Lower Long-term Survival Research Articles

Genomic Analysis of Adult B-ALL Identifies Changes in Copy Number Profile at Relapse and IKZF1/CDKN2A Co-Deletion at Diagnosis As a Marker of Shorter Survival

B lymphoblastic leukemia (B-ALL) in adults has a higher risk of relapse and lower long-term survival than pediatric B-ALL, but data regarding prognostic biomarkers are much more limited for adult patients. Microarray-based genome-wide profiling studies in pediatric B-ALL patients have revealed recurrent abnormalities in B-cell development and cell cycle regulation. IKZF1 alterations convey a negative prognostic impact in pediatric B-ALL, but their significance is not well characterized in adult B-ALL. CDKN2A alterations have been associated with a poorer prognosis in adult Ph+ ALL, possibly by mediating resistance to targeted therapy. The copy number landscape of adult B-ALL has not been fully assessed and is likely distinct from its pediatric counterpart. In addition, the copy number changes in relapsed adult B-ALL, including comparison with initial diagnostic samples, have not been characterized. We identified 70 adult B-ALL patients (median age 45 years, range 18-83) from 1998-2013 at three institutions. DNA was isolated from formalin-fixed, paraffin-embedded (FFPE) diagnostic bone marrow clots, as well as relapse samples when available, and assessed with the OncoScan FFPE Express genome-wide single nucleotide polymorphism (SNP) assay (Affymetrix). Copy number alteration (CNA) and loss of heterozygosity (LOH) analysis was performed using Nexus Software V7 (Biodiscovery) and in-house coding. For cases with adequate DNA, IKZF1 sequencing was also performed. Clinical data included age, gender, hematologic laboratory values at presentation, CSF involvement, receipt of allogeneic transplant, cytogenetic profile, presence of t(9;22), event-free survival (EFS), and overall survival (OS). Recurrent deletions in the diagnostic samples were noted at several loci, including CDKN2A (48.6%), IKZF1 (40%), ICR (38.6%), PAX5 (24.2%), BTG1 (17.1%), ETV6 (15.7%), BTLA (14.3%), RB1 (5.7%), EBF1 (5.7%), LEF1 (2.9%), and TCF3 (2.9%). Recurrent gains were identified at the following loci: ERG (30%), ETS2 (21.4%), MYB (20%), UBASH3B (20%), PTEN (20%), PRKCH (18.6%), CDK6 (17.1%), and ETV6 (12.9%). In addition, LOH was observed in all loci with recurrent CNAs named above. 27 samples obtained at the time of relapse were screened for the recurrent CNAs identified in the diagnostic samples. The cumulative incidence of CNAs at these genes was lower in the relapse cohort than the initial diagnostic cohort, although there was a higher frequency of CNAs at PAX5, BTLA, ETS2, RB1, LEF1, PTEN, and TCF3 in the relapse samples. 16 patients had samples available at both the time of diagnosis and time of relapse. The average number of CNAs at diagnosis and relapse was the same, but analysis of paired samples revealed frequent changes at the previously defined loci of CNAs. There were a number of new CNAs at these loci in relapse samples, but there was also a similar incidence of reversion to the copy neutral state in loci that previously had CNAs in the diagnostic samples. Sequencing data was available on 26 diagnostic samples for the IKZF1 gene. Only two samples had mutations corresponding to amino acid changes. One of these two had a heterozygous deletion at IKZF1, indicating that the mutated isoform was the only one expressed. 11 other samples had a SNP without a corresponding amino acid change. 14 relapse samples were sequenced, two of which harbored a point mutation in IKZF1. Neither of these samples had a CNA at this locus. 10 of the remaining 12 relapse samples had a SNP without a corresponding amino acid change. When correlated with outcomes, no individual CNA heralded a significant prognostic impact in the entire cohort or in subgroup analyses stratified by presence of t(9;22) for either EFS or OS. However, the combination of both CDK2NA and IKZF1 deletions (26%) correlated with a significantly worse OS than having only one or neither of these deletions (both vs. CDKN2A only: p=0.028, both vs. IKZF1 only: p=0.027, both vs. neither deleted: p=0.048). Age was the only other covariate significant in univariate analyses for OS, yet IKZF1/CDKN2A co-deletion remained significant in multivariate analysis adjusting for age. Adult B-ALL demonstrates recurrent copy number changes, and the pattern of CNAs is often different at relapse than at diagnosis indicating clonal evolution. When identified in diagnostic samples, co-deletion of CDKN2A /IKZF1 is a negative prognostic marker in adult B-ALL. DisclosuresSouth:Illumina: Consultancy, Honoraria; Affymetrix: Consultancy, Honoraria; ARUP Laboratories: Employment; Lineagen Corporation: Consultancy. Bixby:Seattle Genetics, Inc.: Research Funding. Gastier-Foster:Bristol-Myers Squibb: Research Funding.

