Daratumumab-based regimens for patients with multiple myeloma plus extramedullary plasmacytomas or paraskeletal plasmacytomas: initial follow-up of an Italian multicenter observational clinical experience.

Myeloma with extramedullary plasmacytomas not adjacent to bone (EMP) is associated with an extremely poor outcome compared with paraosseous plasmacytomas (PP) as current therapeutic approaches are unsatisfactory. The role of new molecules and in particular of monoclonal antibodies is under investigation. To determine whether daratumumab-based regimens are effective for myeloma with EMP, we report herein an initial multicenter observational analysis of 102 myeloma patients with EMP (n = 10) and PP (n = 25) at diagnosis and EMP (n = 28) and PP (n = 39) at relapse, treated with daratumumab-based regimens at 11 Haematological Centers in Italy.EMP and PP at diagnosis were associated with higher biochemical (90% vs. 96%, respectively) and instrumental ORR (86% vs. 83.3%, respectively), while at relapse, biochemical (74% vs. 73%) and instrumental (53% vs. 59%) ORR were lower. Median OS was inferior in EMP patients compared with patients with PP both at diagnosis (21.0 months vs. NR) (p = 0.005) and at relapse (32.0 vs. 40.0 months) (p = 0.428), although, during relapse, there was no statistically significant difference between the two groups. Surprisingly, at diagnosis, median TTP and median TTNT were not reached either in EMP patients or PP patients and during relapse there were no statistically significant differences in terms of median TTP (20 months for two groups), and median TTNT (24 months for PP patients vs. 22 months for EMP patients) between the two groups. Median TTR was 1 month in all populations.These promising results were documented even in the absence of local radiotherapy and in transplant-ineligible patients.

From Indication-Based Pricing to Blended Approach: Evidence on the Price and Reimbursement Negotiation in Italy.

BACKGROUND: New indications for existing medicines are increasing over time. In most countries, drug pricing and reimbursement conditions are renegotiated every time a new indication is approved. There is a growing interest in the price negotiation model for new indications, specifically comparing an indication-based versus blended approach. However, little evidence currently exists regarding the complexity of these negotiations and their impact on actual prices. Italy has recently transitioned from an indication-based approach to a blended price model. This study aims to measure the impact of price and reimbursement negotiation of new indications on discounts (i.e. actual prices) and on the negotiation duration, used as a proxy of its complexity. METHODS: We considered new indications approved through a European centralized procedure from January 2013 to March 2022 for which the price and reimbursement status was approved in Italy between January 2015 and March 2022, amounting to 52 new indications. Data on the timeframe of the Italian price and reimbursement process and its phases were obtained from publicly available sources. Discounts for the first indication and their subsequent increases for new indications were estimated by comparing ex-factory prices and tendered prices. To calculate p-values, we employed the Mann-Whitney test, and multiple regression models were utilized to examine correlations between negotiation time and the characteristics of the medicines. RESULTS: The mean time to reimbursement was 603 days, in contrast to 583 days for the first launch. Price negotiation took longer for rare diseases, cancer drugs, and in case of therapies with minor added therapeutic value. On average, the additional discount (on top of discounts for prior indications) was 13%, significantly lower than the mean discount for the first indications approved (24.9%). The discounts increment was lower, but negotiation took longer if a Managed Entry Agreement accompanied the final agreement. Additionally, discounts have increased over the years. CONCLUSION: The negotiation for new indications takes longer than the first one, and provides, on average, an additional discount of 13%. While our findings bear the potential for significant policy implications, they necessitate prudent interpretation due to a limited number of observations. The increasing trend in additional discounts over time applied to all indications in recent negotiations, may suggest a descending trend of value for new indications and a shift from an indication-based pricing approach to a blended model. Otherwise, budget impact considerations might have outweighed a value-based approach in the recent negotiations. If so, two potential options for restoring a value-based approach are returning to an indication-based pricing or giving explicit and higher weight to value within a blended model.

Study protocol of a clinical randomized controlled trial on the efficacy of an innovative Digital thErapy to proMote wEighT loss in patients with obesity by incReasing their Adherence to treatment: the DEMETRA study.

