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.

The objective of the present study was to evaluate whether integrated ¹⁸F-FDG-PET/MRI can improve the diagnostic workup in patients with cardiac masses. Methods: Twenty patients were prospectively assessed using integrated cardiac ¹⁸F-FDG-PET/MRI: 16 patients with cardiac masses of unknown identity and four patients with cardiac sarcoma after surgical therapy. All scans were performed on an integrated 3-T PET/MR device (mMR Biograph, Siemens Healthcare, Erlangen, Germany). The MR protocol consisted of HASTE, cine and T2-weighted images as well as T1-weighted images before and after injection of gadobutrol. PET data acquisition was performed simultaneously to the MR scan after injection of 199±58 MBq ¹⁸F-FDG. Patients were prepared with a high-fat, low-carbohydrate diet in a period of 24 hours before the examination and 50 IU/kg of unfractionated heparin were administered intravenously 15 minutes prior the ¹⁸F-FDG injection. Results: Cardiac masses were diagnosed as follows: 3 x metastases, 1 x direct tumor infiltration via pulmonary vein, 2 x local relapse of primary sarcoma after surgery, 1 Burkitt’s lymphoma, 2 x scar/patch tissue after surgery of primary sarcoma, 4 x myxoma, 1 x fibroelastoma, 3 x caseous calcification of mitral annulus (CCMA), 3 x thrombus. SUV_max in malignant lesions was significantly higher than in non-malignant cases (13.2±6.2 vs. 2.3±1.2, P = 0.0004). Using a threshold of ≥ 5.2, SUV_max was found to yield 100% sensitivity and 92% specificity for the differentiation between malignant and non-malignant cases. T2-weighted hyperintensity and contrast-enhancement both yielded 100% sensitivity, but a weak specificity of 54% and 46%, respectively. Morphologic tumor features as assessed by cine MRI yielded 86% sensitivity and 92% specificity. Consent reading using all available MR features yielded 100% sensitivity and 92% specificity. A Boolean ‘AND’ combination of SUV_max ≥ 5.2 with consent MRI reading improved sensitivity and specificity to 100%. Conclusion: In selected patients, ¹⁸F-FDG-PET/MRI can improve the noninvasive diagnosis and follow-up of cardiac masses.

Therapeutic decisions in non-small cell lung cancer (NSCLC) patients depend on the tumor stage. PET/CT with (18)F-FDG is widely accepted as the diagnostic standard of care. The purpose of this study was to compare a dedicated pulmonary (18)F-FDG PET/MR imaging protocol with (18)F-FDG PET/CT for primary and locoregional lymph node staging in NSCLC patients using histopathology as the reference. Twenty-two patients (12 men, 10 women; mean age ± SD, 65.1 ± 9.1 y) with histopathologically confirmed NSCLC underwent (18)F-FDG PET/CT, followed by (18)F-FDG PET/MR imaging, including a dedicated pulmonary MR imaging protocol. T and N staging according to the seventh edition of the American Joint Committee on Cancer staging manual was performed by 2 readers in separate sessions for (18)F-FDG PET/CT and PET/MR imaging, respectively. Results from histopathology were used as the standard of reference. The mean and maximum standardized uptake value (SUV(mean) and SUV(max), respectively) and maximum diameter of the primary tumor was measured and compared in (18)F-FDG PET/CT and PET/MR imaging. PET/MR imaging and (18)F-FDG PET/CT agreed on T stages in 16 of 16 of patients (100%). All patients were correctly staged by (18)F-FDG PET/CT and PET/MR (100%), compared with histopathology. There was no statistically significant difference between (18)F-FDG PET/CT and (18)F-FDG PET/MR imaging for lymph node metastases detection (P = 0.48). For definition of thoracic N stages, PET/MR imaging and (18)F-FDG PET/CT were concordant in 20 of 22 patients (91%). PET/MR imaging determined the N stage correctly in 20 of 22 patients (91%). (18)F-FDG PET/CT determined the N stage correctly in 18 of 22 patients (82%). The mean differences for SUV(mean) and SUV(max) of NSCLC in (18)F-FDG PET/MR imaging and (18)F-FDG PET/CT were 0.21 and -5.06. These differences were not statistically significant (P > 0.05). The SUV(mean) and SUV(max) measurements derived from (18)F-FDG PET/CT and (18)F-FDG PET/MR imaging exhibited a high correlation (R = 0.74 and 0.86, respectively; P < 0.0001). Size measurements showed an excellent correlation between (18)F-FDG PET/MR imaging and (18)F-FDG PET/CT (R = 0.99; P < 0.0001). The lower and upper limits of agreement between (18)F-FDG PET/CT and (18)F-FDG PET/MR imaging using Bland-Altman analysis were -2.34 to 3.89 for SUV(mean), -7.42 to 4.40 for SUV(max), and -0.59 to 0.83 for the tumor size, respectively. (18)F-FDG PET/MR imaging using a dedicated pulmonary MR imaging protocol, compared with (18)F-FDG PET/CT, does not provide advantages in thoracic staging in NSCLC patients.

Gastrointestinal (GI) adverse events (AEs) are frequently observed in patients receiving EGF receptor (EGFR; also known as HER1 or ErbB1) tyrosine kinase inhibitor therapy. GI AEs are among the most common and most impactful on a patient's quality of life. Severe diarrhea can result in fluid and electrolyte losses, leading to dehydration, electrolyte imbalances and renal insufficiency. Afatinib is an irreversible, oral, ErbB family blocker, inhibiting EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor kinases. It also inhibits transphosphorylation of ErbB3. Similar to reversible tyrosine kinase inhibitors of EGFR, GI AEs - in particular, diarrhea - have frequently been observed in afatinib-treated patients. This article summarizes current data on afatinib-associated diarrhea and provides strategies for its management. Patient education, early identification, timely management and ongoing assessment will help to prevent aggravation, afatinib dose reductions or therapy discontinuation, encouraging patient compliance and allowing patients to obtain the maximum therapeutic benefit from this agent.