Aortic aneurysms with tricuspid aortic valve have more degeneration than unicuspid aortic valve aneurysms.

OBJECTIVES: The unicuspid aortic valve (UAV) is a rare cardiac malformation and is associated with the formation of ascending aortic aneurysms. To characterize its associated aortic wall changes, normal and aneurysmatic ascending aortic wall specimens were analysed, focusing on the potential mechanisms of aneurysm formation. Patients with tricuspid aortic valve (TAV) served as controls. METHODS: In a retrospective observational study, 74 specimens (dilated and non-dilated aortas; individuals with UAV and TAV) obtained intraoperatively were studied. Standard stains and immunohistochemical labelling of cleaved caspase-3, cluster of differentiation 31 and endothelial nitric oxide synthase (eNOS) were performed to assess the degree of apoptosis, distribution of eNOS within the aortic wall, smooth muscle cell (SMC) nuclei loss and mucoid extracellular matrix accumulation (MEMA). RESULTS: Deeper ingrowth of vasa vasorum was found in dilated aortas. Interestingly, eNOS was expressed mostly in vasa vasorum. More apoptosis was seen in UAV aortas compared to TAV aortas (P < 0.001). Both UAV and TAV aortas were comparable regarding SMC nuclei loss (P = 0.419). In dilated compared to non-dilated aortas regardless valve morphology SMC nuclei loss was increased (P = 0.005) and more pronounced translamellar MEMA was present (P = 0.011). The highest grade of distribution (P = 0.043) and the highest severity (P = 0.005) regarding MEMA were seen in TAV dilated specimens compared to UAV dilated specimens. CONCLUSIONS: Aneurysms with UAV show increased apoptosis, the role of which is unclear. Strikingly, more severe MEMA was found in TAV aneurysms compared to UAV aneurysms. Thus, UAV-associated aortic wall changes and resulting aneurysm may be less aggressive than aneurysms with TAV.

Human(ized) monoclonal antibodies in atopic patients - state of the art.

Asthma is an important chronic disease affecting a lot of people worldwide. Treatment options for asthma like biological agents are being developed more frequently nowadays. Despite a lot of treatment options, some patients still remain symptomatic. As more and more practitioners choose treatment with biologic agents as a convenient way of therapy, biologic agents and other valuable methods must be discovered in order to cope with a growing number of treatment agents. This manuscript emphasizes on new generation monoclonal human(ized) antibodies in asthmatics and off-label use . The first developed biologic agent is the anti-immunoglobulin E monoclonal antibody called omalizumab. Currently it is an approved treatment option for asthma.

Lung cancer mortality reduction by LDCT screening-Results from the randomized German LUSI trial.

In 2011, the U.S. National Lung Cancer Screening Trial (NLST) reported a 20% reduction of lung cancer mortality after regular screening by low-dose computed tomography (LDCT), as compared to X-ray screening. The introduction of lung cancer screening programs in Europe awaits confirmation of these first findings from European trials that started in parallel with the NLST. The German Lung cancer Screening Intervention (LUSI) is a randomized trial among 4,052 long-term smokers, 50-69 years of age, recruited from the general population, comparing five annual rounds of LDCT screening (screening arm; n = 2,029 participants) with a control arm (n = 2,023) followed by annual postal questionnaire inquiries. Data on lung cancer incidence and mortality and vital status were collected from hospitals or office-based physicians, cancer registries, population registers and health offices. Over an average observation time of 8.8 years after randomization, the hazard ratio for lung cancer mortality was 0.74 (95% CI: 0.46-1.19; p = 0.21) among men and women combined. Modeling by sex, however showed a statistically significant reduction in lung cancer mortality among women (HR = 0.31 [95% CI: 0.10-0.96], p = 0.04), but not among men (HR = 0.94 [95% CI: 0.54-1.61], p = 0.81) screened by LDCT (pheterogeneity = 0.09). Findings from LUSI are in line with those from other trials, including NLST, that suggest a stronger reduction of lung cancer mortality after LDCT screening among women as compared to men. This heterogeneity could be the result of different relative counts of lung tumor subtypes occurring in men and women.

The vasa vasorum reach deep into the human thoracic aorta.

