Citations

708 Background: Patients with high risk non-metastatic renal cell cancer (RCC) are at significant risk of recurrence following nephrectomy. Previously, we reported no benefit of adjuvant tyrosine kinase inhibitor (TKI) treatment in high-risk patients. Since our most recent publication, efficacy results from the multicenter double-blind SORCE trial have become available. We updated our meta-analysis to include these additional data and performed a cumulative meta-analysis. Methods: PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials were searched to identify relevant RCTs. A generic variance-weighted random effects model was used to derive estimates for efficacy. Heterogeneity was assessed using the Cochran Q statistic and was quantified using the I2 test. The primary outcome was disease-free survival (DFS), defined as the interval between randomization and the first recurrence, the occurrence of metastasis or a secondary cancer, or death due to any cause. Statistical analysis was performed using Comprehensive Meta-Analysis version 3 (Biostat). Results: Five phase 3 trials were identified, enrolling 6531 patients. Two trials compared sunitinib with placebo (S-TRAC and ECOG-ACRIN), two compared sorafenib with placebo (ECOG-ACRIN and SORCE) and one trial each compared pazopanib (PROTECT) and axitinib (ATLAS) vs placebo. Cumulative evidence suggests that adjuvant therapy with TKIs showed no significant improvement in (DFS) hazard ratio [HR] of 0.93 (95% CI, 0.85-1.02), compared to placebo. There was no significant heterogeneity among included trials ( I2= 52%, P= .41). Overall, the trials were at low risk of bias. Conclusions: Adjuvant vascular endothelial growth factor tyrosine kinase inhibitors in high-risk renal cell carcinoma did not improve DFS as compared to placebo. Improved patient selection using better prognostic biomarkers or scoring systems may identify subsets of patients who can benefit from adjuvant treatments. Toxicity estimates will be updated as data from SORCE trial publication becomes available.

Abstract Background: Inpatient status has been shown to be a predictor of poor bowel preparation for colonoscopy; however, the optimal bowel preparation regimen for hospitalized patients is unknown. Our aim was to compare the efficacy of bowel preparation volume size in hospitalized patients undergoing inpatient colonoscopy. Methods: This prospective, single blinded (endoscopist), randomized controlled trial was conducted as a pilot study at a tertiary referral medical center. Hospitalized patients undergoing inpatient colonoscopy were assigned randomly to receive a high, medium, or low-volume preparation. Data collection included colon preparation quality, based on the Boston Bowel Preparation Scale, and a questionnaire given to all subjects evaluating the ability to completely finish bowel preparation and adverse effects (unpleasant taste, nausea, and vomiting). Results: Twenty-five colonoscopies were performed in 25 subjects. Patients who received low-volume preparation averaged a higher mean total BBPS (7.4, SD 1.62), in comparison to patients who received high-volume (7.0, SD 1.41) and medium-volume prep (6.9, SD 1.55), P = 0.77. When evaluating taste a higher score meant worse taste. The low-volume group scored unpleasant taste as 0.6 (0.74), while the high-volume group gave unpleasant taste a score of 2.2 (0.97) and the medium-volume group gave a score of 2.1 (1.36), P < 0.01. Conclusion: In this pilot study, the low-volume colon preparation Prepopik® may be preferred in the inpatient setting due its better rate of tolerability and comparable bowel cleanliness when compared to larger volume preparation, although we cannot overreach any definitive conclusion. Further more robust studies are required to confirm these findings.

