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Right-sided colon cancer (RCC) has worse prognosis compared to left-sided colon cancer (LCC) and rectal cancer. The reason for this difference in outcomes is not well understood. We performed comparative somatic and proteomic analyses of RCC, LCC and rectal cancers to understand the unique molecular features of each tumor sub-types. Utilizing a novel in silico clonal evolution algorithm, we identified common tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor development and selection of downstream somatic alterations were distinct in all three anatomical locations. Some similarities were noted between LCC and rectal cancer. Hotspot mutation analysis identified a nonsense mutation, APC R1450* specific to RCC. In addition, we discovered new significantly mutated genes at each tumor location, Further in silico proteomic analysis, developed by our group, found distinct central or hub proteins with unique interactomes among each location. Our study revealed significant differences between RCC, LCC and rectal cancers not only at somatic but also at proteomic level that may have therapeutic relevance in these highly complex and heterogeneous tumors.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0923-9) contains supplementary material, which is available to authorized users.

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promise in treating recurrent adult high-grade glioma (HGG). However, there is very little data on recurrent or progressive pediatric HGG treated with bevacizumab. We report the results of a single institution experience using bevacizumab and irinotecan in children who relapsed or progressed following standard therapy. Twelve pediatric patients with recurrent or progressive HGG received bevacizumab at 10 mg/kg every 2 weeks with irinotecan at 125 mg/m(2). Magnetic resonance imaging (MRI) was performed prior to therapy and every 8 weeks subsequently. Ten patients had supratentorial HGG; 2 had DIPG. Radiological responses were defined according to MacDonald's criteria. Progression-free survival (PFS), overall survival (OS), and toxicities were analyzed. Ten (83.3%) patients tolerated bevacizumab without serious toxicity. Therapy was discontinued in 1 patient because of anaphylaxis. Another patient developed grade III delayed wound healing and deep vein thrombosis. Two patients (16.7%) experienced a partial response after the first MRI. No complete radiographic responses were seen. Stable disease was noted in 4 (33.3%) patients. The median PFS and OS were 2.25 and 6.25 months, respectively. A diffuse invasive recurrence pattern was noted in 5 (45.5%) patients. Treatment tolerance, toxicity, and recurrence profiles were comparable to adult HGG patients treated with bevacizumab. However, the radiological response rate, response duration, and survival appeared inferior in pediatric patients. Genetic differences in pediatric gliomas might account for this difference.

The clinical use of IMiDs in MM has significantly improved long-term survival and quality of life. Future studies are looking into novel biomarkers predictive of outcome in MM and new combinations of lenalidomide and pomalidomde with PI, monoclonal antibodies, immune checkpoint blockers and several other chemotherapies.

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Multiple myeloma (MM) is the second most common hematologic malignancy. The diagnosis of MM requires ⩾10% clonal plasma cells in the bone marrow or biopsy-proven plasmacytoma, plus evidence of end-organ damage (hypercalcemia, renal failure, anemia, and lytic bone lesions). The definition of MM has recently been expanded to include a ⩾60% clonal plasma cell burden in the bone marrow, serum involved/uninvolved light chain ratio of ⩾100, or more than one focal lesion on magnetic resonance imaging ⩾5 mm in the absence of endorgan damage. MM is an incurable malignancy previously associated with poor survival rates. However, over the past two decades, the introduction of novel treatment options has resulted in a dramatic improvement in response rates and overall survival (OS). The combination of a proteasome inhibitor and an immunomodulator (IMiD) is the preferred induction treatment for newly diagnosed transplant-eligible MM patients. After induction, high-dose therapy with autologous stem cell transplant (ASCT) is still the standard of care for these patients. In patients who are transplant ineligible, dose adjusted IMiDs or proteasome inhibitor-based combinations are the preferred treatment option. With the recent approval of novel drugs like carfilzomib, ixazomib, pomalidomide, panobinostat, and monoclonal antibodies (elotuzumab and daratumumab), as well as improved understanding of risk stratification, management of comorbidities and treatment side effects, clinicians can optimize anti-MM therapy, particularly in relapse/refractory MM patients. In this review, we outline the current therapeutic approach to the management of MM.