Efficacy and Safety of Allogeneic Double Negative T Cell As a Cellular Therapy for AML and Its Underlying Mechanism

Acute myeloid leukemia (AML) is the most common form of adult acute leukemia that is associated with a low long-term survival rate. While chemotherapy achieves remission in more than 70% of the treated AML patients, most relapse due to residual chemotherapy-resistant AML populations. Allogeneic hematopoietic stem cell transplantation reduces the relapse rate and demonstrates the efficacy of a cell-mediated treatment for the chemotherapy-resistant disease. However, its wide application is limited by donor availability and associated toxicity such as graft-versus-host disease (GvHD). Hence, there is a need for a new treatment approach that targets chemotherapy-resistant AML blasts with minimal side effects. The goals of this study were to characterize allogeneic CD3+ CD4-CD8- double negative T cells (DNTs) as a potential new therapy for AML patients, and to dissect its underlying mechanisms.Using a flow cytometry-based in vitro killing assay, we demonstrated that the allogeneic DNTs expanded from healthy volunteers were cytotoxic against 23/29 primary AML patient blasts in a dose-dependent manner. Thirteen blast samples were obtained from chemotherapy refractory or relapsing AML patients and, of those, 9 were susceptible to DNTs. Further, the average level of specific killing mediated by DNTs against chemotherapy-susceptible and -resistant blasts were comparable (19.30% ± 3.34% and 15.91% ± 3.63%, respectively). The anti-leukemia activity of DNTs was further validated in AML-NSG xenograft models. A single infusion of DNTs into mice pre-engrafted with primary AML blasts from chemoresponsive, chemorefractory, and relapsed patients significantly reduced the leukemia burden. While a single injection of DNTs resulted in a significant reduction of leukemia burden from 30% to 12.8%, it was further reduced to 2.6% after three injections of DNTs. Furthermore, the survival of NSG mice administered with a lethal dose of AML cell line, MV4-11, in DNT-treated group was significantly superior to the untreated group (57% vs. 0% survival on day 34, respectively). Although residual blasts were observed from the DNT -treated group, their susceptibility to DNT cell-mediated cytotoxicity remained comparable to blasts obtained from the PBS-treated group and primary AML blasts initially used for engraftment, suggesting that AMLs do not develop resistance to DNT-mediated cytotoxicity. In contrast to its potent cytolytic activity against leukemic cells, DNTs did not target allogeneic peripheral blood mononuclear cells (PBMC) and hematopoietic stem/progenitor cells (HSPC) in vitro. Administration of allogeneic DNTs into NSG mice engrafted with human HSPC had no effect on the engraftment level of human hematopoietic cells and their differentiation into different lineages. Further, in contrast to human PBMC, infusion of human DNTs did not cause xenogeneic GvHD in mice, collectively demonstrating the selective cytotoxic activity of allogeneic DNTs against leukemic cells. Using blocking assays, we showed that HLA-class I, NKG2D, and DNAM-1 were involved in DNT cell-mediated cytotoxicity against AML, whereas HLA-class II and T cell receptor did not play a significant role. We detected high levels of IFNγ release by DNTs upon encounter of susceptible AML targets. While IFNγ treatment alone did not induce AML cell death, neutralizing IFNγ reduced and pretreating AML cells with recombinant IFNγ increased their susceptibility to DNT cell killing. IFNγ treatment induced higher expressions of NKG2D and DNAM-1 ligands and blocking of NKG2D and DNAM-1 partially abrogated the effect of IFNγ on the AML-DNT interaction. Collectively, these studies demonstrated the safety and efficacy of allogeneic DNT therapy as a potential treatment for AML patients, including those with chemotherapy-resistant leukemia, and revealed the important molecules for the anti-leukemic activity of DNTs. DisclosuresNo relevant conflicts of interest to declare.