Despite the increasing importance of innovative medications and bariatric surgery for the treatment of obesity, lifestyle interventions (diet and physical activity) remain the first-line therapy for this disease. The use of digital devices in healthcare aims to respond to the patient's needs, in order to make obesity treatment more accessible, so our study aims to assess the safety and efficacy of a Digital Therapy for Obesity App (DTxO) for achieving weight loss and its maintenance in patients affected with obesity undergoing an experimental non-pharmacological treatment. Here we present the study protocol of a prospective, multicenter, pragmatic, randomized, double-arm, placebo-controlled, parallel, single-blind study on obese patients who will be treated with a new digital therapy to obtain an improvement in their disease condition through the application of different simultaneous strategies (a dietary regimen and personalized advice program, a tailored physical exercise program, a cognitive-behavioural assessment and program, alerts and reminders, dedicated section on prescribed drugs intake, and chat and online visits with clinical professionals). We believe that DTxO will offer a promising intervention channel and self-regulation tool holding the potentiality to decrease treatment burden and treat more patients thanks to the partial replacement of traditional medical consultation with digital or telephone management, improving self- engagement and reducing the high demands the "obesity pandemic" for both patients and national health services in terms of time, cost, and effort. Clinical trial registration: clinicaltrials.gov, identifier, NCT05394779.

The prognostic role of mitotic rate in cutaneous malignant melanoma: Evidence from a multicenter study on behalf of the Italian Melanoma Intergroup.

BACKGROUND: This study aimed to improve the understanding of the prognostic value of tumor mitotic rate (TMR) in cutaneous melanoma and assessed its significance as a predictor for overall, melanoma-specific, and recurrence-free survival. PATIENTS AND METHODS: This is a retrospective multicenter Italian cohort study of 13,016 patients diagnosed with and treated for invasive primary melanoma between 2005 and 2020 with median follow-up of 5.5 years. The survival probability was assessed by Kaplan-Meier method, hazard ratios (HRs), and corresponding 95% confidence interval (CI) of all-cause mortality and recurrence/death by multivariable Cox proportional hazards models. RESULTS: Higher dermal mitoses number was associated with decreased overall survival. Among patients with TMR 0/mm2 , 1/mm2 , 2/mm2 -3/mm2 , 4/mm2 -10/mm2 , and >10/mm2 , 5-year overall survival (OS) was 97.3%, 93.6%, 88.3%, 73.0%, and 60.9%, respectively. In multivariate analyses, compared to TMR of 0/mm2 , HRs for all-cause mortality were 1.35 (95% CI, 1.08-1.68), 1.70 (95% CI, 1.40-2.07), 2.04 (95% CI, 1.67-2.49), and 2.39 (95% CI, 1.90-3.00) for 1 mitoses/mm2 , 2 mitoses/mm2 -3 mitoses/mm2 , 4 mitoses/mm2 -10 mitoses/mm2 , and >10 mitoses/mm2 , respectively. A similar increase in risks was observed in melanoma-specific survival (MSS) and recurrence-free survival (RFS). The HRs for MSS and RFS for the highest compared to the lowest TMR category were 3.01 (95% CI, 2.20-4.11) and 2.26 (95% CI, 1.88-2.73), respectively. Sentinel lymph-node biopsy positivity was significantly associated with TMR increase even with adjustment for several potential confounders. CONCLUSIONS: A clear association was demonstrated between an increasing TMR and decreased OS, MSS, and RFS, suggesting a reconsideration of TMR prognostic role for future inclusion in the melanoma staging system. PLAIN LANGUAGE SUMMARY: The 8th American Joint Committee on Cancer for melanoma staging removed tumor mitotic rate (TMR) from the staging criteria for T1 melanomas, giving way to ulceration and tumor thickness as stronger prognostic predictors. However, it is still recommended that TMR should be assessed and recorded in all primary invasive melanomas. In a large retrospective multicenter study on primary invasive melanomas, we investigated the prognostic value of TMR to assess its significance as survival predictor. Our results showed a clear association between increasing TMR and decreased patients' survival, suggesting that TMR should be considered for inclusion in the melanoma staging system.

Potential risk factors, clinicopathological features and determinants of survival for multiple primary melanoma patients compared to single primary melanoma: a large single-center Italian study.

