Postoperative 30-day Mortality Following Surgical Resection for Colorectal Cancer in Veterans: Changes in the Right Direction

Temporal changes in short-term mortality following surgery for colorectal cancer (CRC) are unknown. We examined temporal changes in 30-day postoperative mortality, as well as changes in preoperative and postoperative disorders that could contribute to 30-day mortality. Using national Veterans Administration (VA) administrative data, we identified patients with CRC during 1987–2000 who received surgical resection. Cox proportional hazards models were used to evaluate the association between the risk of 30-day mortality and year of surgical resection, while adjusting for several preoperative disorders, disease comorbidity, as well as hospital surgical volume. A total of 32,621 patients were identified. The 30-day postoperative mortality declined from 4.7% during 1987–1988 to 3.9% during 1998–2000. Patients who received surgical resection during 1992–1994, 1995–1997, and 1998–2000 had a 14, 14, and 27% lower adjusted risk of 30-day mortality, respectively, compared with those resected in 1987–1988. Preoperative disorders associated with increased mortality included chronic pulmonary disease, congestive heart failure, diabetes, hemiplegia/paraplegia, moderate/severe liver disease, and renal disease. Significant declines were observed in several postoperative disorders including anesthesia complications and thromboembolism. An improvement in 30-day postoperative mortality following surgical resection for CRC was observed. Declining preoperative and postoperative disorders, as well as improvements in surgical care, could partly explain these findings.     

Detection of genomic deletions of PKP2 in arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease that predominantly affects the right ventricle and is associated with ventricular arrhythmias that may lead to sudden cardiac death. Mutations within at least seven separate genes have been identified to cause ARVC, however a genetic culprit remains elusive in approximately 50% of cases. Although negative genetic testing may be secondary to pathogenic mutations within undiscovered genes, an alternative explanation may be the presence of large deletions or duplications involving known genes. These large copy number variants may not be detected with standard clinical genetic testing which is presently limited to direct DNA sequencing. We describe two cases of ARVC possessing large deletions involving plakophilin‐2 (PKP2) identified with microarray analysis and/or multiplex ligation‐dependent probe amplification (MLPA) that would have been classified as genotype negative with standard clinical genetic testing. A deletion of the entire coding region of PKP2 excluding exon 1 was identified in patient 1 and his son. In patient 2, MLPA analysis of PKP2 revealed deletion of the entire gene with subsequent microarray analysis demonstrating a de novo 7.9 Mb deletion of chromosome 12p12.1p11.1. These findings support screening for large copy number variants in clinically suspected ARVC cases without clear disease causing mutations following initial sequencing analysis.     

Racial differences in survival of hepatocellular carcinoma in the United States: a population-based study.

BACKGROUND & AIMS: Survival after hepatocellular carcinoma (HCC) diagnosis is generally dismal, but there are patients with more favorable outcomes. Racial variation in survival of patients with HCC could be associated with observed differences in survival; however this has not been previously examined. METHODS: During 1987-2001, HCC patients were identified from 9 Surveillance, Epidemiology, and End-Results registries. One- and 3-year survival rates were calculated and compared by race. Models were constructed to examine the effects of race on the mortality risk. RESULTS: Asians had the highest 1- and 3-year observed and relative survival, followed by whites, Hispanics, and blacks. Compared with whites, Asians (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.11-1.69) were more likely to receive local or surgical therapy, whereas blacks (OR, 0.62; 95% CI, 0.49-0.78) and Hispanics (OR, 0.81; 95% CI, 0.60-1.09) were less likely to receive therapy. Adjusting for differences in receipt of therapy, stage of HCC, year of diagnosis, and other demographics, Asians (hazard rate [HR], 0.84; 95% CI, 0.78-0.91) maintained a lower mortality risk compared with whites. In adjusted models, Hispanics (HR, 1.13; 95% CI, 1.03-1.24) maintained a higher mortality risk, whereas the mortality risk for blacks became nonsignificant different from whites (HR, 1.06; 95% CI, 0.99-1.14). Last, a 22% improvement in survival was observed between 1987-1991 and 1997-2001, which was mostly explained by increased receipt of local or surgical therapy. CONCLUSIONS: We observed significant racial variation in survival. These variations in survival are partly explained by a lower likelihood of receipt of therapy and more advanced HCC at diagnosis among blacks and Hispanics.     

Effects on the buoyant density of rabbit platelets of ADP and agents that increase the concentration of cyclic AMP

