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Background: Venous thromboembolism (VTE) is a common complication of cancer. This study aimed to evaluate immature platelet fraction (IPF), mean platelet volume (MPV), P-selectin, D-dimer, and thrombin generation (TG) as predictive biomarkers for VTE and further the improvement of existing risk assessment models (RAMs). Methods: A prospective, observational, exploratory study was conducted on ambulatory cancer patients with indication for systemic chemotherapy. Baseline RAMs included the Khorana-, Vienna Cancer, Thrombosis-, Protecht-, ONKOTEV-, and Catscore. IPF, MPV, P-selectin, D-dimer, and TG were analysed at baseline and 3-month follow-up. Results: We enrolled 100 patients, of whom 89 completed the follow-up. Frequent tumour types were breast (30%), gastric (14%), gynaecological (14%), and colorectal (14%) cancer. Ten of the 89 patients (11.2%) developed VTE. The highest VTE rate was observed in patients with cholangiocarcinoma (3/5; 60%). Baseline D-dimer levels but not IPF, MPV, or P-selectin were associated with the risk of developing VTE (HR 6.9; p = 0.021). None of the RAMs showed statistical significance in predicting VTE. Peak thrombin and endogenous thrombin potential were lower in patients who developed VTE. Biomarker changes between baseline and follow-up were not associated with VTE risk. Conclusions: VTE risk was well predicted by baseline D-dimer levels. Adding D-dimer could improve existing RAMs to better identify patients who may benefit from primary VTE prophylaxis. The VTE risk among patients with cholangiocarcinoma should be further evaluated.

We aimed to evaluate the performance of the Khorana score in predicting venous thromboembolic events in ambulatory cancer patients. Embase and MEDLINE were searched from January 2008 to June 2018 for studies which evaluated the Khorana score. Two authors independently screened studies for eligibility, extracted data, and assessed risk of bias. Additional data on the 6-month incidence of venous thromboembolism were sought by contacting corresponding authors. The incidence in each Khorana score risk group was estimated with random effects meta-analysis. A total of 45 articles and eight abstracts were included, comprising 55 cohorts enrolling 34,555 ambulatory cancer patients. For 27,849 patients (81%), 6-month follow-up data were obtained. Overall, 19% of patients had a Khorana score of 0 points, 64% a score of 1 or 2 points, and 17% a score of 3 or more points. The incidence of venous thromboembolism in the first six months was 5.0% (95% CI: 3.9-6.5) in patients with a low-risk Khorana score (0 points), 6.6% (95% CI: 5.6-7.7) in those with an intermediate-risk Khorana score (1 or 2 points), and 11.0% (95% CI: 8.8-13.8) in those with a high-risk Khorana score (3 points or higher). Of the patients with venous thromboembolism in the first six months, 23.4% (95% CI: 18.4-29.4) had been classified as high risk according to the Khorana score. In conclusion, the Khorana score can be used to select ambulatory cancer patients at high risk of venous thromboembolism for thromboprophylaxis; however, most events occur outside this high-risk group.

To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria 2 (IQR: 0.16–0.50 mL/min per 1.73 m 2 ) on combined therapy, 0.36 mL/min per 1.73 m 2 (IQR: 0.18–0.53 mL/min per 1.73 m 2 ) on delapril, and 0.30 mL/min per 1.73 m 2 (IQR: 0.12–0.50 mL/min per 1.73 m 2 ) on placebo ( P =0.87 and P =0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04–0.78; P =0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07–0.99; P =0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24–0.87; P =0.017) and 0.52 (0.27–0.99; P =0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo ( P =0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.

Trials failed to demonstrate protective effects of investigational treatments on glomerular filtration rate (GFR) reduction in Autosomal Dominant Polycystic Kidney Disease (ADPKD). To assess whether above findings were explained by unreliable GFR estimates, in this academic study we compared GFR values centrally measured by iohexol plasma clearance with corresponding values estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) and abbreviated Modification of Diet in Renal Disease (aMDRD) formulas in ADPKD patients retrieved from four clinical trials run by a Clinical Research Center and five Nephrology Units in Italy. Measured baseline GFRs and one-year GFR changes averaged 78.6±26.7 and 8.4±10.3 mL/min/1.73 m(2) in 111 and 71 ADPKD patients, respectively. CKD-Epi significantly overestimated and aMDRD underestimated baseline GFRs. Less than half estimates deviated by

Neoadjuvant chemotherapy (NAC) significantly improved the prognosis of patients with locally advanced resectable gastric cancer but, despite important progresses, relapse-related death remains a major challenge. Therefore, it appears crucial to understand which patients will benefit from peri-operative treatment. Biomarkers such as human epidermal growth factor receptor-2 (HER2), microsatellite instability (MSI), and Epstein-Barr Virus (EBV) have been widely studied; however, they do not yet guide the choice of perioperative treatment in clinical practice. We performed a narrative review, including 23 studies, addressing the value of tissue- or blood-based biomarkers in the neoadjuvant setting. Ten studies (43.5%) were prospective, and more than half were conducted in East-Asia. Biomarkers were evaluated only post-NAC (on surgical samples or blood) in seven studies (30.4%), only pre-NAC (on endoscopic specimens or blood) in 10 studies (43.5%), and both pre- and post-NAC (26.1%) in six studies. Among the high variety of investigated biomarkers, some of these including MSI-H or enzymatic profile (as TS, UGT1A1, MTHFR, ERCC or XRCC) showed promising results and deserve to be assessed in methodologically sound clinical trials. The identification of molecular biomarkers in patients treated with NAC for locally advanced resectable gastric or EGJ cancer remains crucial.