Outcome of patients with reduced ankle brachial index undergoing open heart surgery with cardiopulmonary bypass.

In open heart surgery using cardiopulmonary bypass, perfusion of the lower extremities is markedly reduced which may induce critical ischaemia in patients with pre-existing peripheral artery disease. Whether these patients have an increased risk for amputation and should better undergo peripheral revascularization prior to surgery remains unclear. From 1 January 2009 to 31 December 2010, 785 consecutive patients undergoing open heart surgery were retrospectively included. In 443 of these patients, preoperative ankle brachial index (ABI) measurements were available. The cohort was divided into four groups: (i) ABI < 0.5, (ii) ABI 0.5-0.69, (iii) ABI 0.7-0.89 or (iv) ABI ≥ 0.9. Follow-up data of 413 (93.2%) patients were analysed with regard to mortality and amputations. The groups differed significantly in terms of age, cardiac risk factors, performed cardiac surgery and renal function. Postoperative delayed wound healing was significantly associated with lower ABI (25.9, 15.2, 27.0 and 9.6% in Groups I-IV, respectively, P = 0.003), whereas 30-day mortality was not significantly higher in patients with lower ABI (0, 4.3, 8.1 and 3.9%, respectively, P = 0.4). Kaplan-Meier models showed a significantly lower long-term survival over 4 years in patients with reduced ABI (P = 0.001, long-rank test) while amputations occurred rarely with only one minor amputation in Group II (P = 0.023). Patients with reduced ABIs undergoing heart surgery showed more wound-healing disturbances, and higher long-term mortality compared with those with normal ABIs. However, no perioperative ischaemia requiring amputation occurred. Thus, reduced ABIs were not associated with increased peripheral risks in open heart surgery but ABI may be helpful in selecting the site for saphenectomy to potentially avoid delayed healing of related wounds in legs with severely impaired arterial perfusion.

Derived neutrophil lymphocyte ratio may predict benefit from cisplatin in the advanced biliary cancer: the ABC-02 and BT-22 studies

The superiority of cisplatin and gemcitabine (CisGem) chemotherapy over gemcitabine (Gem) alone in patients with advanced biliary tract cancer (ABC) has been demonstrated in two randomised trials; ABC02 and the Biliary Tract (BT) 22 study. We used a combined dataset from these two trials to investigate the derived neutrophil-to-lymphocyte ratio (dNLR), which is thought to be a prognostic factor associated with clinical outcomes in several solid tumours, including ABC. White blood cell (WBC) and absolute neutrophil count (ANC) were available for 379 of 410 patients from ABC-02 and all 83 patients in BT-22. The dNLR was calculated as ANC/(WBC-ANC), as previously specified. We examined the association between dNLR and overall survival (OS) and progression-free survival (PFS), as well as comparing the treatment effect in two patient groups defined by their dNLR level. A high dNLR was defined as ≥3.0, which was approximately the upper tertile value. A total of 462 individual patient records were analysed, 328 with baseline dNLR <3 and 134 with dNLR ≥3. There were 443 deaths in the cohort, and all surviving patients had a dNLR <3. There was strong evidence that dNLR was closely associated with both OS [hazard ratio (HR), 1.62; 95% confidence interval (CI) 1.32-2.01] and PFS (HR, 1.40; 95% CI 1.13-1.72). There was limited evidence (P = 0.10) of a differential effect of CisGem on OS between the two dNLR groups, but this was clearest in the ABC-02 dataset (P = 0.06). There was good evidence (P = 0.008) of an association between low baseline dNLR and long-term survival on a CisGem regimen. There was also good evidence of an association between ECOG performance status (split at 0 and 1 versus 2) on both OS (P < 0.001) and PFS (P = 0.01), but no evidence of a differential treatment effect, with both groups receiving benefit from the addition of cisplatin. These data confirm that high dNLR is associated with worse OS and PFS, and suggests it may also be predictive of benefit for the addition of cisplatin to gemcitabine in European patients with ABC. Incorporating dNLR into the clinical context may better inform prognosis and chemotherapy decisions in ABC patients.