Melanoma patients have a high risk of developing subsequent primary melanomas, a condition known as multiple primary melanoma (MPM). We aimed to compare risk factors of patients with MPM and single primary melanoma (SPM). Primary MPM and SPM consecutively treated at the National Cancer Institute in Milan, Italy, from 1978 to 2021 were retrospectively investigated. Demographic and clinicopathological characteristics were analyzed. Multivariate hazard ratios and mortality were estimated using Cox proportional hazards regression models. Overall, 9122 patients with SPM and 944 with MPM were included. A total of 1437 and 85 deaths occurred in SPM and MPM group, respectively. Of these, 1315 (14.4%) within SPM patients and 60 (6.4%) in MPM group were melanoma-specific deaths (MSDs). Males had a higher risk for MPM (hazard ratio = 1.29), while age was not associated with MPM (hazard ratio = 0.98). The risk of MPM decreased by about 50% for Breslow thickness >1 mm, and by about 45 and 75% in presence of mitoses and ulceration, respectively. The multivariate hazard ratio of death for MPM compared to SPM patients was 0.85 (95% confidence interval, CI: 0.67-1.06), while considering MSD the corresponding hazard ratio was 0.93 (95% CI: 0.71-1.22). Melanoma patients should receive regular follow-up with complete skin examination to detect early subsequent primary melanoma. Patients with more advanced primary have decreased risk of MPM, while males have higher risk. Our study reported no significant difference in mortality between SPM and MPM, but the issue is still open for discussion and further studies.

The Evaluation of Drug Innovativeness in Italy: Key Determinants and Internal Consistency.

BACKGROUND: Innovative medicines are provided with dedicated funds and immediate market access in Italy. Innovativeness evaluation considers unmet need, added therapeutic value, and quality of the evidence. OBJECTIVE: We aimed to evaluate the internal consistency and drivers of the innovativeness appraisal process. METHODS: Appraisal reports on innovativeness refer to 1997-2021. We used both a descriptive approach and probabilistic multivariate analysis, using logistic regression models to compute odds ratios and 95% confidence intervals. The dependent variable is innovativeness status (innovative vs. non-innovative; full innovativeness vs. conditional innovativeness). Explanatory variables, besides the three above-mentioned domains, are the year of evaluation, drug type, target disease and population, and the number and type of available studies. RESULTS: Among the 141 medicines scrutinized, 31.9%, 29.8%, and 38.3% were evaluated as fully innovative, conditionally innovative, and non-innovative, respectively. Added therapeutic value and the quality of the evidence were associated with the odds of receiving innovative status, and full compared with conditional innovativeness; unmet need was not a predictive variable. Other factors played a minor role: medicines for both solid tumours and rare diseases are more likely to be judged innovative; conditional innovativeness is more probable for medicines for rare diseases. CONCLUSIONS: Innovativeness status is driven by the added therapeutic value and quality of evidence. The appraisal process is internally consistent and predictable. This provides industry with a clear indication of what is needed to ensure that access to their medicines is prioritized.

Allium vegetables intake and the risk of gastric cancer in the Stomach cancer Pooling (StoP) Project.

BACKGROUND: The role of allium vegetables on gastric cancer (GC) risk remains unclear. METHODS: We evaluated whether higher intakes of allium vegetables reduce GC risk using individual participant data from 17 studies participating in the "Stomach cancer Pooling (StoP) Project", including 6097 GC cases and 13,017 controls. Study-specific odds ratios (ORs) were pooled using a two-stage modelling approach. RESULTS: Total allium vegetables intake was inversely associated with GC risk. The pooled OR for the highest versus the lowest study-specific tertile of consumption was 0.71 (95% confidence interval, CI, 0.56-0.90), with substantial heterogeneity across studies (I2 > 50%). Pooled ORs for high versus low consumption were 0.69 (95% CI, 0.55-0.86) for onions and 0.83 (95% CI, 0.75-0.93) for garlic. The inverse association with allium vegetables was evident in Asian (OR 0.50, 95% CI, 0.29-0.86) but not European (OR 0.96, 95% CI, 0.81-1.13) and American (OR 0.66, 95% CI, 0.39-1.11) studies. Results were consistent across all other strata. CONCLUSIONS: In a worldwide consortium of epidemiological studies, we found an inverse association between allium vegetables and GC, with a stronger association seen in Asian studies. The heterogeneity of results across geographic regions and possible residual confounding suggest caution in results interpretation.

