1a and CD99-positive) T-cell areas (with epithelial cells restricted to small foci of residual thymus) and of B-cell (CD20-positive) areas with germinal centers. Mature T-cells were also present. Furthermore, one case, associated with myasthenia gravis, had an important WHO type B2 (cortical) component. Such a combined case has not been previously reported. Our study demonstrates that so-called micronodular thymomas are rare, usually have clinical and pathological features of WHO type A (medullary) thymomas, and that the lymphoid component is hyperplastic corresponding to both immature T-cell lymphoid tissue and B-cell lymphoid hyperplasia with germinal centers.