Abstract 1723: IKZF1/CDKN2A co-deletion predicts shorter survival in adult B-ALL

Abstract B lymphoblastic leukemia (B-ALL) in adults has a higher risk of relapse and lower long-term survival than pediatric B-ALL. Prognostic biomarkers are needed for better risk-stratification and therapy selection. Microarray-based genome-wide profiling studies in pediatric patients have revealed recurrent abnormalities in B-cell development and cell cycle regulation. IKZF1 alterations convey a negative prognostic impact in pediatric B-ALL, but their significance is not well characterized in adult B-ALL. CDKN2A alterations have also been associated with a poorer prognosis in adult Ph+ ALL, possibly by mediating resistance to targeted therapy. The copy number landscape of adult B-ALL has not been fully assessed, and given its inferior prognosis, may be distinct from its pediatric counterpart. We identified 70 adult B-ALL patients (median age 45 years, range 18-83) from 1998-2013 at three institutions. DNA was isolated from formalin-fixed, paraffin-embedded (FFPE) diagnostic bone marrow clots and assessed with the OncoScan FFPE Express genome-wide single nucleotide polymorphism (SNP) assay (Affymetrix). Copy number alteration (CNA) analysis was performed using Nexus Software V7 (Biodiscovery) and in-house coding. The most frequent CNAs called by the software were manually verified for probe evidence. Clinical data available on this cohort included age, gender, hematologic laboratory values at presentation, CSF involvement, receipt of allogeneic transplant, cytogenetic profile, presence of t(9;22), event-free survival (EFS), and overall survival (OS). Estimated median survival time of the entire adult B-ALL patient cohort was 29 months. Recurrent deletions in the diagnostic samples were noted at several loci, including CDKN2A (47%), IKZF1 (40%), PAX5 (24%), BTG1 (17%), and BTLA (14%). Recurrent gains were identified at the following loci: ERG (30%), ETS2 (21%), MYB (20%), UBASH3B (20%), PRKCH (19%), CDK6 (17%), and ETV6 (16%). No individual CNA heralded a significant prognostic impact in the entire cohort or in subgroup analyses stratified by presence of t(9;22) for either EFS or OS, though this could be due to our relatively smaller sample size in contrast to pediatric studies that have observed a prognostic impact at some of these loci. However, the combination of both CDK2NA and IKZF1 deletions (26%) correlated with a significantly worse overall survival than having only one or neither of these deletions (both vs CDKN2A only: p = 0.028, both vs IKZF1 only: p = 0.027, both vs neither deleted: p = 0.048). Age was the only other covariate significant in univariate analyses for OS, yet IKZF1/CDKN2A co-deletion remained significant in multivariate analysis adjusting for age. Adult B-ALL demonstrates frequent CDKN2A deletions, IKZF1 deletions, and CDKN2A/IKZF1 co-deletions. To our knowledge, the negative prognostic impact of the CDKN2A/IKZF1 co-deletion is a novel finding in adult B-ALL and requires further validation in larger cohorts. Citation Format: Shiven Patel, Clinton C. Mason, Martha J. Glenn, Christian N. Paxton, Sara T. South, Melissa H. Cessna, Julie Asch, Erin F. Cobain, Dale L. Bixby, Lauren B. Smith, Joshua D. Schiffman, Rodney R. Miles. IKZF1/CDKN2A co-deletion predicts shorter survival in adult B-ALL. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1723. doi:10.1158/1538-7445.AM2015-1723

Выживаемость больных с повышенной массой тела после коронарного шунтирования: играет ли роль «парадокс ожирения»?