Key drivers of innovativeness appraisal for medicines: the Italian experience after the adoption of the new ranking system.

OBJECTIVE: In 2017, the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA) introduced a standardised process to appraise innovativeness of medicines. Innovative medicines are provided speeder market access and dedicated funds. Innovativeness criteria are: unmet therapeutic need, added therapeutic value and quality of the evidence (Grading of Recommendations Assessment, Development and Evaluation method). We investigated the role played by these three criteria on the final decision aimed to understand how the new Italian innovativeness appraisal framework was implemented. DESIGN: A desk research gathered AIFA's appraisal reports on innovativeness and data analyses were conducted. No patients were directly involved in this study. SETTING AND PARTICIPANTS: We scrutinised all 77 appraisal reports available on AIFA's website (2017-2020). PRIMARY AND SECONDARY OUTCOME MEASURES: The impact of the three domains on final decision was investigated through a series of univariate analyses. RESULTS: Among 77 appraisal reports on innovativeness available, 49 (64%) and 28 (36%) were for oncology and non-oncology medicines, respectively. The appraisals were equally distributed among 'fully innovative' (36%), 'conditionally innovative' (30%) and 'not innovative' (34%). Added therapeutic value was the most important driver on innovativeness decision, followed by quality of the evidence. Drugs for rare diseases and with paediatric/mixed indications were appraised 'innovative' by a larger proportion, but no statistical significance was found. CONCLUSIONS: Despite some limitations, including the moderate number of appraisals, this paper provides an insight into the determinants of innovativeness appraisals for medicines in Italy and the accuracy of the appraisal process. This has important implications in terms of transparency and accountability in the prioritisation process applied to innovative medicines.

Surgical treatment of melanoma metastases to the small bowel: A single cancer referral center real-life experience.

INTRODUCTION: Treatment of metastatic melanoma has rapidly changed during the last years, and patients often require a multidisciplinary approach to achieve effective results. We aimed to assess the survival benefit achieved through surgical approach to patients with small bowel (SB) metastases from cutaneous melanoma, to emphasize the potential role of surgery in association with novel therapies. METHODS: Ninety consecutive patients with cutaneous melanoma diagnosed as having resectable SB metastases from 1995 to 2015 were retrospectively investigated. RESULTS: Median age at surgery of melanoma metastases was 53.4 years. Among 30 patients who had a curative-intent resection, the 5- and 10-year survival rates were 61% and 54%, respectively, while among 60 patients treated with a palliative surgery the corresponding rates were both 4%. Among 29 patients, for whom the interval time between the occurrence of SB metastases and the previous surgical event on GI tract was ≥36 months, the 5-year overall survival rate was 42%; for 56 patients who had an interval time <36 months the corresponding survival rate was 14%. Within the whole series, an absence of any residual disease after surgery (R0) was a factor affecting better survival, regardless of the evidence of metastases in other organs. CONCLUSION: Our observational data showed that surgical treatment for patients with SB metastases from melanoma might increase survival, but further studies are needed to confirm this finding. In the age of novel available therapies, the increase in survival time given by surgery may offer important chances for patients to benefit from systemic therapies.

The role of sentinel lymph node status performed in melanoma patients with local recurrence or in transit metastasis.

BACKGROUND: Sentinel Node Biopsy (SNB) is routinely performed for primary melanoma, but its role in the treatment of Local Recurrence (LR) and In-Transit metastasis (IT) is controversial. This study aims to assess the role of SNB in melanoma patients who developed first loco-regional recurrence. METHODS: A series of consecutive melanoma patients who received SNB for a first IT or LR at the National Cancer Institute of Milan, Italy, from 2000 to 2015 were selected from a prospective database. Clinicopathological characteristics were analyzed. RESULTS: Seventy-two patients met selection criteria. Forty-three patients (59.7%) received SNB for LR and 29 (40.3%) for IT. The average interval between treatment of primitive melanoma and first recurrence diagnosis was 19 months (interquartile range: 6.9-49.0). SN identification rate was 97.2%. SN positivity was detected in 26 (37.1%) patients. The SN-positive ratein melanoma patients who had LR or IT was significantly higher than reported for primary tumours. Of patients with nodal involvement 17 had LR and 9 IT lesions. Disease Free Survival (DFS) was slightly higher in SN negative patients, in the absence of statistically significant differences. Overall Survival (OS) analysis showed similar values in the two groups. CONCLUSION: Since DFS and OS do not show significant differences between SN negative and positive patients, our data do not give clear indications about performing SNB in case of first LR or IT. However, we suggest submitting patients with LR to this procedure to obtain a more accurate staging and eventually candidate these patients to adjuvant treatment.

