Azienda Ospedaliera Citta' della Salute e della Scienza di Torino

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

PURPOSE: The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify patients with MM. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM). PATIENTS AND METHODS: Clinical and laboratory data from 4,445 patients with NDMM enrolled onto 11 international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival. RESULTS: ISS, CA, and LDH data were simultaneously available in 3,060 of 4,445 patients. We defined the following three groups: revised ISS (R-ISS) I (n = 871), including ISS stage I (serum β2-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (less than the upper limit of normal range); R-ISS III (n = 295), including ISS stage III (serum β2-microglobulin level > 5.5 mg/L) and high-risk CA or high LDH level; and R-ISS II (n = 1,894), including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS I, 62% in the R-ISS II, and 40% in the R-ISS III groups; the 5-year PFS rates were 55%, 36%, and 24%, respectively. CONCLUSION: The R-ISS is a simple and powerful prognostic staging system, and we recommend its use in future clinical studies to stratify patients with NDMM effectively with respect to the relative risk to their survival.

Importance: Detailed information about the association of COVID-19 with outcomes in pregnant individuals compared with not-infected pregnant individuals is much needed. Objective: To evaluate the risks associated with COVID-19 in pregnancy on maternal and neonatal outcomes compared with not-infected, concomitant pregnant individuals. Design, Setting, and Participants: In this cohort study that took place from March to October 2020, involving 43 institutions in 18 countries, 2 unmatched, consecutive, not-infected women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. Exposures: COVID-19 in pregnancy determined by laboratory confirmation of COVID-19 and/or radiological pulmonary findings or 2 or more predefined COVID-19 symptoms. Main Outcomes and Measures: The primary outcome measures were indices of (maternal and severe neonatal/perinatal) morbidity and mortality; the individual components of these indices were secondary outcomes. Models for these outcomes were adjusted for country, month entering study, maternal age, and history of morbidity. Results: A total of 706 pregnant women with COVID-19 diagnosis and 1424 pregnant women without COVID-19 diagnosis were enrolled, all with broadly similar demographic characteristics (mean [SD] age, 30.2 [6.1] years). Overweight early in pregnancy occurred in 323 women (48.6%) with COVID-19 diagnosis and 554 women (40.2%) without. Women with COVID-19 diagnosis were at higher risk for preeclampsia/eclampsia (relative risk [RR], 1.76; 95% CI, 1.27-2.43), severe infections (RR, 3.38; 95% CI, 1.63-7.01), intensive care unit admission (RR, 5.04; 95% CI, 3.13-8.10), maternal mortality (RR, 22.3; 95% CI, 2.88-172), preterm birth (RR, 1.59; 95% CI, 1.30-1.94), medically indicated preterm birth (RR, 1.97; 95% CI, 1.56-2.51), severe neonatal morbidity index (RR, 2.66; 95% CI, 1.69-4.18), and severe perinatal morbidity and mortality index (RR, 2.14; 95% CI, 1.66-2.75). Fever and shortness of breath for any duration was associated with increased risk of severe maternal complications (RR, 2.56; 95% CI, 1.92-3.40) and neonatal complications (RR, 4.97; 95% CI, 2.11-11.69). Asymptomatic women with COVID-19 diagnosis remained at higher risk only for maternal morbidity (RR, 1.24; 95% CI, 1.00-1.54) and preeclampsia (RR, 1.63; 95% CI, 1.01-2.63). Among women who tested positive (98.1% by real-time polymerase chain reaction), 54 (13%) of their neonates tested positive. Cesarean delivery (RR, 2.15; 95% CI, 1.18-3.91) but not breastfeeding (RR, 1.10; 95% CI, 0.66-1.85) was associated with increased risk for neonatal test positivity. Conclusions and Relevance: In this multinational cohort study, COVID-19 in pregnancy was associated with consistent and substantial increases in severe maternal morbidity and mortality and neonatal complications when pregnant women with and without COVID-19 diagnosis were compared. The findings should alert pregnant individuals and clinicians to implement strictly all the recommended COVID-19 preventive measures.