Rabbit platelets were aggregated by adenosine diphosphate (ADP), allowed to deaggregate and then separated into density subpopulations by centrifugation through discontinuous Stractan density gradients. Although ADP causes little or no release of the contents of the amine storage granules of rabbit platelets, ADP caused a decrease in platelet density as compared with control platelets subjected to the same procedures except for exposure to ADP. The density change persisted for at least four hours. The apparent size of platelets stimulated with ADP increased initially, but returned to control values during a one-hour period. A similar decrease in platelet density was observed with an albumin density gradient. Under conditions in which aggregation did not occur in response to ADP with ethylenediaminetetraacetic acid (EDTA) in the medium, little or no decrease in platelet density was observed. Agglutination with polylysine did not change platelet density. Thus, not only agents such as thrombin and plasmin that cause the release of the contents of the platelet granules decrease platelet density, but ADP also has this effect. Platelets would be exposed to all of these stimuli during thromboembolic processes, and their effect on platelets may account for the decrease in platelet density observed previously in experiments with rabbits with indwelling aortic catheters. Agents that increase the concentration of cyclic AMP (cAMP) in platelets (PGE1, adenosine, dibutyryl cAMP, forskolin, and papaverine) also decreased platelet density. This effect persisted when the platelets were washed and resuspended in fresh medium and was also demonstrable in plasma. Platelet size was gradually increased by prostaglandin E1 (PGE1) which maintains platelets in a disc shape and does not cause the release of granule contents, indicating that the decrease in platelet density caused by PGE1 may be attributable to platelet swelling.     

Response patterns of purified myeloma cells to hematopoietic growth factors

Tumor cells were isolated from the bone marrow of seven patients with multiple myeloma and from the peripheral blood of three patients with plasma cell leukemia using Ficoll-Hypaque (FH) density sedimentation followed by immune rosette depletion of T, myeloid, monocytoid, and natural killer (NK) cells. Enrichment to greater than or equal to 93% plasma cells was confirmed with Wright's-Giemsa staining, with intracytoplasmic immunoglobulin staining, and with staining using monoclonal antibodies (MoAbs) directed at B, T, myeloid, monocytoid, and myeloma antigens in indirect immunofluorescence assays. Myeloma cells neither proliferated nor secreted Ig in response to G/M-CSF, G- CSF, M-CSF, interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), or interleukin-4 (IL-4). Significant proliferation (SI greater than or equal to 3.0) was induced by interleukin-6 (IL-6) in six of ten patients (SI of 31 and 43 in two cases); and to interleukin-3 (IL-3) and interleukin-5 (IL-5), independently, in two patients each. Peak proliferation to IL-5 or IL-6 and to IL-3 occurred in cells pulsed with 3[H] thymidine at 24 and 48 hours, respectively; and proliferation to combinations of factors did not exceed that noted to IL-6 alone; Ig secretion was not documented under any culture conditions. Three myeloma-derived cell lines similarly studied demonstrated variable responses. The heterogeneity in the in vitro responses of myeloma cells and derived cell lines to exogenous growth factors enhances our understanding of abnormal plasma cell growth and may yield insight into the pathophysiology of plasma cell dyscrasias.     

Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies

Signaling via the MyD88/IRAK pathway in T cells is indispensable for cell survival; however, it is not known whether this pathway functions in the progression of T acute lymphoblastic leukemia (T-ALL). Here, we determined that compared with thymic and peripheral T cells, T-ALL cells from patients have elevated levels of IRAK1 and IRAK4 mRNA as well as increased total and phosphorylated protein. Targeted inhibition of IRAK1 and IRAK4, either with shRNA or with a pharmacological IRAK1/4 inhibitor, dramatically impeded proliferation of T-ALL cells isolated from patients and T-ALL cells in a murine leukemia model; however, IRAK1/4 inhibition had little effect on cell death. We screened several hundred FDA-approved compounds and identified a set of drugs that had enhanced cytotoxic activity when combined with IRAK inhibition. Administration of an IRAK1/4 inhibitor or IRAK knockdown in combination with either ABT-737 or vincristine markedly reduced leukemia burden in mice and prolonged survival. IRAK1/4 signaling activated the E3 ubiquitin ligase TRAF6, increasing K63-linked ubiquitination and enhancing stability of the antiapoptotic protein MCL1; therefore, IRAK inhibition reduced MCL1 stability and sensitized T-ALL to combination therapy. These studies demonstrate that IRAK1/4 signaling promotes T-ALL progression through stabilization of MCL1 and suggest that impeding this pathway has potential as a therapeutic strategy to enhance chemotherapeutic efficacy.     

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC,PAX6 and CYP1B1

Developmental eye diseases, including cataract/microcornea, Peters anomaly and coloboma/microphthalmia/anophthalmia, are caused by mutations encoding many different signalling and structural proteins in the developing eye. All modes of Mendelian inheritance occur and many are sporadic cases, so provision of accurate recurrence risk information for families and affected individuals is highly challenging. Extreme genetic heterogeneity renders testing for all known disease genes clinically unavailable with traditional methods. We used whole-exome sequencing in 11 unrelated developmental eye disease patients, as it provides a strategy for assessment of multiple disease genes simultaneously. We identified five causative variants in four patients in four different disease genes, GJA8, CRYGC, PAX6 and CYP1B1. This detection rate (36%) is high for a group of patients where clinical testing is frequently not undertaken due to lack of availability and cost. The results affected clinical management in all cases. These variants were detected in the cataract/microcornea and Peters anomaly patients. In two patients with coloboma/microphthalmia, variants in ABCB6 and GDF3 were identified with incomplete penetrance, highlighting the complex inheritance pattern associated with this phenotype. In the coloboma/microphthalmia patients, four other variants were identified in CYP1B1, and CYP1B1 emerged as a candidate gene to be considered as a modifier in coloboma/microphthalmia.