Introduction:Exocrine pancreatic cancers include common type pancreatic ductal adenocarcinoma and cystic neoplasms, which account for 85% and 10% of cases, respectively. The remaining 5% are rare histotypes, comprising adenosquamous carcinoma, acinar cell carcinoma, signet ring cell carcinoma, medullary carcinoma, pancreatoblastoma, hepatoid carcinoma, undifferentiated carcinoma and its variant with osteoclast-like giant cells, solid pseudopapillary carcinoma, and carcinosarcoma. Due to their low incidence, little knowledge is available on their clinical and molecular features as well as on treatment choices. The national initiative presented here aims at the molecular characterization of series of rare histotypes for which therapeutic and follow-up data are available.Methods:A nationwide Italian Rare Pancreatic Cancer (IRaPaCa) task force whose first initiative is a multicentric retrospective study involving 21 Italian cancer centers to retrieve histologic material and clinical and treatment data of at least 100 patients with rare exocrine pancreatic cancers has been created. After histologic revision by a panel of expert pathologists, DNA and RNA from paraffin tissues will be investigated by next-generation sequencing using molecular pathway–oriented and immune-oriented mutational and expression profiling panels constructed availing of the information from the International Cancer Genome Consortium. Bioinformatic analysis of data will drive validation studies by immunohistochemistry and in situ hybridization, as well as nanostring assays.Conclusions:We expect to gather novel data on rare pancreatic cancer types that will be useful to inform the design of therapeutic choices.

OBJECTIVE To describe the prevalence and determinants of hyperfiltration (glomerular filtration rate [GFR] ≥120 mL/min/1.73 m2), GFR decline, and nephropathy onset or progression in type 2 diabetic patients with normo- or microalbuminuria. RESEARCH DESIGN AND METHODS We longitudinally studied 600 hypertensive type 2 diabetic patients with albuminuria RESULTS Over a median (range) follow-up of 4.0 (1.7–8.1) years, GFR declined by 3.37 (5.71–1.31) mL/min/1.73 m2 per year. GFR change was bimodal over time: a larger reduction at 6 months significantly predicted slower subsequent decline (coefficient: −0.0054; SE: 0.0009), particularly among hyperfiltering patients. A total of 90 subjects (15%) were hyperfiltering at inclusion, and 11 of 47 (23.4%) patients with persistent hyperfiltration progressed to micro- or macroalbuminuria versus 53 (10.6%) of the 502 who had their hyperfiltration ameliorated at 6 months or were nonhyperfiltering since inclusion (hazard ratio 2.16 [95% CI 1.13–4.14]). Amelioration of hyperfiltration was independent of baseline characteristics or ACE inhibition. It was significantly associated with improved BP and metabolic control, amelioration of GDR, and slower long-term GFR decline on follow-up. CONCLUSIONS Despite intensified treatment, patients with type 2 diabetes have a fast GFR decline. Hyperfiltration affects a subgroup of patients and may contribute to renal function loss and nephropathy onset or progression. Whether amelioration of hyperfiltration is renoprotective is worth investigating.

There are no adequate studies that have formally tested the performance of different estimating formulas in patients with type 2 diabetes both with and without overt nephropathy. Here we evaluated the agreement between baseline GFRs, GFR changes at month 6, and long-term GFR decline measured by iohexol plasma clearance or estimated by 15 creatinine-based formulas in 600 type 2 diabetics followed for a median of 4.0 years. Ninety patients were hyperfiltering. The number of those identified by estimation formulas ranged from 0 to 24:58 were not identified by any formula. Baseline GFR was significantly underestimated and a 6-month GFR reduction was missed in hyperfiltering patients. Long-term GFR decline was also underestimated by all formulas in the whole study group and in hyper-, normo-, and hypofiltering patients considered separately. Five formulas generated positive slopes in hyperfiltering patients. Baseline concordance correlation coefficients and total deviation indexes ranged from 32.1% to 92.6% and from 0.21 to 0.53, respectively. Concordance correlation coefficients between estimated and measured long-term GFR decline ranged from -0.21 to 0.35. The agreement between estimated and measured values was also poor within each subgroup considered separately. Thus, our study questions the use of any estimation formula to identify hyperfiltering patients and monitor renal disease progression and response to treatment in type 2 diabetics without overt nephropathy.