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

BACKGROUND: A fluoropyrimidine plus irinotecan or oxaliplatin, combined with bevacizumab (a monoclonal antibody against vascular endothelial growth factor), is standard first-line treatment for metastatic colorectal cancer. Before the introduction of bevacizumab, chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) showed superior efficacy as compared with fluorouracil, leucovorin, and irinotecan (FOLFIRI). In a phase 2 study, FOLFOXIRI plus bevacizumab showed promising activity and an acceptable rate of adverse effects. METHODS: We randomly assigned 508 patients with untreated metastatic colorectal cancer to receive either FOLFIRI plus bevacizumab (control group) or FOLFOXIRI plus bevacizumab (experimental group). Up to 12 cycles of treatment were administered, followed by fluorouracil plus bevacizumab until disease progression. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 12.1 months in the experimental group, as compared with 9.7 months in the control group (hazard ratio for progression, 0.75; 95% confidence interval [CI], 0.62 to 0.90; P=0.003). The objective response rate was 65% in the experimental group and 53% in the control group (P=0.006). Overall survival was longer, but not significantly so, in the experimental group (31.0 vs. 25.8 months; hazard ratio for death, 0.79; 95% CI, 0.63 to 1.00; P=0.054). The incidences of grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia were significantly higher in the experimental group. CONCLUSIONS: FOLFOXIRI plus bevacizumab, as compared with FOLFIRI plus bevacizumab, improved the outcome in patients with metastatic colorectal cancer and increased the incidence of some adverse events. (Funded by the Gruppo Oncologico Nord Ovest and others; ClinicalTrials.gov number, NCT00719797.).

Italian experience about the reduction in MI hospital admission during the first wave of COVID-19 pandemic

The burden of hepatocellular carcinoma (HCC), the most common form of liver cancer, is steadily growing because obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD) are replacing viral- and alcohol-related liver disease as major pathogenic promoters. The most worrisome aspects of these new risk factors are their large spread in the general population and their link with HCC arising in noncirrhotic livers. HCC may be the presenting feature of an asymptomatic nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD. The HCC risk connected to metabolic factors has been underestimated so far, and a poorer surveillance has prevented an adequate treatment. Systemic and hepatic molecular mechanisms involved in obesity- and NAFLD-induced hepatocarcinogenesis as well as potential early markers of HCC are being extensively investigated. This review summarizes current evidence linking obesity, NAFLD and liver cancer, discusses its clinical impact and describes the main mechanisms underlying this complex relationship.

BACKGROUND: This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma. METHODS: We randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival. RESULTS: The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P<0.001; and 4-year overall survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P=0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P=0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively). CONCLUSIONS: Consolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with MPR, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00551928.).

We conducted a pooled analysis of 869 individual newly diagnosed elderly patient data from 3 prospective trials. At diagnosis, a geriatric assessment had been performed. An additive scoring system (range 0-5), based on age, comorbidities, and cognitive and physical conditions, was developed to identify 3 groups: fit (score = 0, 39%), intermediate fitness (score = 1, 31%), and frail (score ≥2, 30%). The 3-year overall survival was 84% in fit, 76% in intermediate-fitness (hazard ratio [HR], 1.61; P = .042), and 57% in frail (HR, 3.57; P < .001) patients. The cumulative incidence of grade ≥3 nonhematologic adverse events at 12 months was 22.2% in fit, 26.4% in intermediate-fitness (HR, 1.23; P = .217), and 34.0% in frail (HR, 1.74; P < .001) patients. The cumulative incidence of treatment discontinuation at 12 months was 16.5% in fit, 20.8% in intermediate-fitness (HR, 1.41; P = .052), and 31.2% in frail (HR, 2.21; P < .001) patients. Our frailty score predicts mortality and the risk of toxicity in elderly myeloma patients. The International Myeloma Working group proposes this score for the measurement of frailty in designing future clinical trials. These trials are registered at www.clinicaltrials.gov as #NCT01093136 (EMN01), #NCT01190787 (26866138MMY2069), and #NCT01346787 (IST-CAR-506).

