Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Bone Fragility in Acromegalic Patients: A Mystery Almost Solved?

Background: a high prevalence of vertebral fractures, despite normal bone mineral density (BMD), is reported in acromegalic patients in both the active and inactive phases of the disease. Aim of the study: to analyze the prevalence of vertebral fractures, bone turnover, BMD and histomorphometric parameters including bone microarchitecture in a group of acromegalic patients. Patients and methods: 42 acromegalic patients (26 males, 16 females, mean age 58 \ub112,5 and 58,8 \ub113,8 years), divided in 2 subgroups: one with active disease and one in remission (13, 29 patients respectively) underwent bone turnover evaluation (serum calcium, serum phosphate, PTH, 25- hydroxyvitamin (OH) D , ALP, CTX, urinary calcium/creatinine) and bone densitometry by Dual-Energy X-Ray Absorptiometry (DXA). Vertebral fractures were assessed by morphometric analysis during DXA. In 4 patients iliac crest bone biopsy was performed.Results: the prevalence of vertebral fractures was 64% in the whole population, 69% in the active group, 59% in the remission group. Among fractured patients, vertebral t-score was normal in 59% and it showed osteoporosis in only 11%. Vertebral BMD was higher in fractured patients compared to non-fractured (mean SD 1,108 \ub10,175 vs 0,961\ub1 0,118 g/cm2, p=0,009), also considering the active (1,147\ub10,241 vs 1,107\ub10,169 g/cm2) and inactive subgroups (1,093 \ub10,15 vs 0,945 \ub10,106g/cm2, p0,01). Disease duration was significantly higher in fractured compared to non-fractured patients (respectively 8,67 \ub16,65 and 6,93 \ub13,41 years, p<0,05). As regards bone metabolism parameters, urinary calcium/creatinine was significantly higher in fractured patients compared to non-fractured patients (0,125 \ub10,096 vs 0,074 \ub10,031, p<0,01). 25-OH vitamin D was low in both groups (fractures 24,93 \ub111,5 ng/ml, non-fractured patients 25,02 \ub17,28 ng/ml). Hypogonadism was a risk factor for vertebral fractures in active patients (p=0,04). The preliminary results regarding histomorphometric evaluation showed a greater cortical thickness and an increased porosity compared to that of normal subjects (cortical width 1882\ub1250 vs 816\ub1291 \u3bcm, cortical porosity index 10 \ub14% vs 5,79 \ub12,76%). IGF-1 positively correlated with porosity index (p<0,05).Conclusions: our data confirm a high prevalence of vertebral fractures in acromegalic patients despite a normal BMD. This apparent paradox could be explained by an increased cortical thickness associated with abnormal cortical porosity, mediated by IGF-1

Morphological study of upper airways and long-term follow-up of obstructive sleep apnea syndrome in acromegalic patients

Pathogenesis and long-term outcome of obstructive sleep apnea syndrome (OSAS) in acromegalic patients are still under debate. The aim of the study was to assess the prevalence and long-term follow-up of a series of acromegalic patients with OSAS and to investigate site, degree, and possible causes of upper airway obstruction by morphological study. Cross-sectional and longitudinal study was conducted in 58 acromegalic patients (33 active, 25 controlled) with polysomnography in all subjects, repeated in 25 patients with OSAS, and echocardiography. Morphological study including fiberoptic nasopharyngoscopy with the M\ufcller maneuver (FNMM), magnetic resonance imaging (MRI), with 3-dimensional (3D) elaboration was also performed. The prevalence of OSAS was 58.6\ua0% in the whole series: 63.6\ua0% in the active group and 52\ua0% in the controlled one. Left ventricular hypertrophy was more prevalent in patients with OSAS. OSAS improved in 62.5\ua0% of active patients after achieving hormonal control, whereas it persisted or got worse in 66.6\ua0% of the controlled ones. The uvula and tongue base were the main site of obstruction assessed by FNMM. Uvula diameters obtained by MRI study correlated with the severity of upper airway collapse assessed by FNMM and tongue measure with apnea-hypopnea index (p\ua0=\ua00.044). A greater narrowing and a smaller total volume of upper airways were confirmed by 3D-MRI in patients with more severe OSAS. Uvula and tongue hypertrophy plays a relevant role in the pathogenesis and severity of OSAS. Intensive treatment of acromegaly needs to be promptly adopted in order to reverse it

Comparison of imaging-based and pathological dimensions in pancreatic neuroendocrine tumors