Only limited data are available on the extent of the vasa vasorum of the human thoracic aorta, although this could be important with regard to certain pathophysiological states, i.e. aortic aneurysm or atherosclerosis. A preliminary investigation shows that the vascularization of the human thoracic aorta reaches deeper layers than generally believed.

Impact of EMT in stage IIIB/IV NSCLC treated with erlotinib and bevacizumab when compared with cisplatin, gemcitabine and bevacizumab.

The aim of the present study was to assess the expression of epithelial-mesenchymal transition biomarkers (E-cadherin and vimentin) and their potential significance as prognostic markers in patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC) enrolled in the INNOVATIONS trial, receiving treatment with either erlotinib/bevacizumab (EB) or cisplatin/gemcitabine/bevacizumab (PGB). The tumor tissues of 104 patients were retrospectively analyzed using immunohistochemistry to assess the expression of E-cadherin and vimentin. The distribution between the treatment arms was 46 patients in the EB-arm and 58 in the PGB-arm. Comparing the treatment arms according to E-cadherin and vimentin expression, the analysis revealed that progression-free survival (PFS) was increased in the PGB treatment group when compared with EB treatment in patients with low expression of E-cadherin [hazard ratio (HR)=0.353; 95% confidence interval (CI) 0.189- 0.658; log-rank P=0.0007] and in those with high expression of vimentin [HR=0.276 (95% CI, 0.115- 0.659), log-rank P=0.0021]. In patients that exhibited high E-cadherin and were negative for vimentin, there was no difference in the PFS between the PGB and EB treatment groups. In conclusion, in non-squamous NSCLC with downregulated E-cadherin and upregulated vimentin, the efficacy of chemotherapy with PGB was superior compared with EB; but the same effect was not observed in patients with high E-cadherin and low vimentin. Although increased PFS was observed in patients with PGB treatment compared with EB treatment in the whole analysis populations, in the subgroup of patients with the mesenchymal phenotype, no prognostic or predictive value of either biomarker could be identified. The potential role of bevacizumab in overcoming chemotherapy resistance in the population with the mesenchymal phenotype has to be further explored.

Targeting LINC00673 expression triggers cellular senescence in lung cancer.

Aberrant expression of noncoding RNAs plays a critical role during tumorigenesis. To uncover novel functions of long non-coding RNA (lncRNA) in lung adenocarcinoma, we used a microarray-based screen identifying LINC00673 with elevated expression in matched tumor versus normal tissue. We report that loss of LINC00673 is sufficient to trigger cellular senescence, a tumor suppressive mechanism associated with permanent cell cycle arrest, both in lung cancer and normal cells in a p53-dependent manner. LINC00673-depleted cells fail to efficiently transit from G1- to S-phase. Using a quantitative proteomics approach, we confirm the modulation of senescence-associated genes as a result of LINC00673 knockdown. In addition, we uncover that depletion of p53 in normal and tumor cells is sufficient to overcome LINC00673-mediated cell cycle arrest and cellular senescence. Furthermore, we report that overexpression of LINC00673 reduces p53 translation and contributes to the bypass of Ras-induced senescence. In summary, our findings highlight LINC00673 as a crucial regulator of proliferation and cellular senescence in lung cancer.

Molecular signatures in IASLC/ATS/ERS classified growth patterns of lung adenocarcinoma.

BACKGROUND: The current classification of human lung adenocarcinoma defines five different histological growth patterns within the group of conventional invasive adenocarcinomas. The five growth patterns are characterised by their typical architecture, but also by variable tumor biological behaviour. AIMS: The aim of this study was to identify specific gene signatures of the five adenocarcinoma growth patterns defined by the joint IASLC/ATS/ERS working group. METHODS: Total RNA from microdissected adenocarcinoma tissue samples of ten lepidic, ten acinar, ten solid, nine papillary, and nine micropapillary tumor portions was isolated and prepared for gene expression analysis. Differential expression of genes was determined using the R package "LIMMA". The overall significance of each signature was assessed via global test. Gene ontology statistics were analysed using GOstat. For immunohistochemical validation, tissue specimens from 20 tumors with solid and 20 tumors with lepidic growth pattern were used. RESULTS: Microarray analyses between the growth patterns resulted in numerous differentially expressed genes between the solid architecture and other patterns. The comparison of transcriptomic activity in the solid and lepidic patterns revealed 705 up- and 110 downregulated non-redundant genes. The pattern-specific protein expression of Inositol-1,4,5-trisphosphate-kinase-A (ITPKA) and angiogenin by immunohistochemistry confirmed the RNA levels. The strongest differences in protein expression between the two patterns were shown for ITPKA (p = 0.02) and angiogenin (p = 0.113). CONCLUSIONS: In this study growth pattern-specific gene signatures in pulmonary adenocarcinoma were identified and distinct transcriptomic differences between lung adenocarcinoma growth patterns were defined. The study provides valuable new information about pulmonary adenocarcinoma and allows a better assessment of the five adenocarcinoma subgroups.

