Implantable hearing devices in clinical practice. Systematic review and consensus statements.

Objective: Implantable hearing devices represent a modern and innovative solution for hearing restoration. Over the years, these high-tech devices have increasingly evolved but their use in clinical practice is not universally agreed in the scientific literature. Congresses, meetings, conferences, and consensus statements to achieve international agreement have been made. This work follows this line and aims to answer unsolved questions regarding examinations, selection criteria and surgery for implantable hearing devices. Materials and methods: A Consensus Working Group was established by the Italian Society of Otorhinolaryngology. A method group performed a systematic review for each single question to identify the current best evidence on the topic and to guide a multidisciplinary panel in developing the statements. Results: Twenty-nine consensus statements were approved by the Italian Society of Otorhinolaryngology. These were associated with 4 key area subtopics regarding pre-operative tests, otological, audiological and surgical indications. Conclusions: This consensus can be considered a further step forward to establish realistic guidelines on the debated topic of implantable hearing devices.

Multidisciplinary treatment of hepatocellular carcinoma in 2023: Italian practice Treatment Guidelines of the Italian Association for the Study of the Liver (AISF), Italian Association of Medical Oncology (AIOM), Italian Association of Hepato-Bilio-Pancreatic Surgery (AICEP), Italian Association of Hospital Gastroenterologists (AIGO), Italian Association of Radiology and Clinical Oncology (AIRO), Italian Society of Pathological Anatomy and Diagnostic Cytology (SIAPeC-IAP), Italian Society of Surgery (SIC), Italian Society of Gastroenterology (SIGE), Italian Society of Medical and Interventional Radiology (SIRM), Italian Organ Transplant Society (SITO), and Association of Patients with Hepatitis and Liver Disease (EpaC) - Part II - Non-surgical treatments.

Worldwide, hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. The remarkable improvements in treating HCC achieved in the last years have increased the complexity of its management. Following the need to have updated guidelines on the multidisciplinary treatment management of HCC, the Italian Scientific Societies involved in the management of this cancer have promoted the drafting of a new dedicated document. This document was drawn up according to the GRADE methodology needed to produce guidelines based on evidence. Here is presented the second part of guidelines, focused on the multidisciplinary tumor board of experts and non-surgical treatments of HCC.

Systematic review and meta-analysis of immune checkpoint inhibitors as single agent or in combination with chemotherapy in early-stage non-small cell lung cancer: Impact of clinicopathological factors and indirect comparison between treatment strategies.

BACKGROUND: In non-small cell lung cancer (NSCLC), the immune checkpoint inhibitors (ICI) revolution is rapidly moving from metastatic to early-stage, however, the impact of clinicopathological variables and optimal treatment sequencing remain unclear. METHODS: Randomized controlled trials (RCTs) in patients with early-stage NSCLC treated with ICI as single agent or in combination with platinum-based chemotherapy (PCT) were included. Primary outcomes were pathological complete response (pCR), event free survival (EFS) (neoadjuvant/perioperative), and disease-free survival (DFS) (adjuvant). Secondary outcomes were major pathological response (MPR), overall survival (OS), toxicity, surgical outcomes (neoadjuvant/perioperative); OS and toxicity (adjuvant). An additional secondary endpoint was to compare EFS and OS between neoadjuvant and perioperative strategies. RESULTS: 8 RCTs (2 neoadjuvant, 4 perioperative, 2 adjuvant) (4661 participants) were included. Neoadjuvant/perioperative ICI+PCT significantly improved pCR, EFS, OS, MPR and R0 resection compared to PCT. Adjuvant ICI significantly improved DFS compared to placebo. There was a significant subgroup interaction by PD-L1 status (χ2 = 10.72, P = 0.005), pCR (χ2 = 17.80, P < 0.0001), and stage (χ2 = 4.46, P = 0.003) for EFS. No difference according to PD-L1 status was found for pCR, with 14% of patients having PD-L1 negative tumors still experiencing a pCR. No interaction by PD-L1 status was found for DFS upon adjuvant ICI. Indirect comparison showed no difference in EFS and OS between neoadjuvant and perioperative ICI+PCT. CONCLUSIONS: PD-L1 status, pCR and stage impact on survival upon neoadjuvant/perioperative ICI. The restriction of neoadjuvant/perioperative ICI to PD-L1 + patients could preclude pCR and long-term benefit in the PD-L1- subgroup. Neoadjuvant and perioperative could be equivalent strategies.