AIMTo establish the ability of magnetic resonance (MR) and computer tomography (CT) to predict pathologic dimensions of pancreatic neuroendocrine tumors (PanNET) in a caseload of a tertiary referral center.METHODSPatients submitted to surgery for PanNET at the Surgical Unit of the Pancreas Institute with at least 1 preoperative imaging examination (MR or CT scan) from January 2005 to December 2015 were included and data retrospectively collected. Exclusion criteria were: multifocal lesions, genetic syndromes, microadenomas or mixed tumors, metastatic disease and neoadjuvant therapy. Bland-Altman (BA) and Mountain-Plot (MP) statistics were used to compare size measured by each modality with the pathology size. Passing-Bablok (PB) regression analysis was used to check the agreement between MR and CT.RESULTSOur study population consisted of 292 patients. Seventy-nine (27.1%) were functioning PanNET. The mean biases were 0.17 +/- 7.99 mm, 1 +/- 8.51 mm and 0.23 +/- 9 mm, 1.2 +/- 9.8 mm for MR and CT, considering the overall population and the subgroup of non-functioning-PanNET, respectively. Limits of agreement (LOA) included the vast majority of observations, indicating a good agreement between imaging and pathology. The MP further confirmed this finding and showed that the two methods are unbiased with respect to each other. Considering = 2 cm non-functioning-PanNET, no statistical significance was found in the size estimation rate of MR and CT (P = 0.433). PBR analysis did not reveal significant differences between MR, CT and pathology.CONCLUSIONMR and CT scan are accurate and interchangeable imaging techniques in predicting pathologic dimensions of PanNET

Role of Combined Ga-68-DOTATOC and F-18-FDG Positron Emission Tomography/Computed Tomography in the Diagnostic Workup of Pancreas Neuroendocrine Tumors Implications for Managing Surgical Decisions

Objectives: Ga-68-DOTATOC (Ga) positron emission tomography (PET)/computed tomography (CT) is recommended in the workup of pancreas neuroendocrine tumors (PanNETs); evidence suggests that F-18-FDG (F) PET/CT can also provide prognostic information. Aims of this study were to assess the role of combined Ga-and F-PET/CT in the evaluation of grade (G) 1-2 PanNETs and to test the correlation between F-PET/CT positivity and tumor grade.Methods: Preoperative Ga-and F-PET/CT of 35 patients with surgically resected G1-2 PanNETs were evaluated. For grading, the 2010 World Health Organization Classification was used; an ancillary analysis with Ki67 cutoffs at 5% to 20% was conducted. Correlation between F-PET/ CT positivity (SUVmax &gt; 3.5) and grade was assessed.Results: Of 35 PanNETs, 28.6% and 71.4% were G1 and G2 as per World Health Organization. Ga-PET/CT showed high sensitivity (94.3%) in detecting G1-2 PanNETs. F-PET/CT was positive in 20% and 76% G1 and G2 tumors (P = 0.002). F-PET/CT identified G2 PanNETs with high positive predictive value (PPV, 90.5%). F-PET/CT correlated with tumor grade also in the ancillary analysis (P = 0.009).Conclusions: The high sensitivity of Ga-PET/CT in NET detection is known. The high PPV of F-PET/CT in the identification of G2 forms suggests its potential role in PanNETs prognostication and risk stratification

Prognostic factors in ectopic Cushing's syndrome due to neuroendocrine tumors: a multicenter study

Objective: Evidence is limited regarding outcome of patients with ectopic Cushing's syndrome (ECS) due to neuroendocrine tumors (NETs). DESIGN: We assessed the prognostic factors affecting the survival of patients with NETs and ECS. METHODS: Retrospective analysis of clinicopathological features, severity of hormonal syndrome, treatments from a large cohort of patients with NETs and ECS collected from 17 Italian centers. RESULTS: Our series included 110 patients, 58.2% female, with mean (\ub1s.d.) age at diagnosis of 49.5\u2009\ub1\u200915.9 years. The main sources of ectopic ACTH were bronchial carcinoids (BC) (40.9%), occult tumors (22.7%) and pancreatic (p)NETs (15.5%). Curative surgery was performed in 56.7% (70.2% of BC, 11% of pNETs). Overall survival was significantly higher in BC compared with pNETs and occult tumors (P\u2009=\u20090.033) and in G1-NETs compared with G2 and G3 (P\u2009=\u20090.007). Negative predictive factors for survival were severity of hypercortisolism (P\u2009&lt;\u20090.02), hypokalemia (P\u2009=\u20090.001), diabetes mellitus (P\u2009=\u20090.0146) and distant metastases (P\u2009&lt;\u20090.001). Improved survival was observed in patients who underwent NET removal (P\u2009&lt;\u20090.001). Adrenalectomy improved short-term survival. CONCLUSIONS: Multiple factors affect prognosis of ECS patients: type of NET, grading, distant metastases, severity of hypercortisolism, hypokalemia and diabetes mellitus. BCs have the highest curative surgical rate and better survival compared with occult tumors and pNETs. Hypercortisolism plays a primary role in affecting outcome and quality of life; therefore, prompt and vigorous treatment of hormonal excess by NET surgery and medical therapy should be a key therapeutic goal. In refractory cases, adrenalectomy should be considered as it affects outcome positively at least in the first 2 years