ERCC1 assessment in upfront treatment with and without cisplatin-based chemotherapy in stage IIIB/IV non-squamous non-small cell lung cancer.

Prior studies have demonstrated an association between excision repair cross-complementation group 1 (ERCC1) expression level and outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy. The aim of this study was to assess the impact of ERCC1 on survival for patients with stage IIIB/IV non-squamous NSCLC (NS-NSCLC) enrolled in the INNOVATIONS trial, thus receiving as treatment either erlotinib/bevacizumab (EB) or cisplatin/gemcitabine/bevacizumab (PGB). We retrospectively analyzed tumor tissue of 72 patients using immunohistochemistry to assess the expression of ERCC1. The distribution between treatment arms was equal (36 patients each). Two different H scores were calculated and correlated with survival. In ERCC1-positive patients, no significant difference in terms of progression-free survival (PFS) between treatment arms has been detected. ERCC1-negative patients benefited from PGB compared to EB arm (H score: HR = 0.377, 95% CI [0.167-0.849], p = 0.0151; modified H score: HR = 0.484, 95% CI [0.234-1.004], p = 0.0468). With respect to the scoring system, in the EB-arm, a significant superior PFS turned out in ERCC1-positive patients when employing the H-score (HR = 0.430, 95% CI [0.188-0.981], p = 0.0397; median 4.9 vs. 3.9 months), but not with the modified H-score. Our findings support the hypothesis that NS-NSCLC displaying a low ERCC1 expression might benefit from cisplatin-based chemotherapy. High expression indicated better PFS in the EB arm supporting the prognostic impact. However, as impact of ERCC1-assessment even might depend on scoring systems differences, the need in standardization of assessment methodology is emphasized.

Large cell neuroendocrine lung carcinoma induces peripheral T-cell repertoire alterations with predictive and prognostic significance.

OBJECTIVES: This study was performed to evaluate for a potentially important role of T cells in the pathophysiology and treatment sensitivity of large cell neuroendocrine lung carcinoma (LCNEC), an orphan disease with poor prognosis and scarce data to guide novel therapeutic strategies. MATERIALS AND METHODS: We performed T-cell receptor (TCR) ß-chain spectratyping on blood samples of patients treated within the CRAD001KDE37 trial (n = 35) using age-matched current or former (n = 11) and never smokers (n = 10) as controls. The data were analyzed in conjunction with the complete blood counts of the probands as well as the data about response to treatment and overall survival in the clinical trial. RESULTS AND CONCLUSION: Untreated stage IV LCNEC patients had significant T-cell repertoire alterations (p < 0.001) compared to age-matched smokers. These changes correlated positively with blood lymphocyte counts (r = 0.49, p < 0.01), suggesting antigen-induced T-cell proliferation as the causative mechanism. At the same time, LCNEC patients showed mild lymphopenia (1.54 vs. 2.51/nl in median, p < 0.01), which reveals a second, antigen-independent mechanism of systemic immune dysregulation. More pronounced T-cell repertoire alterations and higher blood lymphocyte counts at diagnosis were associated with a better treatment response by RECIST and with a longer overall survival (441 vs. 157 days in median, p = 0.019). A higher degree of T-cell repertoire normalization after 3 months of therapy also distinguished a patient group with more favourable prognosis (median overall survival 617 vs. 316 days, p = 0.036) independent of radiological response. Thus, LCNEC induces clinically relevant changes of the T-cell repertoire, which are measurable in the blood and could be exploited for prognostic, predictive and therapeutic purposes. Their pathogenesis appears to involve antigen-induced oligoclonal T-cell expansions superimposed on TCR-independent lymphopenia.