A systematic review and meta-analysis on the optimal treatment duration of checkpoint inhibitoRS in solid tumors: The OTHERS study.

No clear evidence supports the advantage of fixed (up to two years (2yICI)) or continuous treatment (more than two years (prolonged ICI)) in cancer patients achieving stable disease or response on immune checkpoint inhibitors (ICIs). We performed a systematic review and meta-analysis of randomized controlled trials reporting the duration of ICIs (alone or in combination with standard of care (SoC)) across various solid tumors. Overall, we identified 28,417 records through database searching. Based on the eligibility criteria, 57 studies were identified for the quantitative synthesis, including 22,977 patients receiving ICIs (with or without SoC). Prolonged ICI correlated with better overall survival (OS) than 2yICI in patients with melanoma (HR:1.55; 95%CI: 1.22,1.98), while 2yICI-SoC led to better OS than prolonged ICI-SoC in patients with NSCLC (HR: 0.84; 95%CI: 0.68,0.89). Prospective randomized trials are needed to assess the most appropriate duration of ICIs. OBJECTIVE: No clear evidence supports the advantage of fixed (up to two years (2yICI)) or continuous treatment (more than two years (prolonged ICI)) in cancer patients achieving stable disease or response on immune checkpoint inhibitors (ICIs). Here, we assessed the optimal treatment duration for ICIs in solid tumors. CONCLUSIONS: Prolonged ICIs administration does not seem to improve the outcomes of patients with NSCLC an RCC.

Laparoscopic treatment of ventral hernias: the Italian national guidelines.

Primary and incisional ventral hernias are significant public health issues for their prevalence, variability of professional practices, and high costs associated with the treatment In 2019, the Board of Directors of the Italian Society for Endoscopic Surgery (SICE) promoted the development of new guidelines on the laparoscopic treatment of ventral hernias, according to the new national regulation. In 2022, the guideline was accepted by the government agency, and it was published, in Italian, on the SNLG website. Here, we report the adopted methodology and the guideline's recommendations, as established in its diffusion policy. This guideline is produced according to the methodology indicated by the SNGL and applying the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology. Fifteen recommendations were produced as a result of 4 PICO questions. The level of recommendation was conditional for 12 of them and conditional to moderate for one. This guideline's strengths include relying on an extensive systematic review of the literature and applying a rigorous GRADE method. It also has several limitations. The literature on the topic is continuously and rapidly evolving; our results are based on findings that need constant re-appraisal. It is focused only on minimally invasive techniques and cannot consider broader issues (e.g., diagnostics, indication for surgery, pre-habilitation).

Should Acellular Dermal Matrices Be Used for Implant-based Breast Reconstruction after Mastectomy? Clinical Recommendation Based on the GRADE Approach.

Acellular dermal matrices (ADMs) entered the market in the early 2000s and their use has increased thereafter. Several retrospective cohort studies and single surgeon series reported benefits with the use of ADMs. However, robust evidence supporting these advantages is lacking. There is the need to define the role for ADMs in implant-based breast reconstruction (IBBR) after mastectomy. Methods: A panel of world-renowned breast specialists was convened to evaluate evidence, express personal viewpoints, and establish recommendation for the use of ADMs for subpectoral one-/two-stage IBBR (compared with no ADM use) for adult women undergoing mastectomy for breast cancer treatment or risk reduction using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Results: Based on the voting outcome, the following recommendation emerged as a consensus statement: the panel members suggest subpectoral one- or two-stage IBBR either with ADMs or without ADMs for adult women undergoing mastectomy for breast cancer treatment or risk reduction (with very low certainty of evidence). Conclusions: The systematic review has revealed a very low certainty of evidence for most of the important outcomes in ADM-assisted IBBR and the absence of standard tools for evaluating clinical outcomes. Forty-five percent of panel members expressed a conditional recommendation either in favor of or against the use of ADMs in subpectoral one- or two-stages IBBR for adult women undergoing mastectomy for breast cancer treatment or risk reduction. Future subgroup analyses could help identify relevant clinical and pathological factors to select patients for whom one technique could be preferable to another.