Protocol Implementation for Normothermia in Surgery Settings in Italy: Budget-Impact Analysis.

INTRODUCTION: Hypothermia is a well-known risk of the perioperative period and considered a preventable effect of anesthesia care. Nevertheless, it is not fully controlled, causing a number of adverse outcomes following surgical operations and thus increasing length of stay in hospital and treatment costs. The aim of this study was to assess the budget impact (BI) of the implementation of proactive strategies to prevent inadvertent perioperative hypothermia (IPH) in surgical patients in Italy, as recommended by international guidelines and by a good clinical practice (GCP) guideline of the Italian Society of Anesthesia, Analgesia, Reanimation, and Intensive Care. METHODS: BI was calculated over a 3-year period from the perspective of the Italian National Health Service (NHS). Model inputs were extracted from national literature when available and otherwise from international sources. The reference analytic model was based on the cost-effectiveness analysis of the National Institute for Health and Care Excellence clinical guidance 65. Estimates were based on assessments made about current malpractice in Italy and on a hypothesis of how future practice might change by implementing the GCP. Model output included overall BI results, variations in the number of warmed patients, medical-device average costs and use of mix. RESULTS: The base-case estimate quantified a decrease of 35% in extra days of hospital stay due to IPH and a net BI of -€60.92 million. CONCLUSION: Increasing protocol adoption for preventing IPH would lead to both clinical advantages and significant savings for the NHS. Its large diffusion in Italian hospitals is thus desirable.

PERsistent Sitagliptin treatment & Outcomes (PERS&O 2.0) study, long-term results: a real-world observation on DPP4-inhibitor effectiveness.

INTRODUCTION: Sitagliptin is a dipeptidyl peptidase 4 inhibitor for the treatment of type 2 diabetes (T2D). Limited real-world data on its effectiveness and safety are available from an Italian population. RESEARCH DESIGN AND METHODS: We evaluated long-term clinical data from the single-arm PERsistent Sitagliptin Treatment & Outcomes (PERS&O) study, which collected information on 440 patients with TD2 (275 men, 165 women; mean age 64.1 years; disease median duration: 12 years) treated with sitagliptin 'add-on'. For each patient, we estimated the 10-year cardiovascular (CV) risk using the UK Prospective Diabetes Study (UKPDS) Risk Engine (RE). Drug survival was evaluated using Kaplan-Meier survival curves; repeated measures mixed effects models were used to evaluate the evolution of glycated hemoglobin (HbA1c) and CV risk during sitagliptin treatment. RESULTS: At baseline, most patients were overweight or obese (median body mass index (BMI) (kg/m2) 30.2); median HbA1c was 8.4%; median fasting plasma glucose: 172 mg/dL; median UKPDS RE score: 24.8%, being higher in men (median 30.2%) than in women (median 17.0%) as expected. Median follow-up from starting sitagliptin treatment was 5.6 years. From Kaplan-Meier curves, the estimated median drug survival was 32.8 months when considering discontinuation for any cause and 58.4 months when considering discontinuation for loss of efficacy. A significant improvement in HbA1c was evident during treatment with sitagliptin (p<0.01): the reduction was rapid (median HbA1c after 4-6 months: 7.5%) and continued at longer follow-up. When comparing patients treated with sitagliptin versus those stopping sitagliptin and switching to another antihyperglycemic drug, we detected a significant difference in the evolution of HbA1c in favor of patients who continued sitagliptin treatment. The UKPDS RE score at 10 years and the BMI significantly improved during treatment with sitagliptin (p<0.001). Adverse events were relatively uncommon. CONCLUSION: Patients with T2D treated with sitagliptin achieved an improvement in metabolic control and a reduction in CV risk and did not experience relevant adverse events.

Methadone for postoperative analgesia: contribution of N-methyl-D-aspartate receptor antagonism: A randomised controlled trial.