We evaluate the effects of adjuvant treatment with the angiogenesis inhibitor Avastin (bevacizumab) on pathological tissue specimens of high-grade glioma. Tissue from five patients before and after treatment with Avastin was subjected to histological evaluation and compared to four control cases of glioma before and after similar treatment protocols not including bevacizumab. Clinical and radiographic data were reviewed. Histological analysis focused on microvessel density and vascular morphology, and expression patterns of vascular endothelial growth factor-A (VEGF-A) and the hematopoietic stem cell, mesenchymal, and cell motility markers CD34, smooth muscle actin, D2-40, and fascin. All patients with a decrease in microvessel density had a radiographic response, whereas no response was seen in the patients with increased microvessel density. Vascular morphology showed apparent "normalization" after Avastin treatment in two cases, with thin-walled and evenly distributed vessels. VEGF-A expression in tumor cells was increased in two cases and decreased in three and did not correlate with treatment response. There was a trend toward a relative increase of CD34, smooth muscle actin, D2-40, and fascin immunostaining following treatment with Avastin. Specimens from four patients with recurrent malignant gliomas before and after adjuvant treatment (not including bevacizumab) had features dissimilar from our study cases. We conclude that a change in vascular morphology can be observed following antiangiogenic treatment. There seems to be no correlation between VEGF-A expression and clinical parameters. While the phenomena we describe may not be specific to Avastin, they demonstrate the potential of tissue-based analysis for the discovery of clinically relevant treatment response biomarkers.

BackgroundTransfusion-associated hyperkalemic cardiac arrest is a serious complication in patients receiving packed red blood cell (PRBC) transfusions. Mortality from hyperkalemia increases with large volumes of PRBC transfusion, increased rate of transfusion, and the use of stored PRBCs. Theoretically, hyperkalemia may be complicated by low cardiac output, acidosis, hyperglycemia, hypocalcemia, and hypothermia. In this study, we focus on transfusion-related hyperkalemia involving only medical intensive care unit (MICU) patients.MethodThis prospective observational study focuses on PRBC transfusions among MICU patients greater than 18 years of age. Factors considered during each transfusion included patient’s diagnosis, indication for transfusion, medical co-morbidities, acid-base disorders, K+ levels before and after each PRBC transfusion, age of stored blood, volume and rate of transfusion, and other adverse events. We used Pearson correlation and multivariate analysis for each factor listed above and performed a logistic regression analysis.ResultsBetween June 2011 and December 2011, 125 patients received a total of 160 units of PRBCs. Median age was 63 years (22 - 92 years). Seventy-one (57%) were females. Sixty-three patients (50%) had metabolic acidosis, 75 (60%) had acute renal failure (ARF), and 12 (10%) had end-stage renal disease (ESRD). Indications for transfusion included septic shock (n = 65, 52%), acute blood loss (n = 25, 20%), non-ST elevation myocardial infarction (NSTEMI) (n = 25, 20%) and preparation for procedures (n = 14, 11%). Baseline K+ value was 3.9 ± 1.1 mEq/L compared to 4.3 ± 1.2 mEq/L post-transfusion respectively (P = 0.9). During this study period, 4% of patients developed hyperkalemia (K+ 5.5 mEq/L or above). The mean change of serum potassium in patients receiving transfusion ≥ 12 days old blood was 4.1 ± 0.4 mEq/L compared to 4.8 ± 0.3 mEq/L (mean ± SD) in patients receiving blood 12 days or less old. Sixty-two patients (77.5%) that were transfused stored blood (for more than 12 days) had increased serum K+; eight (17.7%) patients received blood that was stored for less than 12 days. In both univariate (P = 0.02) and multivariate (P = 0.04) analysis, findings showed that among all factors, transfusion of stored blood was the only factor that affected serum potassium levels (95% CI: 0.32 - 0.91). No difference was found between central and peripheral intravenous access (P = 0.12), acidosis (P = 0.12), ARF (P = 0.6), ESRD (P = 0.5), and multiple transfusions (P = 0.09). One subject developed a sustained cardiac arrest after developing severe hyperkalemia (K+ = 9.0) following transfusion of seven units of PRBCs. Multivariate logistic regression showed linear correlation between duration of stored blood and serum K+ (R2 = 0.889).ConclusionThis study assesses factors that affect K+ in patients admitted to MICU. Results from the study show that rise in serum K+ level is more pronounced in patients who receive stored blood (> 12 days). Future studies should focus on the use of altered s...