PARP-inhibitors for BRCA1/2-related advanced HER2-negative breast cancer: A meta-analysis and GRADE recommendations by the Italian Association of Medical Oncology.

BACKGROUND: Approximately 5-10% of unselected breast cancer (BC) patients retain a hereditary predisposition related to a germline mutation in BRCA1/2 genes. The poly-ADP ribose polymerase (PARP)-inhibitors olaparib and talazoparib have been granted marketing authorization by both FDA and EMA for adults with BRCA1/2 germline mutations and HER2-negative (HER2-) advanced BC based on the results from the phase III OlympiAd and EMBRACA trials. METHODS: The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer addressed two critical clinical questions, adopting the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach and the Evidence to Decision framework (EtD), to develop recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related triple-negative (clinical question 1) and hormone receptor-positive (HR+)/HER2- (clinical question 2) advanced BC. RESULTS: Two studies were eligible (OlympiAd and EMBRACA). For both clinical questions, the Panel judged the benefit/harm balance probably in favor of the intervention, given the favorable impact in terms of PFS, ORR, and QoL at an acceptable cost in terms of toxicity; the overall certainty of the evidence was low. The panel's final recommendations were conditional in favor of PARP-inhibitors over single-agent chemotherapy in both HR+/HER2-and triple-negative BC. Finally, the Panel identified and discussed areas of uncertainty calling for further exploration. CONCLUSIONS: The Panel of AIOM BC Clinical Practice Guideline provided clinical recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related HER2-advanced BC by adopting the GRADE methodology.

Comparative assessment of early mortality risk upon immune checkpoint inhibitors alone or in combination with other agents across solid malignancies: a systematic review and meta-analysis.

BACKGROUND: The early crossing of survival curves in randomised clinical trials (RCTs) with immune checkpoint blockers suggests an excess of mortality in the first months of treatment. However, the exact estimation of the early death (ED) rate, the comparison between ED upon immune checkpoint inhibitors (ICI) alone or in combination with other agents and the impact of tumour type, and PD-L1 expression on ED are unknown. METHODS: RCTs comparing ICI alone (ICI-only group) or in combination with other non-ICI therapies (ICI-OT group) (experimental arms) versus non-ICI treatments (control arm) were included. ED was defined as death within the first 3 months of treatment. The primary outcome was the comparison of ED between experimental and control arms, and the secondary outcome was the comparison of ED risk between ICI-only and ICI-OT. ED rates estimated by risk ratio (RR) were pooled by random effect model. RESULTS: A total of 56 RCTs (40,215 participants, 14 cancer types) were included. ED occurred in 14.2% and 6.7% of patients in ICI-only and ICI-OT groups, respectively. ED risk significantly increased with ICI-only (RR: 1.29, 95% CI 1.05-1.57) versus non-ICI therapies, while it was lower with ICI-OT versus non-ICI treatments (RR: 0.81, 95% CI 0.73-0.90). ED risk was significantly higher upon ICI-only compared to ICI-OT (RR: 1.57, 95% CI 1.26-1.95). Gastric and urothelial carcinoma were at higher risk of ED. PD-L1 expression and ICI drug classes were not associated with ED. CONCLUSIONS: ED upon first-line ICI is a clinically relevant phenomenon across solid malignancies, not predictable by PD-L1 expression but preventable through the addition of other treatments to ICI.

Adherence of systematic reviews to Cochrane RoB2 guidance was frequently poor: a meta epidemiological study.

