Citations

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

Abstract The identification of the t(4;14) translocation in Multiple Myeloma (MM) provided the first indication that fibroblast growth factor 3 (FGFR3) could act as an oncogene. Several studies have assessed the potential of FGFR3 as a drug target and have shown that inhibition of FGFRs using tyrosine kinase inhibitors induces cell death of FGFR3 expressing MM cells. To clarify the signaling pathways implicated in FGFR3 dependent myeloma, we assessed gene expression changes associated with treatment of MM cell lines with three known small molecule FGFR inhibitors, PD173074, SU5402 and a third novel compound using Human U133_Plus2 arrays. In addition to describing the unique pharmacogenomic signals of each drug in myeloma, 845 differentially expressed genes, common to all three FGFR3 inhibitors, were identified. Cell cycle, DNA replication and ATP binding proteins were the most common (47%) functional classes of genes effected. Further validation and refinement of this gene list was conducted using FGFR3 siRNA inhibition and FGF ligand induction. 120 genes were altered between FGFR3 RNAi and scrambled control and 892 were induced by FGF ligand. Ten genes were commonly identified as significantly regulated by all 4 FGFR3 inhibitors and induced in the opposing direction by ligand. Of these macrophage inflammatory protein (MIP)-1alpha, and dual specific phosphatase 6 (DUSP6) were positively regulative while ANXA9, CR2, AL531683, ZNF589, AW274468, FRMD3, LTB and WDR42A were negatively regulated by FGFR3 signaling. Validating our findings, a feedback loop between FGFR/ERK/MAP kinase activation and DUSP6 has previously been described in the literature. MIP-1alpha however was the most significantly altered (12 fold) on array, and MIP-1alpha regulation in response to FGFR3 pathway stimulation was confirmed by flow cytometry and Western blot. Mining of publicly available array datasets on 174 MM patients significantly associated MIP1-alpha with FGFR3 expression (p=0.01). Of note down-regulation of MIP-1alpha was not observed following FGFR3 inhibition in MM cells with RAS mutations. Based on these, and previous findings, we hypothesized that MIP-1alpha was regulated by the FGFR3/ERK/MAP kinase pathway. Indeed, inhibition of ERK in FGFR inhibitor resistant cells with RAS mutations also led to down regulation of MIP-1alpha. Because of the recognized role of MIP1-alpha (CCL3) in survival and proliferation of MM cells and in MM bone disease, our observations raise the possibility that pharmacological inhibition of MIP-1 alpha may hold therapeutic promise in t(4;14) MM and may serve as a biomarker for successful FGFR3 or RAS signaling inhibition.

Abstract Oral cyclophosphamide and prednisone is a convenient regimen in relapsed and refractory multiple myeloma (MM), with a partial response (PR) rate of 40% and median progression-free survival of 19 months in our retrospective analysis of patients in first or second relapse after autologous stem cell transplantation (ASCT) (Trieu Y, et al, Mayo Clin Proc2005; 80: 1582). We sought to enhance the efficacy of this regimen by adding oral lenalidomide (Revlimid®), a potent anti-myeloma agent, in a phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15, lenalidomide on days 1–21, and prednisone 100 mg every other day in a 28-day cycle. ASA 81 mg/day was given to all patients (pts) as prophylaxis for DVT. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2008, 15 pts with relapsed/refractory MM were entered onto study. Median age was 60 (45–78) years and 60% were male. Immunoglobulin subtype was IgGκ:λ in 10:1; IgA κ:λ in 2:1 and κ light chain in 1. Median number of prior regimens was 2 (1–3) and 14 had undergone previous ASCT, including double transplants in 2 pts. Prior therapy also included thalidomide in 3 (20%) and bortezomib in 6 (40%). FISH cytogenetics were available in 9, but none had 13q deletion, t(4;14) or p53 deletion. At the time of protocol entry, median β2-microglobulin level was 222 (92–325) nm/L, albumin 38 (35–46) g/L, creatinine 78 (50–100) μmol/L, platelet count 230 (93–318) x 109/L and ANC 2.5 (1.9–9.0) x 109/L. Protocol treatment is summarized in Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 9 2 3 150 25 100 6 3 6 300 25 100 4 3 (expanded) 3 300 25 100 1 Dose limiting toxicity was not observed during cycle 1 at any of the dose levels and the maximum tolerated dose of this regimen has not yet been reached at the highest dose level planned; all pts remain on active therapy. Grade 3/4 thrombocytopenia was seen in 1 pt (cohort 2) and neutropenia in 4 pts (1 in cohort 1, 1 in cohort 2 and 2 in cohort 3) and were managed with dose reduction and/or growth factor support. No episodes of febrile neutropenia occurred in any pt. Only 1 pt experienced varicella zoster; routine antiviral prophylaxis was not used. Other grade 3/4 non-hematologic toxicities were uncommon and included abdominal pain/bacteremia in 1 pt in cohort 1, hypokalemia in 1 pt in cohort 2, and DVT in 1 pt in cohort 3. Mild grade 1/2 constipation (47%), muscle cramps (33%) and fatigue (33%) were also noted. To date, best response includes the following: dose level 1 (1 near complete remission [nCR], 2 PR); dose level 2 (3 PR); dose level 3 (4 PR, 2 minimal response [MR]); expanded cohort 3 (1 MR, 2 too early). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; 2) the overall response rate (nCR + PR + MR) in 13 evaluable pts to date is 87%; 3) no pts have progressed in this preliminary analysis; 4) longer follow-up is required to assess the long-term efficacy of this regimen.