Gastrointestinal stromal tumours (GISTs) are rare tumours, with an estimated unadjusted incidence of around 1/100 000/year [1.Nilsson B. Bümming P. Meis-Kindblom J.M. et al.Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era–a population-based study in western Sweden.Cancer. 2005; 103: 821-829Crossref PubMed Scopus (1027) Google Scholar]. This only covers clinically relevant GISTs, since, if investigated, a much higher number of lesions ≤ 1 cm in diameter (microGISTs) can be found at histopathological examination of stomach tissue in middle-aged and elderly individuals. There is a slight prevalence in males. The median age is around 60–65 years, with a wide range. Occurrence in children is very rare. Paediatric GIST represents a clinically and molecularly distinct subset, marked by female predominance, absence of KIT/platelet-derived growth factor alpha (PDGFRA) mutations, frequent mutations or silencing of the four genes that encode the subunits of the succinate dehydrogenase (SDH) enzyme complex, gastric multicentric location and possible lymph node metastases [2.Pappo A.S. Janeway K.A. Pediatric gastrointestinal stromal tumors.Hematol Oncol Clin North Am. 2009; 23 (vii): 15-34Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. Some syndromes are linked to GISTs: •The Carney triad syndrome, marked by gastric GISTs, paraganglioma and pulmonary chondromas (these may occur at different ages) [3.Zhang L. Smyrk T.C. Young Jr, W.F. et al.Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases.Am J Surg Pathol. 2010; 34: 53-64Crossref PubMed Scopus (167) Google Scholar];•Carney–Stratakis syndrome, marked by a dyad of GIST and paraganglioma [4.Gaal J. Stratakis C.A. Carney J.A. et al.SDHB immunohistochemistry: a useful tool in the diagnosis of Carney–Stratakis and Carney triad gastrointestinal stromal tumors.Mod Pathol. 2011; 24: 147-151Crossref PubMed Scopus (162) Google Scholar, 5.Pasini B. McWhinney S.R. Bei T. et al.Clinical and molecular genetics of patients with the Carney–Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD.Eur J Hum Genet. 2008; 16: 79-88Crossref PubMed Scopus (363) Google Scholar]; and•Neurofibromatosis type 1(NF1), possibly leading to wild-type (WT), often multicentric GIST, predominantly located in the small bowel [6.Miettinen M. Fetsch J.F. Sobin L.H. Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases.Am J Surg Pathol. 2006; 30: 90-96Crossref PubMed Scopus (377) Google Scholar]. Families with germline autosomal dominant mutations of KIT are an extremely rare finding, presenting with multiple GISTs at an early age, possibly along with other associated features such as pigmented skin macules, urticaria pigmentosa and diffuse hyperplasia of the interstitial cells of Cajal in the gut wall. When small oesophagogastric or duodenal nodules < 2 cm in size are detected, endoscopic biopsy may be difficult and laparoscopic/laparotomic excision may be the only way to make a histological diagnosis. Many of these small nodules, if diagnosed as GISTs, will be either low-risk or entities whose clinical significance remains unclear. Therefore, the standard approach to patients with oesophagogastric or duodenal nodules < 2 cm is endoscopic ultrasound assessment and then follow-up, reserving excision for patients whose tumour increases in size or becomes symptomatic [IV, C]. As an option, the patient can choose to undergo a histological assessment, also depending on age, life expectancy and comorbidities. If follow-up is the choice, an evidence-based, optimal surveillance policy is lacking. A logical approach may be to have a short-term first control (e.g. at 3 months) and then, in the case of no evidence of growth, a more relaxed follow-up schedule may be selected. In a histologically proven small GIST, standard treatment is excision, unless major morbidity is expected. Alternatively, in the case of a likely low-risk GIST on biopsy, the decision can be made with the patient to follow up the lesion. However, an exception is the standard approach to rectal nodules represented by biopsy or excision after endorectal ultrasound assessment and pelvic magnetic resonance imaging (MRI), regardless of the tumour size and mitotic rate. In fact, the progression risk of a clinically significant GIST at this site is higher, its prognosis is significantly worse compared with most gastric GISTs and the local implications for surgery are more critical. A follow-up policy may be an option, to be discussed with the patient, in the case of small lesions and whenever the surgical risk is particularly high (comorbidities, age, etc.). The standard approach to tumours ≥2 cm in size is biopsy/excision, because they are associated with a higher risk of progression if confirmed as GIST [IV, C]. If there is an abdominal nodule not amenable to endoscopic assessment, laparoscopic/laparotomic excision is the standard approach. If there is a mass, especially if surgery is likely to be a multivisceral resection, multiple core needle biopsies are the standard approach. They should be obtained through endoscopic ultrasound guidance, or through an ultrasound/computed tomography (CT)-guided percutaneous approach. This may allow the surgeon to plan the best approach according to the histological diagnosis and avoid surgery for diseases which might not benefit (e.g. lymphomas, mesenteric fibromatosis and germ cell tumours). The risk of peritoneal contamination is negligible if the procedure is properly carried out. Moreover, lesions at risk in this regard (e.g. cystic masses) should be biopsied only in specialised centres. Immediate laparoscopic/laparotomic excision is an option on an individualised basis, especially if surgery is limited. If a patient presents with obvious metastatic disease, a biopsy of the metastatic focus is sufficient and the patient usually does not require a laparotomy for diagnostic purposes. The tumour sample should be fixed in 4% buffered formalin (Bouin fixative should not be used, since it prevents molecular analysis). Pathologically, the diagnosis of GIST relies on morphology and immunohistochemistry, the latter being positive for CD117 (KIT) and/or DOG1 (see Table 1) [7.Rubin B.P. Blanke C.D. Demetri G.D. et al.Protocol for the examination of specimens from patients with gastrointestinal stromal tumor.Arch Pathol Lab Med. 2010; 134: 165-170Crossref PubMed Google Scholar, 8.Novelli M. Rossi S. Rodriguez-Justo M. et al.DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours.Histopathology. 2010; 57: 259-270Crossref PubMed Scopus (147) Google Scholar]. A proportion of GISTs (in the range of 5%) are CD117-negative. The mitotic count has a prognostic value and should be expressed as the number of mitoses on a total area of 5 mm2 [which replaces the former 50 high-power field (HPF) area]. Mutational analysis for known mutations involving KIT and PDGFRA can confirm the diagnosis of GIST, if doubtful (particularly in rare CD117/DOG1-negative suspect GIST). Mutational analysis has a predictive value for sensitivity to molecular-targeted therapy and to prognostic value. Its inclusion in the diagnostic work-up of all GISTs should be considered standard practice [II, A] (with the possible exclusion of < 2 cm non-rectal GISTs, which are very unlikely ever to be candidates for medical treatment). Centralisation of mutational analysis in a laboratory enrolled in an external quality assurance programme and with expertise in the may be diagnosis is more for GIST, to confirm the diagnosis of GIST with an at a In GIST, for is to In GIST an syndrome should be Rossi S. M. et GIST is a for neurofibromatosis type 1 PubMed Scopus Google Scholar]. The of tissue is to allow molecular to be made at a for tumour to local and should be and for medical treatment or for medical treatment for medical treatment of of growth factor succinate in a of of growth factor succinate treatment is involving medical as as as should be carried in for and GISTs and/or expertise and a high number of patients The for node and of tumours the prognostic in GIST (see Table of for GIST from of of of to of KIT site in KIT or PDGFRA of and gastrointestinal stromal neurofibromatosis type growth factor tumour for from of with from in a GIST, gastrointestinal stromal neurofibromatosis type growth factor tumour for from of with from are the mitotic tumour size and tumour site GISTs have a prognosis small bowel or rectal is an prognostic factor and should be regardless of it or Mutational has not in risk at have a distinct GISTs have clinical and GIST with are associated with a prognosis and to risk have A risk by the of which the mitotic tumour size and tumour the prognostic in GISTs M. Lasota J. Gastrointestinal stromal tumors: on molecular and Pathol Lab Med. 2006; PubMed Google Scholar, M. Lasota J. Gastrointestinal stromal tumors: and prognosis at different Pathol. 