OBJECTIVES: To assess whether the use of the revised Cochrane risk of bias tool for randomized trials (RoB2) in systematic reviews (SRs) adheres to RoB2 guidance. METHODS: We searched MEDLINE, Embase, Cochrane Library from 2019 to May 2021 to identify SRs using RoB2. We analyzed methods and results sections to see whether risk of bias was assessed at outcome measure level and applied to primary outcomes of the SR as per RoB2 guidance. The relation between SR characteristics and adequacy of RoB2 use was examined by logistic regression analysis. RESULTS: Two hundred-eight SRs were included. We could assess adherence in 137 SRs as 12 declared using RoB2 but actually used RoB1 and 59 did not report the number of primary outcomes. The tool usage was adherent in 69.3% SRs. Considering SRs with multiple primary outcomes, adherence dropped to 28.8%. We found a positive association between RoB2 guidance adherence and the methodological quality of the reviews assessed by AMSTAR2 (p-for-trend 0.007). Multivariable regression analysis suggested journal impact factor [first quartile vs. other quartiles] was associated with RoB2 adherence (OR 0.34; 95% CI: 0.16-0.72). CONCLUSIONS: Many SRs did not adhere to RoB2 guidance as they applied the tool at the study level rather than at the outcome measure level. Lack of adherence was more likely among low and very low quality reviews.

More than one third of clinical practice guidelines on low back pain overlap in AGREE II appraisals. Research wasted?

BACKGROUND: Systematic reviews can apply the Appraisal of Guidelines for Research & Evaluation (AGREE) II tool to critically appraise clinical practice guidelines (CPGs) for treating low back pain (LBP); however, when appraisals differ in CPG quality rating, stakeholders, clinicians, and policy-makers will find it difficult to discern a unique judgement of CPG quality. We wanted to determine the proportion of overlapping CPGs for LBP in appraisals that applied AGREE II. We also compared inter-rater reliability and variability across appraisals. METHODS: For this meta-epidemiological study we searched six databases for appraisals of CPGs for LBP. The general characteristics of the appraisals were collected; the unit of analysis was the CPG evaluated in each appraisal. The inter-rater reliability and the variability of AGREE II domain scores for overall assessment were measured using the intraclass correlation coefficient and descriptive statistics. RESULTS: Overall, 43 CPGs out of 106 (40.6%) overlapped in seventeen appraisals. Half of the appraisals (53%) reported a protocol registration. Reporting of AGREE II assessment was heterogeneous and generally of poor quality: overall assessment 1 (overall CPG quality) was rated in 11 appraisals (64.7%) and overall assessment 2 (recommendation for use) in four (23.5%). Inter-rater reliability was substantial/perfect in 78.3% of overlapping CPGs. The domains with most variability were Domain 6 (mean interquartile range [IQR] 38.6), Domain 5 (mean IQR 28.9), and Domain 2 (mean IQR 27.7). CONCLUSIONS: More than one third of CPGs for LBP have been re-appraised in the last six years with CPGs quality confirmed in most assessments. Our findings suggest that before conducting a new appraisal, researchers should check systematic review registers for existing appraisals. Clinicians need to rely on updated CPGs of high quality and confirmed by perfect agreement in multiple appraisals. TRIAL REGISTRATION: Protocol Registration OSF: https://osf.io/rz7nh/.

Cannabis and cannabinoids for symptomatic treatment for people with multiple sclerosis.