Background: Direct stenting without pre-dilation or post-dilation has been advocated for saphenous vein graft percutaneous coronary intervention to decrease the incidence of distal embolization, periprocedural myocardial infarction, and target lesion revascularization. Methods: We performed a post hoc analysis of patients enrolled in the DIVA (Drug-Eluting Stents Versus Bare Metal Stents in Saphenous Vein Graft Angioplasty; NCT 01121224) prospective, double-blind, randomized controlled trial. Patients were stratified into stent-only and balloon-stent groups. Primary end point was 12-month incidence of target vessel failure (defined as the composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization). Secondary end points included all-cause death, stent thrombosis, myocardial infarction, and target lesion revascularization during follow-up. Results: Of the 575 patients included in this substudy, 185 (32%) patients underwent stent-only percutaneous coronary intervention. Patients in the stent-only versus balloon-stent group had similar baseline characteristics and similar incidence of target vessel failure at 12-months (15% versus 19%; hazard ratio, 1.34 [95% CI, 0.86–2.08]; P =0.19). During long-term follow-up (median of 2.7 years), the incidence of definite stent thrombosis (1% versus 5%; hazard ratio, 9.20 [95% CI, 1.23–68.92]; P =0.0085), the composite of definite or probable stent thrombosis (5% versus 11%; hazard ratio, 2.52 [95% CI, 1.23–5.18]; P =0.009), and target vessel myocardial infarction (8% versus 14%; hazard ratio, 1.92 [95% CI, 1.08–3.40]; P =0.023) was lower in the stent-only group. Multivariable analysis showed that a higher number of years since coronary artery bypass grafting and >1 target saphenous vein graft lesions were associated with increased target vessel failure during entire follow-up, while preintervention Thrombolysis in Myocardial Infarction-3 flow was protective. Conclusions: In patients undergoing percutaneous coronary intervention of de novo saphenous vein graft lesions, there was no difference in target vessel failure at 12 months and long-term follow-up in the stent-only versus the balloon-stent group; however, the incidence of stent thrombosis was lower in the stent-only group, as was target vessel myocardial infarction. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT 01121224.

Background The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates. Methods Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm—the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate. Results For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced. Conclusions The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum.

Objective Activin A, an inflammatory mediator implicated in cellular senescence-induced adipose tissue dysfunction and profibrotic kidney injury, may become a new target for the treatment of diabetic kidney disease (DKD) and chronic kidney diseases. We tested the hypothesis that human DKD-related injury leads to upregulation of activin A in blood and urine and in a human kidney cell model. We further hypothesized that circulating activin A parallels kidney injury markers in DKD. Research design and methods In two adult diabetes cohorts and controls (Minnesota, USA; Galway, Ireland), the relationships between plasma (or urine) activin A, estimated glomerular filtration rate (eGFR) and DKD injury biomarkers were tested with logistic regression and correlation coefficients. Activin A, inflammatory, epithelial-mesenchymal-transition (EMT) and senescence markers were assayed in human kidney (HK-2) cells incubated in high glucose plus transforming growth factor-β1 or albumin. Results Plasma activin A levels were elevated in diabetes (n=206) compared with controls (n=76; 418.1 vs 259.3 pg/mL; p<0.001) and correlated inversely with eGFR (r s =−0.61; p<0.001; diabetes). After eGFR adjustment, only albuminuria (OR 1.56, 95% CI 1.16 to 2.09) and tumor necrosis factor receptor-1 (OR 6.40, 95% CI 1.08 to 38.00) associated with the highest activin tertile. Albuminuria also related to urinary activin (r s =0.65; p<0.001). Following in vitro HK-2 injury, activin, inflammatory, EMT genes and supernatant activin levels were increased. Conclusions Circulating activin A is increased in human DKD and correlates with reduced kidney function and kidney injury markers. DKD-injured human renal tubule cells develop a profibrotic and inflammatory phenotype with activin A upregulation. These findings underscore the role of inflammation and provide a basis for further exploration of activin A as a diagnostic marker and therapeutic target in DKD.