2006; PubMed Scopus Google Scholar]. A all has on M. et and of a prognostic for after surgical of gastrointestinal stromal a 2009; Full Text Full Text PDF PubMed Scopus Google Scholar]. When these it is to that the mitotic and tumour size are that are through a of of GIST patients not with which the mitotic and tumour size as tumour is considered in to tumour site J. et of of gastrointestinal stromal tumour after an analysis of population-based Full Text Full Text PDF PubMed Scopus Google Scholar]. They have a that most the and the abdominal and pelvic is the of choice for and may be an rectal GISTs, and laboratory the work-up of the The of an tomography or is useful early of the tumour to molecular-targeted therapy is of The standard treatment of GISTs is surgical excision of the with no of clinically lymph If excision is the to follow the of surgery A] et of and surgery for gastric gastrointestinal stromal Google Scholar]. A approach is in patients have tumours, because of the risk of tumour which is associated with a very high risk of excision is the an excision whose are of tumour When surgery major and medical treatment is not the decision can be made with the patient to possible [IV, This is more for low-risk the of that surgery is associated with a worse If excision carried may be an option, the site of can be and major are not The risk of can be as by risk treatment with for 3 associated with a and in with 1 of therapy in patients in a M. et for stromal analysis of a Clin 34: PubMed Scopus (147) Google Scholar]. a that for a of 1 can in GISTs a diameter 3 cm with a et mesylate after of gastrointestinal stromal a 2009; Full Text Full Text PDF PubMed Scopus Google Scholar]. Therefore, therapy with for 3 is the standard treatment for patients with a significant risk of A is the risk is T. et treatment of GIST with or A on of the and the the the on GIST, the and the J 2009; Full Text Full Text PDF PubMed Scopus Google Scholar]. clinical are to of therapy in The benefit associated of may according to the type of being in patients with KIT mutations et of KIT and PDGFRA mutations on in patients with gastrointestinal stromal tumors with an analysis of a clinical PubMed Scopus Google Scholar, et and molecular features with after therapy of stromal the Clin PubMed Scopus Google Scholar]. Mutational analysis is to make a clinical decision There is a that PDGFRA GISTs should not be with the of sensitivity of this in and in [IV, the the of a higher of in the case of an KIT in GIST, to this in the for this [II, M. et mutations and for in patients with gastrointestinal stromal J 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, et of and clinical in the North of mesylate for treatment of gastrointestinal stromal by and and Clin 2008; PubMed Scopus Google Scholar, Demetri G.D. et mutations and in patients with metastatic gastrointestinal stromal Clin PubMed Scopus Google Scholar]. may this which is not in the by regard to GIST, there is a on treatment in and GISTs [IV, This of sensitivity to and other in the as as which is often more of to sufficient and be to best in the rare In case of tumour at the of there is of tumour cells the peritoneal peritoneal can be to This the patient at a very high risk of peritoneal P. et of in patients with gastrointestinal stromal J 2010; PubMed Scopus Google Scholar]. Therefore, these patients should be considered for therapy [IV, The optimal of treatment in these is the these cells should be considered as If surgery is not or it be through surgery in the case of total and all other major with is standard A] J. Blanke C.D. et of mesylate for and gastrointestinal stromal early of Surg 2009; PubMed Scopus Google Scholar, P. P. et in gastrointestinal stromal tumors the Surg PubMed Scopus Google Scholar]. This may also be the case if the surgeon that the surgical is after (e.g. the risk of and tumour is A may be the of mitotic for risk for A biopsy with histological and mutational is to confirm the histological to to therapy with (e.g. PDGFRA and to the for KIT tumour after surgery is carried out. tumour assessment is to avoid surgery in the case of imaging it possible to the tumour very a particularly in the absence of mutational There are to the on to treatment it can be a or surgery and can be the patient from is the standard treatment for and metastatic A] C.D. Demetri G.D. M. et from a of mesylate for patients with or metastatic gastrointestinal stromal tumors Clin 2008; PubMed Scopus Google Scholar, C.D. Demetri G.D. et mesylate at in patients with or metastatic gastrointestinal stromal tumors the Clin 2008; PubMed Scopus Google Scholar, J. J. et in gastrointestinal stromal tumours with Full Text Full Text PDF PubMed Scopus Google Scholar, J. et of patients with stromal tumours to a of after progression on J 2005; Full Text Full Text PDF PubMed Scopus Google as as for patients with not is also the standard treatment for patients with metastatic have all lesions surgery is not as a approach in the metastatic The standard of is However, have that patients with tumours the KIT have significantly on a higher which is as standard treatment in this of of for the treatment of or metastatic gastrointestinal stromal tumors: a of Clin 2010; PubMed Scopus Google Scholar]. with a PDGFRA are to S. et al.Clinical and treatment in a of PDGFRA gastrointestinal stromal tumour J Full Text Full Text PDF PubMed Scopus Google and other and candidates for clinical on this is doubtful patients with GIST benefit from there are of of K.A. et treatment in patients with GIST of 2009; PubMed Scopus Google Scholar]. In the metastatic treatment with should be since treatment is by tumour lesions have A] et of in patients with gastrointestinal stromal tumours after 3 of an 3 2010; Full Text Full Text PDF PubMed Scopus Google Scholar]. When treatment is the patient should be to the of with as as with and and the best to should be by of and a policy of and should be in the case of that of are associated with a worse a with the has G.D. et are with clinical benefit in patients with gastrointestinal stromal Clin 2009; PubMed Scopus Google Scholar]. from its to the assessment of may be useful in the case patients that at a risk of major or patients with surgical to and progression on to the to the to of the tumour should be carried in the early of should be the since the risk of progression excision of metastatic has to be associated with a the patient is to it has this is to surgery or to patient J. et surgery in is it in all 2010; Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. et of gastrointestinal stromal tumors after treatment with therapy Clin 2006; 24: PubMed Scopus Google Scholar, Blanke C.D. et of mesylate for and gastrointestinal stromal tumors: follow-up of Surg PubMed Scopus Google Scholar, S. P. P. et follow-up of patients with GIST in the of analysis of prognostic J Surg Full Text Full Text PDF PubMed Scopus Google Scholar]. not early because of for a small positive in which all patients peritoneal et there a of surgery in patients with or metastatic gastrointestinal stromal tumours to a in J Full Text Full Text PDF PubMed Scopus Google Scholar]. the surgical option should be individualised after the decision with the patient in the case of C]. excision of has not in surgery of such as the a has associated with a in the range as for treatment with Therefore, this may be a option for an patient with [IV, C]. (e.g. local such as or may be selected. 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The miniaturization, sophistication, proliferation, and accessibility of technologies are enabling the capture of more and previously inaccessible phenomena in Parkinson's disease (PD). However, more information has not translated into a greater understanding of disease complexity to satisfy diagnostic and therapeutic needs. Challenges include noncompatible technology platforms, the need for wide-scale and long-term deployment of sensor technology (among vulnerable elderly patients in particular), and the gap between the "big data" acquired with sensitive measurement technologies and their limited clinical application. Major opportunities could be realized if new technologies are developed as part of open-source and/or open-hardware platforms that enable multichannel data capture sensitive to the broad range of motor and nonmotor problems that characterize PD and are adaptable into self-adjusting, individualized treatment delivery systems. The International Parkinson and Movement Disorders Society Task Force on Technology is entrusted to convene engineers, clinicians, researchers, and patients to promote the development of integrated measurement and closed-loop therapeutic systems with high patient adherence that also serve to (1) encourage the adoption of clinico-pathophysiologic phenotyping and early detection of critical disease milestones, (2) enhance the tailoring of symptomatic therapy, (3) improve subgroup targeting of patients for future testing of disease-modifying treatments, and (4) identify objective biomarkers to improve the longitudinal tracking of impairments in clinical care and research. This article summarizes the work carried out by the task force toward identifying challenges and opportunities in the development of technologies with potential for improving the clinical management and the quality of life of individuals with PD. © 2016 International Parkinson and Movement Disorder Society.