BACKGROUND: Spasticity and chronic neuropathic pain are common and serious symptoms in people with multiple sclerosis (MS). These symptoms increase with disease progression and lead to worsening disability, impaired activities of daily living and quality of life. Anti-spasticity medications and analgesics are of limited benefit or poorly tolerated. Cannabinoids may reduce spasticity and pain in people with MS. Demand for symptomatic treatment with cannabinoids is high. A thorough understanding of the current body of evidence regarding benefits and harms of these drugs is required. OBJECTIVES: To assess benefit and harms of cannabinoids, including synthetic, or herbal and plant-derived cannabinoids, for reducing symptoms for adults with MS. SEARCH METHODS: We searched the following databases from inception to December 2021: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), CINAHL (EBSCO host), LILACS, the Physiotherapy Evidence Database (PEDro), the World Health Organisation International Clinical Trials Registry Platform, the US National Institutes of Health clinical trial register, the European Union Clinical Trials Register, the International Association for Cannabinoid Medicines databank. We hand searched citation lists of included studies and relevant reviews. SELECTION CRITERIA: We included randomised parallel or cross-over trials (RCTs) evaluating any cannabinoid (including herbal Cannabis, Cannabis flowers, plant-based cannabinoids, or synthetic cannabinoids) irrespective of dose, route, frequency, or duration of use for adults with MS. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane Risk of bias 2 tool for parallel RCTs and crossover trials. We rated the certainty of evidence using the GRADE approach for the following outcomes: reduction of 30% in the spasticity Numeric Rating Scale, pain relief of 50% or greater in the Numeric Rating Scale-Pain Intensity, much or very much improvement in the Patient Global Impression of Change (PGIC), Health-Related Quality of Life (HRQoL), withdrawals due to adverse events (AEs) (tolerability), serious adverse events (SAEs), nervous system disorders, psychiatric disorders, physical dependence. MAIN RESULTS: We included 25 RCTs with 3763 participants of whom 2290 received cannabinoids. Age ranged from 18 to 60 years, and between 50% and 88% participants across the studies were female.  The included studies were 3 to 48 weeks long and compared nabiximols, an oromucosal spray with a plant derived equal (1:1) combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (13 studies), synthetic cannabinoids mimicking THC (7 studies), an oral THC extract of Cannabis sativa (2 studies), inhaled herbal Cannabis (1 study) against placebo. One study compared dronabinol, THC extract of Cannabis sativa and placebo, one compared inhaled herbal Cannabis, dronabinol and placebo. We identified eight ongoing studies. Critical outcomes • Spasticity: nabiximols probably increases the number of people who report an important reduction of perceived severity of spasticity compared with placebo (odds ratio (OR) 2.51, 95% confidence interval (CI) 1.56 to 4.04; 5 RCTs, 1143 participants; I2 = 67%; moderate-certainty evidence). The absolute effect was 216 more people (95% CI 99 more to 332 more) per 1000 reporting benefit with cannabinoids than with placebo. • Chronic neuropathic pain: we found only one small trial that measured the number of participants reporting substantial pain relief with a synthetic cannabinoid compared with placebo (OR 4.23, 95% CI 1.11 to 16.17; 1 study, 48 participants; very low-certainty evidence). We are uncertain whether cannabinoids reduce chronic neuropathic pain intensity. • Treatment discontinuation due to AEs: cannabinoids may increase slightly the number of participants who discontinue treatment compared with placebo (OR 2.41, 95% CI 1.51 to 3.84; 21 studies, 3110 participants; I² = 17%; low-certainty evidence); the absolute effect is 39 more people (95% CI 15 more to 76 more) per 1000 people. Important outcomes • PGIC: cannabinoids probably increase the number of people who report 'very much' or 'much' improvement in health status compared with placebo (OR 1.80, 95% CI 1.37 to 2.36; 8 studies, 1215 participants; I² = 0%; moderate-certainty evidence). The absolute effect is 113 more people (95% CI 57 more to 175 more) per 1000 people reporting improvement. • HRQoL: cannabinoids may have little to no effect on HRQoL (SMD -0.08, 95% CI -0.17 to 0.02; 8 studies, 1942 participants; I2 = 0%; low-certainty evidence); • SAEs: cannabinoids may result in little to no difference in the number of participants who have SAEs compared with placebo (OR 1.38, 95% CI 0.96 to 1.99; 20 studies, 3124 participants; I² = 0%; low-certainty evidence); • AEs of the nervous system: cannabinoids may increase nervous system disorders compared with placebo (OR 2.61, 95% CI 1.53 to 4.44; 7 studies, 1154 participants; I² = 63%; low-certainty evidence); • Psychiatric disorders: cannabinoids may increase psychiatric disorders compared with placebo (OR 1.94, 95% CI 1.31 to 2.88; 6 studies, 1122 participants; I² = 0%; low-certainty evidence); • Drug tolerance: the evidence is very uncertain about the effect of cannabinoids on drug tolerance (OR 3.07, 95% CI 0.12 to 75.95; 2 studies, 458 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Compared with placebo, nabiximols probably reduces the severity of spasticity in the short-term in people with MS. We are uncertain about the effect on chronic neurological pain and health-related quality of life. Cannabinoids may increase slightly treatment discontinuation due to AEs, nervous system and psychiatric disorders compared with placebo. We are uncertain about the effect on drug tolerance. The overall certainty of evidence is limited by short-term duration of the included studies.