Confocal microscopy as an early relapse marker for acanthamoeba keratitis.

Acanthameoba keratitis is a serious ophthalmological condition with a potentially vision-threatening prognosis. Early diagnosis and recognition of relapse, and the detection of persistent Acanthamoeba cysts, are essential for informing the prognosis and managing the condition. We suggest the use of in vivo confocal microscopy not only to identify the early signs of relapse after keratoplasty in patients with Acanthamoeba keratitis, but also as an additional follow-up tool after antimicrobial crosslinking. This study shows that in vivo confocal microscopy is, in experienced hands, a quick and reliable diagnostic tool. Clin. Anat. 31:60-63, 2018. © 2017 Wiley Periodicals, Inc.

CT characteristics in pulmonary adenocarcinoma with epidermal growth factor receptor mutation.

Comprehensively investigate the association of CT morphology and clinical findings of adenocarcinoma with EGFR mutation status. Retrospectively included 282 patients who was pathologically proved as lung adenocarcinoma with known EGFR mutation status (mutations: 138 patients, female: 86, median age: 66 years; wildtype: 144 patients, female: 67, median age: 62 years) and their pre-treatment CT scans were analyzed. CT findings and clinical information were collected. Univariate and multivariable logistic regression analysis were performed. Adjusted for age, gender and smoking history of two groups, significantly more patients with pleural tags, pleural and liver metastases were found in the EGFR mutated group (P = 0.007, 0.004, and 0.043, respectively). Multivariable logistic regression analysis found that the model included age, gender, smoking history, air bronchogram, pleural tags, pleural and liver metastasis had a moderate predictive value for EGFR mutation status (AUC = 0.741, P < .0001). Exon-19 deletion was associated with air bronchogram which adjusted for age, gender and smoking history (P = 0.007, OR: 2.91, 95%CI: 1.25-7.79). The evidence of pleural tags, pleural and liver metastases go along with a higher probability of EGFR mutation in adenocarcinoma patients and air bronchogram is positively associated with Exon-19 deletion mutation.

Nontypeable Haemophilus influenzae-Promoted Proliferation of Kras-Induced Early Adenomatous Lesions Is Completely Dependent on Toll-Like Receptor Signaling.

Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. COPD is characterized by chronic airway inflammation and lung infections. The airways of patients with COPD are frequently colonized with bacteria [eg, nontypeable Haemophilus influenzae (NTHi)] that cause pulmonary inflammation and exacerbations. Pulmonary adenocarcinomas are frequently associated with an activating mutation in the KRAS gene. We determined the function of Toll-like receptor (TLR) signaling on the progression of Kras-induced early adenomatous lesions in the lung. Wild-type (WT) mice and mice doubly deficient in Tlr-2 and -4 (Tlr2/4-/-), both with an oncogenic Kras allele in lung epithelium, were exposed to NTHi for 4 weeks. Exposure to NTHi resulted in increased tumor proliferation and growth in WT mice, but not in Tlr2/4-/- mice. Alveolar adenomatous hyperplasia and adenocarcinoma were significantly increased in WT mice compared with Tlr2/4-/- mice. The average size of tumors was significantly larger in WT mice, whereas there was no difference in the number of alveolar lesions between WT and Tlr2/4-/- mice. NTHi-induced pulmonary neutrophilic inflammation and tumor-associated neutrophils were reduced in Tlr2/4-/- mice. Thus, subsequent to a driver mutation, NTHi-induced inflammation promotes proliferation of early adenomatous lesions in a TLR-dependent manner.

Genomics, microRNA, epigenetics, and proteomics for future diagnosis, treatment and monitoring response in upper GI cancers.