BACKGROUND: Standard treatment for patients with primary CNS lymphoma remains to be defined. Active therapies are often associated with increased risk of haematological or neurological toxicity. In this trial, we addressed the tolerability and efficacy of adding rituximab with or without thiotepa to methotrexate-cytarabine combination therapy (the MATRix regimen), followed by a second randomisation comparing consolidation with whole-brain radiotherapy or autologous stem cell transplantation in patients with primary CNS lymphoma. We report the results of the first randomisation in this Article. METHODS: For the international randomised phase 2 International Extranodal Lymphoma Study Group-32 (IELSG32) trial, HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and measurable disease were enrolled from 53 cancer centres in five European countries (Denmark, Germany, Italy, Switzerland, and the UK) and randomly assigned (1:1:1) to receive four courses of methotrexate 3·5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m(2) on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m(2) on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after the first stage were then randomly allocated between whole-brain radiotherapy and autologous stem cell transplantation. A permuted blocks randomised design (block size four) was used for both randomisations, and a computer-generated randomisation list was used within each stratum to preserve allocation concealment. Randomisation was stratified by IELSG risk score (low vs intermediate vs high). No masking after assignment to intervention was used. The primary endpoint of the first randomisation was the complete remission rate, analysed by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01011920. FINDINGS: Between Feb 19, 2010, and Aug 27, 2014, 227 eligible patients were recruited. 219 of these 227 enrolled patients were assessable. At median follow-up of 30 months (IQR 22-38), patients treated with rituximab and thiotepa had a complete remission rate of 49% (95% CI 38-60), compared with 23% (14-31) of those treated with methotrexate-cytarabine alone (hazard ratio 0·46, 95% CI 0·28-0·74) and 30% (21-42) of those treated with methotrexate-cytarabine plus rituximab (0·61, 0·40-0·94). Grade 4 haematological toxicity was more frequent in patients treated with methotrexate-cytarabine plus rituximab and thiotepa, but infective complications were similar in the three groups. The most common grade 3-4 adverse events in all three groups were neutropenia, thrombocytopenia, anaemia, and febrile neutropenia or infections. 13 (6%) patients died of toxicity. INTERPRETATION: With the limitations of a randomised phase 2 study design, the IELSG32 trial provides a high level of evidence supporting the use of MATRix combination as the new standard chemoimmunotherapy for patients aged up to 70 years with newly diagnosed primary CNS lymphoma and as the control group for future randomised trials. FUNDING: Associazione Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Foundation.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.