Effects of goal-oriented care for adults with multimorbidity: A systematic review and meta-analysis.

OBJECTIVE: To systematically review the evidence from randomized controlled trials comparing the effects of goal-oriented care against standard care for multimorbid adults. DATA SOURCES/STUDY SETTING: The literature presenting the results of randomized trials assessing the outcomes of goal-oriented care compared with usual care for adults with multimorbidity. STUDY DESIGN: Systematic review and meta-analysis. DATA COLLECTION/EXTRACTION METHODS: We searched the Cochrane Database of Systematic Reviews (CENTRAL), EMBASE, MEDLINE, CINHAL, trial registries such as ClinicalTrial.gov and World Health Organization International Clinical Trials Registry Platform (ICTRP), and the references of eligible trials and relevant reviews. Goal-oriented care was defined as an approach that engages patients, establishes personal goals, and sets targets for patients and clinicians to plan a course of action and measure outcome. We reviewed 228 trials, and 12 were included. We extracted outcome data on quality of life, hospital admission, patients' satisfaction, patient and caregiver burden. Risk of bias was assessed and certainty of evidence was evaluated using GRADE. PRINCIPAL FINDINGS: No study was fully free of bias. No effect was found on quality of life (standardized mean difference [SMD]: 0.05; 95% CI: -0.05 to 0.16) and hospital admission (risk ratio [RR]: 0.87; 95% CI: 0.65 to 1.17). There was a very small effect for patients' satisfaction (SMD: 0.15; 95% CI: 0.00 to 0.29) and caregiver burden (SMD: -0.13; 95% CI: -0.26 to 0.00). Certainty of evidence was low for all outcomes. CONCLUSIONS: No firm conclusions can be reached about the effects of goal-oriented care for multimorbid adults. Future research should overcome the shortcomings of trials assessed in this meta-analysis. Sound application of the indications for research of complex healthcare interventions is warranted.

[10 years of stagnant clinical research in the Italian academic context.] / Dieci anni di stagnazione della ricerca, non solo clinica, nel contesto accademico italiano.

This article is about current challenges to evidence-based medicine (EMB) in Italy. The authors, who share a 20-year commitment to the field of clinical research, discuss what they define as a phase of "stagnation" in practicing and teaching methods and research tactics, both in clinical and academic settings. Early success of EBM cultural movement was not persistent. The authors reason about how the teaching of EBM has remained a niche, concerning few professionals compared to the needs of the country. The authors identify some reasons that might have led to inconsistent attention to research methodology and address ways to strengthen the contribution of academic medicine to clinical research.

Psychosocial Care for Adult Cancer Patients: Guidelines of the Italian Medical Oncology Association.

Psychosocial morbidity can have negative consequences for cancer patients, including maladaptive coping, poor treatment adherence, and lower quality of life. Evidence shows that psychosocial interventions can positively impact quality of life, as well as symptoms and side effects; however, they are not always offered to patients who might benefit from them. These guidelines were produced by a multidisciplinary panel of 16 experts, including patients, following GRADE methodology. The panel framed clinical questions and voted on outcomes to investigate. Studies identified by rigorous search strategies were assessed to rate certainty of evidence, and recommendations were formulated by the panel. Although the quality of the evidence found was generally moderate, interventions could be recommended aimed at improving patient information, communication with healthcare professionals and involvement in decision-making; detecting and managing patient psychosocial needs, particularly with non-pharmacological therapy; and supporting families of patients with advanced cancer. The role of nurses as providers of information and psychosocial care is stressed. Most recommended interventions do not appear to necessitate new services or infrastructures, and therefore do not require allocation of additional resources, but predominantly involve changes in clinical staff behavior and/or ward organization. Patients should be made aware of psychosocial care standards so that they can expect to receive them.

AGREE II appraisals of clinical practice guidelines in rehabilitation showed poor reporting and moderate variability in quality ratings when users apply different cuff-offs: a methodological study.