BACKGROUND: Over the past number of years, N-methyl-D-aspartate (NMDA) inhibitory drugs, like ketamine, have been introduced as adjuvant treatments for postoperative acute pain, within a multimodal approach. A further extension of this strategy could be the use of opioids with NMDA receptor (NMDAr) antagonism activity for control of postoperative pain. Methadone has a unique pharmacodynamic profile: it is both a µ-agonist and an NMDAr-blocker. OBJECTIVE: We designed this study to investigate the precise contribution of NMDAr antagonism in methadone-induced analgesia. DESIGN: Single-centre, prospective, randomised, double-blind study. SETTING: National Cancer Center - Fondazione IRCCS Istituto Nazionale Tumori Milano; patients were recruited between March 2010 and June 2012. PATIENTS: Ninety-six patients scheduled for an open laparotomy for anterior resection of the rectum. INTERVENTIONS: We randomly assigned patients to four groups: 0-Mo (placebo and morphine), K-Mo [S(+)-ketamine and morphine], 0-Me (placebo and methadone), K-Me [S(+)-ketamine and methadone]. MAIN OUTCOME MEASURES: The primary end-point was the extent of mechanical static (punctuate) hyperalgesia to von Frey hair stimulation lateral to the surgical incision. RESULTS: Peri-incisional hyperalgesia was 8.4 cm (95% confidence interval, 1.5 to 15.41) lower in the treatment group (K-Me) compared with the control group (0-Mo) at 24 h after surgery (P = 0.02). No significant differences were observed between the groups at 48 h after surgery (P = 0.88). Both groups treated with methadone had significantly lower pain during rest and movement, as measured with a Numerical Rating Scale at 24 h. At 48 h, only the movement Numerical Rating Scale was significantly lower. No difference occurred in opioid consumption. CONCLUSION: Methadone provides effective control of acute postoperative pain, independently, by modulation of the hyperalgesia mechanism. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, no.: NCT01594047.

Stratification of long-term outcome in stable idiopathic pulmonary fibrosis by combining longitudinal computed tomography and forced vital capacity.

OBJECTIVES: To test HRCT with either visual or quantitative analysis in both short-term and long-term follow-up of stable IPF against long-term (transplant-free) survival, beyond 2 years of disease stability. METHODS: Fifty-eight IPF patients had FVC measurements and HRCTs at baseline (HRCT0), 10-14 months (HRCT1) and 22-26 months (HRCT2). Visual scoring, CALIPER quantitative analysis of HRCT measures, and their deltas were evaluated against combined all-cause mortality and lung transplantation by adjusted Cox proportional hazard models at each time interval. RESULTS: At HRCT1, a ≥ 20% relative increase in CALIPER-total lung fibrosis yielded the highest radiological association with outcome (C-statistic 0.62). Moreover, the model combining FVC% drop ≥ 10% and ≥ 20% relative increase of CALIPER-total lung fibrosis improved the stratification of outcome (C-statistic 0.69, high-risk category HR 12.1; landmark analysis at HRCT1 C-statistic 0.66, HR 14.9 and at HRCT2 C-statistic 0.61, HR 21.8). Likewise, at HRCT2, the model combining FVC% decrease trend and ≥ 20% relative increase of CALIPER-pulmonary vessel-related volume (VRS) improved the stratification of outcome (C-statistic 0.65, HR 11.0; landmark analysis at HRCT1 C-statistic 0.62, HR 13.8 and at HRCT2 C-statistic 0.58, HR 12.6). A less robust stratification of outcome distinction was also demonstrated with the categorical visual scoring of disease change. CONCLUSIONS: Annual combined CALIPER -FVC changes showed the greatest stratification of long-term outcome in stable IPF patients, beyond 2 years. KEY POINTS: • Longitudinal high-resolution computed tomography (HRCT) data is more helpful than baseline HRCT alone for stratification of long-term outcome in IPF. • HRCT changes by visual or quantitative analysis can be added with benefit to the current spirometric reference standard to improve stratification of long-term outcome in IPF. • HRCT follow-up at 12-14 months is more helpful than HRCT follow-up at 23-26 months in clinically stable subjects with IPF.

Education and gastric cancer risk-An individual participant data meta-analysis in the StoP project consortium.