AbstractPlatinum‐induced peripheral neurotoxicity (PIPN) is a common side effect of platinum‐based chemotherapy that may cause dose reduction and discontinuation, with oxaliplatin being more neurotoxic. PIPN includes acute neurotoxicity restricted to oxaliplatin, and chronic non‐length‐dependent sensory neuronopathy with positive and negative sensory symptoms and neuropathic pain in both upper and lower limbs. Chronic sensory axonal neuropathy manifesting as stocking‐and‐glove distribution is also frequent. Worsening of neuropathic symptoms after completing the last chemotherapy course may occur. Motor and autonomic involvement is uncommon. Ototoxicity is frequent in children and more commonly to cisplatin. Platinum‐based compounds result in more prolonged neuropathic symptoms in comparison to other chemotherapy agents. Patient reported outcomes questionnaires, clinical evaluation and instrumental tools offer complementary information in PIPN. Electrodiagnostic features include diffusely reduced/abolished sensory action potentials, in keeping with a sensory neuronopathy. PIPN is dependent on cumulative dose but there is a large variability in its occurrence. The search for additional risk factors for PIPN has thus far yielded no consistent findings. There are currently no neuroprotective strategies to reduce the risk of PIPN, and symptomatic treatment is limited to duloxetine that was found effective in a single phase III intervention study. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of PIPN.

AbstractVinca alkaloids, thalidomide, and eribulin are widely used to treat patients with childhood acute lymphoblastic leukemia (ALL), adults affected by multiple myeloma and locally invasive or metastatic breast cancer, respectively. However, soon after their introduction into clinical practice, chemotherapy‐induced peripheral neurotoxicity (CIPN) emerged as their main non‐hematological and among dose‐limiting adverse events. It is generally perceived that vinca alkaloids and the antiangiogenic agent thalidomide are more neurotoxic, compared to eribulin. The exposure to these chemotherapeutic agents is associated with an axonal, length‐dependent, sensory polyneuropathy of mild to moderate severity, whereas it is considered that the peripheral nerve damage, unless severe, usually resolves soon after treatment discontinuation. Advanced age, high initial and prolonged dosing, coadministration of other neurotoxic chemotherapeutic agents and pre‐existing neuropathy are the common risk factors. Pharmacogenetic biomarkers might be used to define patients at increased susceptibility of CIPN. Currently, there is no established therapy for CIPN prevention or treatment; symptomatic treatment for neuropathic pain and dose reduction or withdrawal in severe cases is considered, at the cost of reduced cancer therapeutic efficacy. This review critically examines the pathogenesis, epidemiology, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of CIPN as a result of exposure to vinca alkaloids, thalidomide and its analogue lenalidomide as also eribulin.