OBJECTIVES: To analyze the reporting characteristics of Appraisal of Guidelines Research and Evaluation (AGREE) II appraisals in rehabilitation and explore how much quality ratings of Clinical Practice Guidelines (CPGs) vary applying different cut-offs. STUDY DESIGN AND SETTING: We conducted a methodological study re-analyzing data of an overview of AGREE II CPG appraisals in rehabilitation. Reporting characteristics of appraisals and methods used for quality rating were abstracted. We applied the most frequent cut-offs retrieved on all CPG sample to explore changes in quality ratings (i.e., high/low). RESULTS: We included 40 appraisals (n = 544 CPGs).The AGREE II overall assessment 1 (overall CPG quality) was reported in 26 appraisals (65%) and the overall assessment 2 (recommendation for use) in 17 (42.5%). Twenty-five appraisals (62.5%) reported the use of cut-offs based on domains and/or overall assessments. Application of the most reported cut-offs led to variability in quality ratings in 26% of the CPGs, of which 92% CPGs shifted their rating from low to high-quality and 8% shifted from high to low-quality. CONCLUSION: Rehabilitation stakeholders should take care to select the highest quality CPG in view of the poor reporting of AGREE II overall assessment 1 and 2 and moderate variability of quality ratings.

GRADE Notes 2: Criteria for searching non-randomized or indirect evidence should be defined early in the guideline production process.

OBJECTIVE: To discuss two alternative approaches for complementing the body of direct evidence from Randomized Controlled Trials (RCTs) when it is judged insufficient from a guideline panel making recommendations. The approaches included expanding the evidence's body to non-randomises studies on the population of interest or to RCTs on indirect populations. STUDY DESIGN AND SETTING: In this report, we adopt the perspective of an evidence review team developing guidelines following the GRADE approach. Our experience is based on the development of two evidence-based guidelines promoted by The Italian National Institute of Health (ISS) and focusing on diagnosis and treatment of Autism Spectrum Disorders (ASD) in children/adolescents and adults. RESULTS: We left panel members deciding case by case whether the direct evidence from RCTs was sufficient or not and indicating which alternative to implement. This strategy presented unanticipated challenges both from an organizational and methodological standpoint. CONCLUSION: We suggest an early-stage production of a research protocol to define the criteria for expanding the body of evidence. These criteria should be informed by considerations around the certainty in the evidence, the clinical applicability of the results, feasibility and conflict of interest.

Benefits and Harms of Lung Cancer Screening by Chest Computed Tomography: A Systematic Review and Meta-Analysis.

PURPOSE: This meta-analysis aims to combine and analyze randomized clinical trials comparing computed tomography lung screening (CTLS) versus either no screening (NS) or chest x-ray (CXR) in subjects with cigarette smoking history, to provide a precise and reliable estimation of the benefits and harms associated with CTLS. MATERIALS AND METHODS: Data from all published randomized trials comparing CTLS versus either NS or CXR in a highly tobacco-exposed population were collected, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Subgroup analyses by comparator (NS or CXR) were performed. Pooled risk ratio (RR) and relative 95% CIs were calculated for dichotomous outcomes. The certainty of the evidence was assessed using the GRADE approach. RESULTS: Nine eligible trials (88,497 patients) were included. Pooled analysis showed that CTLS is associated with: a significant reduction of lung cancer-related mortality (overall RR, 0.87; 95% CI, 0.78 to 0.98; NS RR, 0.80; 95% CI, 0.69 to 0.92); a significant increase of early-stage tumors diagnosis (overall RR, 2.84; 95% CI 1.76 to 4.58; NS RR, 3.33; 95% CI, 2.27 to 4.89; CXR RR, 1.52; 95% CI, 1.04 to 2.23); a significant decrease of late-stage tumors diagnosis (overall RR, 0.75; 95% CI, 0.68 to 0.83; NS RR, 0.67; 95% CI, 0.56 to 0.80); a significant increase of resectability rate (NS RR, 2.57; 95% CI, 1.76 to 3.74); a nonsignificant reduction of all-cause mortality (overall RR, 0.99; 95% CI, 0.94 to 1.05); and a significant increase of overdiagnosis rate (NS, 38%; 95% CI, 14 to 63). The analysis of lung cancer-related mortality by sex revealed nonsignificant differences between men and women (P = .21; I-squared = 33.6%). CONCLUSION: Despite there still being uncertainty about overdiagnosis estimate, this meta-analysis suggested that the CTLS benefits outweigh harms, in subjects with cigarette smoking history, ultimately supporting the systematic implementation of lung cancer screening worldwide.