Low socioeconomic position (SEP) is a strong risk factor for incidence and premature mortality from several cancers. Our study aimed at quantifying the association between SEP and gastric cancer (GC) risk through an individual participant data meta-analysis within the "Stomach cancer Pooling (StoP) Project". Educational level and household income were used as proxies for the SEP. We estimated pooled odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) across levels of education and household income by pooling study-specific ORs through random-effects meta-analytic models. The relative index of inequality (RII) was also computed. A total of 9,773 GC cases and 24,373 controls from 25 studies from Europe, Asia and America were included. The pooled OR for the highest compared to the lowest level of education was 0.60 (95% CI, 0.44-0.84), while the pooled RII was 0.45 (95% CI, 0.29-0.69). A strong inverse association was observed both for noncardia (OR 0.39, 95% CI, 0.22-0.70) and cardia GC (OR 0.47, 95% CI, 0.22-0.99). The relation was stronger among H. pylori negative subjects (RII 0.14, 95% CI, 0.04-0.48) as compared to H. pylori positive ones (RII 0.29, 95% CI, 0.10-0.84), in the absence of a significant interaction (p = 0.28). The highest household income category showed a pooled OR of 0.65 (95% CI, 0.48-0.89), while the corresponding RII was 0.40 (95% CI, 0.22-0.72). Our collaborative pooled-analysis showed a strong inverse relationship between SEP indicators and GC risk. Our data call for public health interventions to reduce GC risk among the more vulnerable groups of the population.

Residual Lesions After Pharmacological and Dye-Laser Treatment of Infantile Hemangiomas: Critical Review of 432 Cases.

BACKGROUND AND OBJECTIVES: Infantile hemangiomas (IHs) are the most common benign tumors in infanthood. Although they are often self-limiting, management of IHs is still controversial because residual lesions may persist in some cases. The aim of this study is to report our experience with patients affected with IH and investigate the frequency of residual lesions in treated versus untreated patients. STUDY DESIGN/MATERIALS AND METHODS: This retrospective observational study enrolled patients with IHs evaluated over the past 10 years. Patients were managed with systemic or local pharmacotherapy, laser therapy, a combination of them, or with observation only. RESULTS: A total of 432 patients were included: 71% received one or more therapies for IHs; 75.2% of untreated patients had at least one residual lesion compared with 41.4% of treated patients (P < 0.001). Patients treated with laser therapy or topical timolol had the lowest rate of residual lesions. CONCLUSIONS: This rather large case series suggests that IHs management with pharmacotherapy and especially laser therapy is associated with a lower number of residual lesions than observation only. Although propranolol can be very useful to avoid life-threatening complications and severe tissue impairment, laser therapy and topical timolol are potential effective treatments to decrease the incidence of residual lesions, mostly associated with superficial IHs. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Correction: Circulating microRNA signature as liquid-biopsy to monitor lung cancer in low-dose computed tomography screening.

[This corrects the article DOI: 10.18632/oncotarget.5210.].

Plasma levels of polychlorinated biphenyls (PCB) and the risk of soft tissue sarcoma.

BACKGROUND: Soft tissue sarcoma (STS) is a heterogeneous group of rare neoplasms whose aetiology is largely unknown. Dioxin and dioxin-like compounds, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and polychlorinated biphenyls (PCBs), are potential risk factors for STS. OBJECTIVES: To investigate the relation of 17 PCBs congeners, assessed in human plasma, with STS risk. METHODS: We conducted a case-control study in Italy, including 52 STS cases and 99 hospital-based controls. Selected PCB were extracted by high-performance liquid chromatography (HPLC) and measured with gas chromatography-mass spectrometry (GC-MS). Odds ratios (OR), and the corresponding 95% confidence intervals (CI), were estimated through multivariate logistic regression models. RESULTS: The most frequently detected PCB congeners were 138, 170, 180 and 149 (detected in 40-77% of controls). The OR for the sum of all 17 PCB congeners was 1.20 (95% CI 0.50-2.92). In categorical analysis no consistent association was found for individual congeners and for groups based on Wolff's classification or the degree of chlorination. For continuous estimates, borderline positive associations emerged for Wolff's groups 2A (OR 1.23, 95% CI 0.97-1.55), 2B (OR 1.34, 95% CI 1.00-1.77, and 3 (OR 1.19, 95% CI 0.96-1.49), for moderately (OR 1.20, 95% CI 0.96-1.51) and highly (OR 1.18, 95% CI 0.99-1.41) chlorinated PCBs, and for congeners 170 (OR 1.26, 95% CI 0.98-1.63), 180 (OR 1.26, 95% CI 0.97-1.64) and 138 (OR 1.45, 95% CI 1.02-2.04). DISCUSSION: Most associations between PCBs and STS risk were not significant, but, given the limited sample size, we cannot exclude moderate associations.