Abstract Background: MDX-060 is a fully human anti-CD30 IgG1k monoclonal antibody that induces Fc-receptor mediated killing of CD30 expressing cell lines and inhibits the growth of CD30-expressing tumor cells in a murine xenograft model. We previously reported data from the first 31 patients in a Phase I/II open-label, dose escalation study of MDX-060 in patients with relapsed or refractory CD30+ lymphomas. The purpose of the study is to determine the safety and tolerability profile of the drug, and to preliminarily evaluate efficacy. We now update the findings of this study, including reporting the results of a new higher dose cohort. Methods: In the Phase I portion of the study, MDX-060 was administered intravenously at dose levels of 0.1, 1, 5, or 10 mg/kg weekly for 4 weeks to cohorts of 3–6 patients. In the Phase II portion of the study additional patients were administered MDX-060 intravenously at 10 (n=10) or 15 (n=17) mg/kg weekly for 4 weeks. Responses were assessed at month 2. Results: To date, MDX-060 has been administered to 48 patients; 40 with Hodgkin’s disease (HD), 6 with anaplastic large cell lymphoma (ALCL) and 2 with other CD30 positive lymphomas. MDX-060 has been well tolerated, and a maximum tolerated dose has not been identified. There were 2 drug-related serious adverse events, 1 patient in the 1 mg/kg dosing cohort had Grade 3 elevated liver transaminase, and 1 patient in the 15 mg/kg cohort had Grade 3 pneumonia/Grade 4 ARDS. Objective clinical responses have been observed in 5 patients. Two patients had complete responses; 1 patient with ALCL in the 1 mg/kg cohort lasting 100 days, and 1 patient with HD in the 15 mg/kg cohort lasting 117 days. Retreatment of the ALCL patient with MDX-060 resulted in a second complete response. Three patients had partial responses; 1 patient with HD in the 5 mg/kg cohort lasting 92 days, and 1 patient with HD in the 15 mg/kg cohort, which is continuing at 176 days. In addition, 1 patient with ALCL in the 15 mg/kg cohort had a partial response. Stable disease was observed in 17 patients following MDX-060 administration with a median duration of 132 days (range:15–387 days). Baseline soluble CD30 levels in the plasma were evaluated, but did not appear to correlate with clinical outcome. Conclusions: Preliminary evidence indicates MDX-060 to be well tolerated in heavily pre-treated patients with CD30+ lymphomas, with minimal toxicity, and with clinical activity observed at 1 mg/kg, 5 mg/kg and 15 mg/kg. Additional patients are being accrued at 1 mg/kg and 5 mg/kg to more accurately assess efficacy at these dose levels.

Abstract Background Lymphedema is an accumulation of protein-rich fluid in the interstitial spaces resulting from impairment in the lymphatic circulation that can impair quality of life and cause considerable morbidity. Lower extremity lymphedema (LEL) has an overall incidence rate of 20%. Conservative therapies are the first step in treatment of LEL; however, they do not provide a cure because they fail to address the underlying physiologic dysfunction of the lymphatic system. Among several surgical alternatives, lymphaticovenous anastomosis (LVA) has gained popularity due to its improved outcomes and less invasive approach. This study aims to review the published literature on LVA for LEL treatment and to analyze the surgical outcomes. Methods PubMed database was used to perform a comprehensive literature review of all articles describing LVA for treatment of LEL from Novemeber 1985 to June 2019. Search terms included “lymphovenous” OR “lymphaticovenous” AND “bypass” OR “anastomosis” OR “shunt” AND “lower extremity lymphedema.” Results A total of 95 articles were identified in the initial query, out of which 58 individual articles were deemed eligible. The studies included in this review describe notable variations in surgical techniques, number of anastomoses, and supplementary interventions. All, except one study, reported positive outcomes based on limb circumference and volume changes or subjective clinical improvement. The largest reduction rate in limb circumference and volume was 63.8%. Conclusion LVA demonstrated a considerable reduction in limb volume and improvement in subjective findings of lymphedema in the majority of patients. The maintained effectiveness of this treatment modality in long-term follow-up suggests great efficacy of LVA in LEL treatment.

Active learning has the benefit of being more engaging and interactive, making it more suitable for adult learners who prefer a task/problem centered approach to learning. Implementation of small‐group sessions in the material‐rich course is not always possible and other alternatives that engage learners should be explored. To incorporate active learning strategies, a team learning exercise “Talking Points” (TP), was introduced in a microscopic anatomy sessions for first year medical students. At the beginning of the laboratory period, students were given 5–7 subject‐related basic science/clinical problems and were encouraged to discuss within small “ad hoc” formed teams. Near the end of the laboratory session, these items were discussed by the entire group. This exercise gave the students the opportunity to learn relevant clinical material within small teams and present their findings to other classmates. Many students remarked that TP facilitated their learning of the material, stimulated questions, encouraged peer teaching, and provided a preview of learning strategies for the final examination. The participation and students' performance during TP was not included in the final grade. Incorporation of the TP into the microscopic anatomy curriculum increased students' participation and ended the laboratory session with an enthusiastic conclusion.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2 , pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.