Should oncoplastic breast conserving surgery be used for the treatment of early stage breast cancer? Using the GRADE approach for development of clinical recommendations.

INTRODUCTION: The potential advantages of oncoplastic breast conserving surgery (BCS) have not been validated in robust studies that constitute high levels of evidence, despite oncoplastic techniques being widely adopted around the globe. There is hence the need to define the precise role of oncoplastic BCS in the treatment of early breast cancer, with consensual recommendations for clinical practice. METHODS: A panel of world-renowned breast specialists was convened to evaluate evidence, express personal viewpoints and establish recommendations for the use of oncoplastic BCS as primary treatment of unifocal early stage breast cancers using the GRADE approach. RESULTS: According to the results of the systematic review of literature, the panelists were asked to comment on the recommendation for use of oncoplastic BCS for treatment of operable breast cancer that is suitable for breast conserving surgery, with the GRADE approach. Based on the voting outcome, the following recommendation emerged as a consensus statement: Oncoplastic breast conserving surgery should be recommended versus standard breast conserving surgery for the treatment of operable breast cancer in adult women who are suitable candidates for breast conserving surgery (with very low certainty of evidence). DISCUSSION: This review has revealed a low level of evidence for most of the important outcomes in oncoplastic surgery with lack of any randomized data and absence of standard tools for evaluation of clinical outcomes and especially patients' values. Despite areas of controversy, about one-third (36%) of panel members expressed a strong recommendation in support of oncoplastic BCS. Presumably, this reflects a synthesis of views on the relative complexity of these techniques, associated complications, impact on quality of life and costs.

Consensus on molecular imaging and theranostics in neuroendocrine neoplasms.

Nuclear medicine plays an increasingly important role in the management neuroendocrine neoplasms (NEN). Somatostatin analogue (SSA)-based positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT) have been used in clinical trials and approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). European Association of Nuclear Medicine (EANM) Focus 3 performed a multidisciplinary Delphi process to deliver a balanced perspective on molecular imaging and radionuclide therapy in well-differentiated neuroendocrine tumours (NETs). NETs form in cells that interact with the nervous system or in glands that produce hormones. These cells, called neuroendocrine cells, can be found throughout the body, but NETs are most often found in the abdomen, especially in the gastrointestinal tract. These tumours may also be found in the lungs, pancreas and adrenal glands. In addition to being rare, NETs are also complex and may be difficult to diagnose. Most NETs are non-functioning; however, a minority present with symptoms related to hypersecretion of bioactive compounds. NETs often do not cause symptoms early in the disease process. When diagnosed, substantial number of patients are already found to have metastatic disease. Several societies' guidelines address Neuroendocrine neoplasms (NENs) management; however, many issues are still debated, due to both the difficulty in acquiring strong clinical evidence in a rare and heterogeneous disease and the different availability of diagnostic and therapeutic options across countries. EANM Focus 3 reached consensus on employing 68gallium-labelled somatostatin analogue ([68Ga]Ga-DOTA-SSA)-based PET/CT with diagnostic CT or magnetic resonance imaging (MRI) for unknown primary NET detection, metastatic NET, NET staging/restaging, suspected extra-adrenal pheochromocytoma/paraganglioma and suspected paraganglioma. Consensus was reached on employing 18fluorine-fluoro-2-deoxyglucose ([18F]FDG) PET/CT in neuroendocrine carcinoma, G3 NET and in G1-2 NET with mismatched lesions (CT-positive/[68Ga]Ga-DOTA-SSA-negative). Peptide receptor radionuclide therapy (PRRT) was recommended for second line treatment for gastrointestinal NET with [68Ga]Ga-DOTA-SSA uptake in all lesions, in G1/G2 NET at disease progression, and in a subset of G3 NET provided all lesions are positive at [18F]FDG and [68Ga]Ga-DOTA-SSA. PRRT rechallenge may be used for in patients with stable disease for at least 1 year after therapy completion. An international consensus is not only a prelude to a more standardised management across countries but also serves as a guide for the direction to follow when designing new research studies.