Our aim is evaluating the changes in weight and dietary habits in a sample of outpatients with obesity after 1 month of enforced lockdown during the COVID-19 pandemic in Northern Italy. In this observational retrospective study, the patients of our Obesity Unit were invited to answer to a 12-question multiple-choice questionnaire relative to weight changes, working activity, exercise, dietary habits, and conditions potentially impacting on nutritional choices. A multivariate regression analysis was performed to evaluate the associations among weight/BMI changes and the analyzed variables. A total of 150 subjects (91.5%) completed the questionnaire. Mean self-reported weight gain was ≈1.5 kg (p &lt; 0.001). Lower exercise, self-reported boredom/solitude, anxiety/depression, enhanced eating, consumption of snacks, unhealthy foods, cereals, and sweets were correlated with a significantly higher weight gain. Multiple regression analyses showed that increased education (inversely, β = −1.15; 95%CI −2.13, −0.17, p = 0.022), self-reported anxiety/depression (β = 1.61; 0.53, 2.69, p = 0.004), and not consuming healthy foods (β = 1.48; 0.19, 2.77, p = 0.026) were significantly associated with increased weight gain. The estimated direct effect of self-reported anxiety/depression on weight was 2.07 kg (1.07, 3.07, p &lt; 0.001). Individuals with obesity significantly gained weight 1 month after the beginning of the quarantine. The adverse mental burden linked to the COVID-19 pandemic was greatly associated with increased weight gain.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES: Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks. RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