Although excessive body mass and obesity are considered risk factors of a number of diseases and conditions numerous results of studies evidence for the existence of the "obesity paradox"--higher long-term survival of overweight and obese patients. Aim of this study was to elucidate impact of body mass index (BMI) on postoperative mortality and long-term survival of patients after coronary artery bypass grafting (CABG).The study was conducted on the basis of register of patients with ischemic heart disease who had undergone CABG with or without correction of valvular defects and/or resection of left ventricular (LV) aneurism during the period from 2000 to 2009 in the Chelyabinsk Interregional Cardiosurgical Center. Duration of follow-up was 1 to 10 years (mean--2.3 ± 2.4 years). The patients were divided into groups in dependence on BMI. Multifactorial logistic regression analysis of association of BMI and hospital mortality was carried out with adjustment for age, sex, arterial pressure, presence of diabetes mellitus (DM), chronic obstructive pulmonary disease, LV aneurism, LV ejection fraction, and character of involvement of vessels. Long term survival was studied using Cox's regression model.Compared with group of patients with normal BMI DM and arterial hypertension were more often registered among patients with excessive body mass and obesity. Elevated body mass was not an independent factor of risk of postoperative and lower long-term survival. There was a tendency to lower survival among patients with BMI > 35 rg/m2.Results of this study evidence for the absence of proof of negative impact of excessive BMI on hospital mortality and long term survival.

Urgency or Outcome as Guiding Principle for the Allocation of Deceased Donor Livers: A Questionnaire Survey Among Outpatients of a University Medical Department in Germany

IntroductionThe sickest-first principle has been pursued in the allocation of donor livers for transplantation with the introduction of algorithms based on the model of end-stage liver disease (MELD) score. In Germany outcomes of liver transplantation appear to be negatively influenced by the transplantation of patients with very high MELD scores and the use of donor organs with lower quality. Therefore, some have claimed, allocation should be based more on outcome-oriented criteria. MethodsA survey with binary questions (yes/no) regarding the appreciation of values concerning the allocation of donor livers was performed among general medical outpatients of a university hospital. End-stage liver disease patients were excluded. Two hundred four returned forms were analyzed. Percentages of valid answers are given. ResultsIn this study, 88%, 73%, and 41% of subjects answered they would be willing to undergo transplantation with an estimated outcome of 20%, 50%, and 80% 1-year mortality rate, respectively, for themselves. Choosing a possible recipient between 2 case examples, 68% of valid answers voted for the case with higher age and urgency and lower long-term survival. Seventy percent said urgency was more important than long-term outcome as a criterion for organ allocation. Under the assumption that urgency-based allocation would decrease average long-term survival of liver transplantation, 58% refused to deny even the sickest patients transplantation. Seventy-eight percent said that patients likely to achieve 50% long-term survival should not be denied liver transplantation. ConclusionIn our study a majority of subjects prioritize urgency and granting a chance to avert imminent death over long-term survival per procedure. Equitable distribution of chances for survival may be estimated more than outcome maximization in terms of aggregate life-years gained.

Immunotherapy of Metastatic Colorectal Cancer: Prevailing Challenges and New Perspectives.

Patients with recurring or metastatic colorectal cancer (mCRC) have strikingly low long-term survival, while conventional treatments such as chemotherapeutic intervention and radiation therapy marginally improve longevity. Although, many factors involving immunosurveillance and immunosuppression were recently validated as important for patient prognosis and care, a multitude of experimental immunotherapies designed to combat unresectable mCRC have, in few cases, successfully mobilized antitumor immune cells against malignancies, nor conclusively or consistently granted protection, complete remission, and/or stable disease from immunotherapy - of which benefit less than 10% of those receiving therapy. After decades of progress, however, new insights into the mechanisms of immunosuppression, tolerance, and mutation profiling established novel therapies that circumvent these immunological barriers. This review underlines the most exciting methods to date that manipulate immune cells to curb mCRC, including adoptive cell therapy, dendritic cell vaccines, and checkpoint inhibitor antibodies - of which hint at effective and enduring protection against disease progression and undetected micrometastases.

LONG TERM SURVIVAL OF MYOCARDIAL INFARCTION PATIENTS COMPLICATED WITH CARDIOGENIC SHOCK

Aim. To study the parameters of long term survival of patients with myocardial infarction (MI), complicated with cardiogenic shock (CS) and the main medical and social factor influencing survival rate. Material and methods. The patients included in the study were treated in Kemerovo Cardiological dispensary in 2006-2011 yy. Number of patients was 6462, of those with cardiogenic shock — 493. Statistics was done with the standard licensed software Statistica 6.0. For survival estimation we used the methods of tables construction on life duration and multiplying Kaplan-Meier marks. Results. During 2006-2011 yy. CS developed in 7,6%. Among patients more prevalent were older and retired ages, the comorbidity level was high (anamesis of MI and stroke, diabetes and chronic obstructive lung disease). Annual survival rate in CS was 9,6%, triannual — 7,9%. Conclusion. Long term survival rate is negatively correlated with the age and does not depend on the patients' gender. Retired and older age, disability, anamnesis of MI, significant aortic stenosis, prominent chronic heart failure, multivessel coronary disease are associated with lower long-term survival rate. Reperfusion therapy by percutaneous intervention, the use of intraaortal balloon contrapulsation and renal replacement therapy in the complex CS therapy significantly improve long term survival of patients.

