Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors.

BACKGROUND: The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs). PATIENTS AND METHODS: We established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs. RESULTS: In addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3-TACC3 fusion in EGFR-mutant tumors. CONCLUSIONS: We found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients.

[Ventriculopleural shunt to treat hydrocephalus]. / Tratamiento de la hidrocefalia mediante la derivación ventriculopleural.

INTRODUCTION: Ventriculoatrial and ventriculopleural shunts (VPS) are alternatives to ventriculoperitoneal shunts for draining cerebrospinal fluid from patients with hydrocephalus. VPS has seldom been used because of the risk of respiratory insufficiency due to pneumothorax or pleural effusion. However, valves are currently available with anti-siphon devices for use with standard shunting systems to prevent the development of pleural effusion. The aim of this study was to analyze outcome after VPS in eight patients in whom we used the new valves for avoiding overdrainage of cerebrospinal fluid. MATERIAL AND METHOD: Nine VPS procedures were performed in eight hydrocephalic patients between 1988 and 2000. We used differential pressure valves in eight procedures and a flow regulator valve in one. The externally adjustable Sophy valve was used in six cases. The indication for VPS was peritoneal adhesions in four cases, persistent ascites in two, ventriculoatrial valve obstruction in one, and infection of the peritoneal shunt (peritonitis) in one. The ninth case involved replacement of a previously obstructed valve. RESULTS: After a follow-up period of 22 months all shunts were functioning well and the only patient with symptoms of hydrocephalus was the one who required valve replacement at six months. No surgical morbidity or mortality was observed, and only one patient developed transitory signs of excessive cerebrospinal fluid drainage, which was corrected by regulating the magnetic valve gradient. The death of one patient 36 months after surgery was unrelated to pleural drainage. CONCLUSIONS: Valves newly designed to prevent overdrainage of cerebrospinal fluid give satisfactory results, such that VPS should be considered as an alternative to peritoneal drainage.

Chronic pneumomediastinum and subcutaneous emphysema: association with dermatomyositis.

We describe a 41-year-old patient with adult-onset dermatomyositis who developed persistent pneumomediastinum and severe subcutaneous emphysema due to end-stage interstitial lung disease. The diagnosis of dermatomyositis was based on proximal muscle weakness, electromyographic findings of inflammatory myopathy, and positive findings on muscle biopsy. Low levels of creatine kinase elevation were found at the time of diagnosis (a form of dermatomyositis which has been associated with a poor prognosis). The patient had no signs of cutaneous vasculitis. Despite treatment with prednisone and azathioprine, she died of intercurrent gram-negative sepsis 15 months after the diagnosis of dermatomyositis.