BACKGROUND: Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed. METHODS: In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status. RESULTS: At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group. CONCLUSIONS: The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.).

• This ESMO Clinical Practice Guideline provides key recommendations for managing cancer-related cachexia. • It covers screening, assessment and multimodal management of cancer cachexia. • All recommendations were compiled by a multidisciplinary group of experts. • Recommendations are based on available scientific data and the author's expert opinion.

The following recommendations for post-polypectomy colonoscopic surveillance apply to all patients who had one or more polyps that were completely removed during a high quality baseline colonoscopy. 1: ESGE recommends that patients with complete removal of 1 - 4 < 10 mm adenomas with low grade dysplasia, irrespective of villous components, or any serrated polyp < 10 mm without dysplasia, do not require endoscopic surveillance and should be returned to screening.Strong recommendation, moderate quality evidence.If organized screening is not available, repetition of colonoscopy 10 years after the index procedure is recommended.Strong recommendation, moderate quality evidence. 2: ESGE recommends surveillance colonoscopy after 3 years for patients with complete removal of at least 1 adenoma ≥ 10 mm or with high grade dysplasia, or ≥ 5 adenomas, or any serrated polyp ≥ 10 mm or with dysplasia. Strong recommendation, moderate quality evidence. 3: ESGE recommends a 3 - 6-month early repeat colonoscopy following piecemeal endoscopic resection of polyps ≥ 20 mm.Strong recommendation, moderate quality evidence. A first surveillance colonoscopy 12 months after the repeat colonoscopy is recommended to detect late recurrence.Strong recommendation, high quality evidence. 4: If no polyps requiring surveillance are detected at the first surveillance colonoscopy, ESGE suggests to perform a second surveillance colonoscopy after 5 years. Weak recommendation, low quality evidence.After that, if no polyps requiring surveillance are detected, patients can be returned to screening. 5: ESGE suggests that, if polyps requiring surveillance are detected at first or subsequent surveillance examinations, surveillance colonoscopy may be performed at 3 years. Weak recommendation, low quality evidence.A flowchart showing the recommended surveillance intervals is provided (Fig. 1).