Abstract Abstract 1618 Introduction: Primary breast lymphoma is a rare type of non-Hodgkin lymphoma (NHL), representing about 1% of breast tumors and 2% of extranodal NHL. Diffuse large B-cell lymphoma (DLBCL) is the most common primary subtype presenting in the breast. Due to the low incidence of primary breast DLBCL, outcome data is limited. The aim of this study was to retrospectively assess the natural history of primary breast DLBCL in the pre and post rituximab eras, with specific emphasis on the incidence of local, systemic and central nervous system (CNS) relapses. Methods: Data was retrospectively collected on patients with primary breast DLBCL from seven USA academic medical centers. Institutional review board approval was obtained at each participating site. Patients were identified through institutional databases and tumor registries at each site. Charts were reviewed to obtain demographic and clinical variables including treatment history and dates of relapse and death when applicable. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. All histologies apart from primary DLBCL were excluded. Overall survival (OS) was calculated from the diagnosis date to the date of death or last follow-up. Time to Progression (TTP) was calculated from diagnosis data until the date of pathological evidence of recurrence or death. Data were summarized using descriptive statistics, and survival was analyzed using the Kaplan-Meier method. Results: Between 1984 and 2012, 75 patients were identified who met the eligibility criteria. The median age was 62 years (range 17–87); 81% presented with a palpable mass; 12% had their disease detected incidentally by mammography; 4% presented with B-symptoms; 59% had right breast involvement; 67% had stage I and 33% had stage II disease. The stage-adjusted international prognostic index (IPI) score was 0 in 28% of patients, 1 in 41%, 2, in 25%, 3 in 4% and 4 in 1%. 91% of patients were treated with chemotherapy; 31% of these were treated in the pre-rituximab era and 69% received rituximab. Radiation therapy (RT) was utilized in 68% of patients and was the only treatment modality in 8% of those receiving RT. 8% of patients received CNS prophylaxis with intrathecal chemotherapy. After a median follow-up of 4.5 years (range 0.6 – 20.6 years), the Kaplan-Meier estimated median TTP was 10.4 years (95% CI 6.2 – 14.6 years) and the median OS was 14.6 years (95% CI 6.5 – 22.6 years). The 5-year TTP and 5-year OS were 65% (95% CI 53–77%) and 75% (95% CI 64–86%) respectively. Among the patients who relapsed, 67% occurred within the first 2 years. A total of 7 relapses in the breast were observed, none in patients treated with combination of chemotherapy and RT. In univariate analysis, rituximab exposure was not associated with any difference in TTP or OS. The stage-adjusted IPI was associated with OS; the 5-year OS was 88% (95% CI 79–98%) in patients with a score of 0–1 versus 48% (95% CI 25–71%) in those with a score of 2–4 (log rank p < 0.001). The very limited-disease group with a stage-adjusted IPI of 0 had a 5-year OS of 94% (95% CI 83–100%) compared to all others who had a 5-year OS of 67% (95% CI 52–81%; log rank p = 0.001). There was no difference in TTP and OS in patients with solitary versus multiple breast masses or between patients with tumors less than versus more than 7cm. Patients receiving RT in addition to chemotherapy had a longer TTP than those who did not (log rank p = 0.03), but RT was not associated with an improved OS. Patients who relapsed and underwent stem cell transplant (SCT) had similar OS to those who never relapsed. Ten patients (13%) had CNS relapse (3 with leptomeningeal disease, 5 with brain parenchymal disease and 2 with both). All CNS relapses occurred within the first 2.8 years from the time of diagnosis. There was no difference in the rate of CNS relapse in the patients who received IT prophylaxis versus those who did not. Conclusions: In this multicenter study, the largest published to date, primary breast DLBCL appears to have a worse prognosis than early-stage DLBCL in nodal or other extranodal sites. RT was associated with improved TTP. Patients who relapsed were successfully salvaged with SCT, and had similar survival times to those who never relapsed. A high CNS relapse rate (∼1 in 8 patients, including parenchymal disease in 70%) was observed. The small numbers preclude definitive conclusions on the value of intrathecal prophylaxis or the utility of rituximab. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Inpatient status has been shown to be a predictor of poor bowel preparation for colonoscopy; however, the optimal colon cleansing regimen protocol for hospitalized patients is unknown. Our aim was to compare the efficacy of bowel preparation volume size in hospitalized patients undergoing inpatient colonoscopy.Methods: This prospective, single blinded (endoscopist), randomized controlled trial was conducted as a pilot study at a tertiary referral medical center. Hospitalized patients undergoing inpatient colonoscopy were assigned randomly to receive a high, medium, or low-volume solution. Data collection included colon preparation quality based on the Boston Bowel Preparation Scale and a questionnaire given to all subjects, in which we evaluated the ability to completely finish bowel preparation and adverse effects (unpleasant taste, nausea, and vomiting). Results: Twenty-five colonoscopies were performed in 25 subjects. Patients who received low-volume prep averaged a higher mean total BBPS (7.4, SD 1.62), in comparison to patients who received high-volume (6.6, SD 2.19) and medium-volume prep (6.9, SD 1.55), P = 0.64. The low-volume group scored unpleasant taste as 0.6 (0.74), while the high-volume group gave unpleasant taste a score of 2.2 (0.97) and the medium-volume group gave a score of 2.1 (1.36), P < 0.01.Conclusion: Although not statistically significant, a low-volume colon preparation showed a trend of equivalent quality of bowel preparation measured by BBPS in comparison to traditional volume regimens, with less unpleasant taste, which may contribute to better patient compliance and therefore better bowel preparation in the inpatient setting. Further more robust studies are required to confirm these findings.Trial registration: clinicaltrials.gov NCT01978509