Glycemic Index, Glycemic Load and Cancer Risk: An Updated Meta-Analysis.

Diets high in glycemic index (GI) and glycemic load (GL) have been related to an increased risk of selected cancers, but additional quantification is required. We updated a systematic review and meta-analysis published in 2015 to May 2019 to provide quantitative information on GI/GL and cancer risk. Relative risks (RR) and the corresponding 95 % confidence intervals (CI) for the highest versus the lowest categories of GI and GL were extracted from selected studies and pooled using random-effects models. Twenty reports (>22,000 cancer cases) have become available after January 2015, and 15 were added to the meta-analyses by cancer sites, which considered a total of 88 investigations. The five additional reports were reviewed, but not included in the meta-analyses, since data were inadequate to be pooled. For hormone-related cancers, summary RRs for the highest versus lowest GI and GL intakes were moderately increased. They ranged from 1.04 (breast) to 1.12 (endometrium) for GI and from 1.03 (prostate) to 1.22 (ovary) for GL, of borderline significance. High GI was associated with small increased risks of colorectal (summary RR for GI: 1.20, 95% CI, 1.07-1.34-GL: 1.09, 95% CI, 0.97-1.22, 19 studies), bladder (GI: 1.25, 95% CI, 1.11-1.41-GL: 1.10, 95% CI, 0.85-1.42, four studies) and kidney cancers (GI: 1.16, 95% CI, 1.02-1.32-GL: 1.14, 95% CI, 0.81-1.60, five studies). GL was not significantly related to those cancer sites. Stomach, prostate and lung cancers were not associated with GI and GL. The present analysis, based on an updated comprehensive evaluation of the epidemiological literature, indicates moderate unfavorable effects of high versus low GI on colorectal, and possibly bladder and kidney cancers, and a possible moderate positive association between GL and endometrial cancer.

Real-world experience with decitabine as a first-line treatment in 306 elderly acute myeloid leukaemia patients unfit for intensive chemotherapy.

Despite widespread use of decitabine to treat acute myeloid leukaemia (AML), data on its effectiveness and safety in the real-world setting are scanty. Thus, to analyze the performance of decitabine in clinical practice, we pooled together patient-level data of three multicentric observational studies conducted since 2013 throughout Italy, including 306 elderly AML patients (median age 75 years), unfit for intensive chemotherapy, treated with first-line decitabine therapy at the registered schedule of 20 mg/m2 /iv daily for 5 days every 4 weeks. Overall response rate (ORR), overall survival (OS) curves, and multivariate hazard ratios (HRs) of all-cause mortality were computed. Overall, 1940 cycles of therapy were administered (median, 5 cycles/patient). A total of 148 subjects were responders and, therefore, ORR was 48.4%. Seventy-one patients (23.2%) had complete remission, 32 (10.5%) had partial remission, and 45 (14.7%) had haematologic improvement. Median OS was 11.6 months for patients with favourable-intermediate cytogenetic risk and 7.9 months for those with adverse cytogenetic risk. Median relapse-free survival after CR was 10.9 months (95% confidence interval [CI]: 8.7-16.0). In multivariate analysis, mortality was higher in patients with adverse cytogenetic risk (HR=1.58; 95% CI: 1.13-2.21) and increased continuously with white blood cell (WBC) count (HR=1.12; 95% CI: 1.06-1.18). A total of 183 infectious adverse events occurred in 136 patients mainly (>90%) within the first five cycles of therapy. This pooled analysis of clinical care studies confirmed, outside of clinical trials, the effectiveness of decitabine as first-line therapy for AML in elderly patients unfit for intensive chemotherapy. An adverse cytogenetic profile and a higher WBC count at diagnosis were, in this real life setting, unfavourable predictors of survival.