One major objective for our evolving understanding in the treatment of cancers will be to address how a combination of diagnosis and treatment strategies can be used to integrate patient and tumor variables with an outcome-oriented approach. Such an approach, in a multimodal therapy setting, could identify those patients (1) who should undergo a defined treatment (personalized therapy) (2) in whom modifications of the multimodal therapy due to observed responses might lead to an improvement of the response and/or prognosis (individualized therapy), (3) who might not benefit from a particular toxic treatment regimen, and (4) who could be identified early on and thereby be spared the morbidity associated with such treatments. These strategies could lead in the direction of precision medicine and there is hope of integrating translational molecular data to improve cancer classifications. In order to achieve these goals, it is necessary to understand the key issues in different aspects of biotechnology to anticipate future directions of personalized and individualized diagnosis and multimodal treatment strategies. Providing an overview of translational data in cancers proved to be a challenge as different methods and techniques used to obtain molecular data are used and studies are based on different tumor entities with different tumor biology and prognoses as well as vastly different therapeutic approaches. The pros and cons of the available methodologies and the potential response data in genomics, microRNA, epigenetics and proteomics with a focus on upper gastrointestinal cancers are considered herein to allow for an understanding of where these technologies stand with respect to cancer diagnosis, prognosis and treatment.

Myocardial Perfusion Reserve and Strain-Encoded CMR for Evaluation of Cardiac Allograft Microvasculopathy.

OBJECTIVES: This study sought to evaluate myocardial perfusion reserve index (MPRI) and diastolic strain rate, both assessed by cardiac magnetic resonance (CMR) as a noninvasive tool for the detection of microvasculopathy. BACKGROUND: Long-term survival of cardiac allograft recipients is limited primarily by cancer and cardiac allograft vasculopathy (CAV). Besides epicardial CAV, diagnosed by coronary angiography, stenotic microvasculopathy was found to be an additional independent risk factor for survival after heart transplantation. METHODS: Sixty-three consecutive heart transplant recipients who underwent CMR, coronary angiography, and myocardial biopsy were enrolled. Stenotic vasculopathy in microvessels was considered in myocardial biopsies by immunohistochemistry and CAV was graded during coronary angiography according to International Society of Heart and Lung Transplantation criteria. In addition, by CMR microvasculopathy was assessed by myocardial perfusion reserve during pharmacologic hyperemia with adenosine and strain-encoded magnetic resonance using a modified spatial modulation of magnetization tagging pulse sequence in all patients. RESULTS: Decreasing MPRI and diastolic strain rates were observed in patients with decreasing microvessel luminal radius to wall thickness ratio and decreasing capillary density (r = 0.45 and r = 0.61 for MPRI and r = 0.50 and r = 0.38 for diastolic strain rate, respectively; p < 0.005 for all). Using multivariable analysis, both MPRI and diastolic strain rate were robust predictors of stenotic microvasculopathy, independent of age, organ age, and CAV by International Society of Heart and Lung Transplantation criteria (hazard ratio: 0.07, p = 0.006 for MPRI; hazard ratio: 0.91, p = 0.002 for diastolic strain rate). Patients without stenotic microvasculopathy in the presence of no or mild CAV (n = 36) exhibited significantly higher median survival free of events, compared with patients with stenotic microvasculopathy in the presence of no or mild CAV (n = 18; p = 0.04 by log rank). CONCLUSIONS: CMR represents a valuable noninvasive diagnostic tool, which may be used for the early detection of transplant microvasculopathy before the manifestation of CAV during surveillance coronary angiographic procedures.

Phospholipid profiling identifies acyl chain elongation as a ubiquitous trait and potential target for the treatment of lung squamous cell carcinoma.

Lung cancer is the leading cause of cancer death. Beyond first line treatment, few therapeutic options are available, particularly for squamous cell carcinoma (SCC). Here, we have explored the phospholipidomes of 30 human SCCs and found that they almost invariably (in 96.7% of cases) contain phospholipids with longer acyl chains compared to matched normal tissues. This trait was confirmed using in situ 2D-imaging MS on tissue sections and by phospholipidomics of tumor and normal lung tissue of the L-IkkαKA/KA mouse model of lung SCC. In both human and mouse, the increase in acyl chain length in cancer tissue was accompanied by significant changes in the expression of acyl chain elongases (ELOVLs). Functional screening of differentially expressed ELOVLs by selective gene knockdown in SCC cell lines followed by phospholipidomics revealed ELOVL6 as the main elongation enzyme responsible for acyl chain elongation in cancer cells. Interestingly, inhibition of ELOVL6 drastically reduced colony formation of multiple SCC cell lines in vitro and significantly attenuated their growth as xenografts in vivo in mouse models. These findings identify acyl chain elongation as one of the most common traits of lung SCC discovered so far and pinpoint ELOVL6 as a novel potential target for cancer intervention.

Cisplatin and carboplatin-based chemotherapy in the first-line treatment of non-small cell lung cancer: Analysis from the European FRAME study.

OBJECTIVES: To explore patient and disease factors, and reasons behind the physician's choice of platinum backbone for the first-line treatment of non-small cell lung cancer (NSCLC), as observed in a European prospective observational study of patients receiving platinum-based chemotherapy as first-line treatment for advanced or metastatic NSCLC (the FRAME study). Additionally, overall survival (OS) for patients who received cisplatin or carboplatin was evaluated. MATERIALS AND METHODS: A post-hoc analysis of the prospective study population was conducted. Baseline characteristics of patients receiving cisplatin versus carboplatin were compared and summarized by propensity score. Survival for matched patients was summarized using the Kaplan-Meier approach. RESULTS: Of the 1564 patients who were included in the prospective study, 1520 received either cisplatin (54%) or carboplatin (46%) in combination with pemetrexed, gemcitabine, taxanes or vinorelbine. Patients treated with carboplatin were older than patients receiving cisplatin (mean age 67 versus 61 years; p<0.001), had poorer performance status (p<0.001), and more comorbidities (p<0.001). Cisplatin was most frequently combined with pemetrexed (47%), and carboplatin most frequently with taxanes (31%). Unadjusted median OS estimates for patients from the total prospective study sample were 11.5 months (95% confidence interval [CI] 10.1-12.9) for cisplatin recipients and 9.0 months (95% CI 8.1-10.6) for carboplatin recipients. Median (95% CI) overall survival for the matched cohorts was 10.8 months (8.8-14.3) for cisplatin versus 9.5 months (8.2-11.3) for carboplatin; p=0.086. CONCLUSION: This post-hoc analysis illustrated real-life differences in patients with NSCLC prescribed platinum-based first-line treatment, and suggested that baseline patient and disease characteristics were associated with physician's choice of platinum agent, with cisplatin being more frequently prescribed to younger and fitter patients.

Outcome and prognostic factors of postoperative radiation therapy (PORT) after incomplete resection of non-small cell lung cancer (NSCLC).

PURPOSE: Current guidelines recommend postoperative radiation therapy (PORT) for incompletely resected non-small cell lung cancer (NSCLC). However, there is still a paucity of evidence for this approach. Hence, we analyzed survival in 78 patients following radiotherapy for incompletely resected NSCLC (R1) and investigated prognostic factors. PATIENTS AND METHODS: All 78 patients with incompletely resected NSCLC (R1) received PORT between December 2001 and September 2014. The median total dose for PORT was 60 Gy (range 44-68 Gy). The majority of patients had locally advanced tumor stages (stage IIA (2.6%), stage IIB (19.2%), stage IIIA (57.7%) and stage IIIB (20.5%)). 21 patients (25%) received postoperative chemotherapy. RESULTS: Median follow-up after radiotherapy was 17.7 months. Three-year overall (OS), progression-free (PFS), local (LPFS) and distant progression-free survival (DPFS) rates were 34.1, 29.1, 44.9 and 51.9%, respectively. OS was significantly prolonged at lower nodal status (pN0/1) and following dose-escalated PORT with total radiation doses >54 Gy (p=0.012, p=0.013). Furthermore, radiation doses >54 Gy significantly improved PFS, LPFS and DPFS (p=0.005; p=0.050, p=0.022). Interestingly, survival was neither significantly influenced by R1 localization nor by extent (localized vs. diffuse). Multivariate analyses revealed lower nodal status and radiation doses >54.0 Gy as the only independent prognostic factors for OS (p=0.021, p=0.036). CONCLUSION: For incompletely resected NSCLC, PORT is used for improving local tumor control. Local progression is still the major pattern of failure. Radiation doses >54 Gy seem to support improved local control and were associated with better OS in this retrospective study.

Thoracic oncology HERMES: European curriculum recommendations for training in thoracic oncology.

Thoracic oncology HERMES: European curriculum recommendations for training in thoracic oncology http://ow.ly/mdqT300NHqO.

Comprehensive genomic profiles of small cell lung cancer.

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.