Radiotherapy in early stage classical Hodgkin lymphoma: past, present and future.

For early stage classical Hodgkin lymphoma (HL), extended field irradiation (EFRT) alone has shown excellent results in low relapse rate and high long-term survival rate. With the patients achieving long-term survival, the risk of the RT-related late complications was increased, such as secondary malignancies and heart infarctions. According to a series of studies, the combined modality therapy (CMT) as the first-line therapy has replaced the radiotherapy (RT) alone. The recommended regimens are 2 cycles of ABVD followed by involved field radiotherapy (IFRT) (20-30 Gy) for the favorable patients, and 4 cycles of ABVD followed by IFRT (30 Gy) for unfavorable patients. The involved nodular radiotherapy (INRT) has shown the potential to achieve satisfactory primary tumor control with lower RT-related toxicity than EFRT or IFRT in combined therapy. Some prospective randomized studies are going about chemotherapy (CT) plus INRT under the guidance of PET. It is not certain that whether CT alone has more benefits to cure limited HL. Appropriate application of new RT techniques can improve the radiation dose distribution in target fields and protect normal tissues from excess RT-related damage.

Peripheral blood monocyte and T-lymphocyte activation levels at diagnosis predict long-term survival in head and neck squamous cell carcinoma patients.

This study was performed to determine whether peripheral blood (PB) monocyte and/or lymphocyte activation at diagnosis were associated with long-term prognosis in patients with head and neck squamous cell carcinoma (HNSCC), and to what extent such prognostic properties relate to human papilloma virus (HPV)-associated tumor infection of the included patients. This was a long-term prospective study describing patient survival in relation to PB T lymphocyte and monocyte activation in patients observed for up to 14 years following diagnosis. Sixty-four patients from a consecutive cohort of newly diagnosed HNSCC patients along with 16 non-cancer control patients were included over a period of almost 2 years. Monocyte responsiveness was assessed at diagnosis (N = 56 HNSCC/16 non-cancer controls) by measuring net levels of spontaneous vs lipopolysaccharide-induced monocyte chemotactic protein (MCP)-1 secretion in vitro. PB T lymphocyte activation was determined (N = 58 HNSCC/16 controls) by measuring the percentage of T cells expressing CD69 by flow cytometry. Whether HPV infection or not was determined by PCR analysis on formalin fixed paraffin-embedded tumor tissue. Tumor HPV-positive patients had better prognosis than HPV-negative patients. A low net MCP-1 response in monocytes predicted increased survival (Relative risk (RR) = 2.1; Confidence interval (CI): 1.1-4.0; p < 0.05). A low percentage of CD69 positive T lymphocytes also predicted better prognosis (RR = 2.6; CI: 1.3-5.0; p = 0.005). The predictive power of MCP-1 monocyte and CD69 T lymphocyte measures were retained when adjusted for age and gender of the patients and shown to be independent of each other (N = 50 HNSCC/16 controls). The results were similar in HPV tumor-positive and -negative patients. Patients with high monocyte- and/or T lymphocyte activation status had low survival with 8% 5 year overall survival (OS) compared to 65% 5 year OS for patients with dual low activation levels (RR = 0.27; CI: 0.14-0.56; p < 0.001), mostly secondary to disease-specific survival. Both tumor HPV-positive and -negative HNSCC patients with high percentage of CD69 positive T lymphocytes and/or high monocyte MCP-1 secretion had low long-term survival. The data suggest that the general inflammatory and adaptive immune systems are independently linked to the clinical aggressiveness of both tumor HPV-negative and -positive HNSCC patients.

Cerebral performance category at hospital discharge predicts long-term survival of cardiac arrest survivors receiving targeted temperature management*.

Despite recent advancements in post-cardiac arrest resuscitation, the optimal measurement of postarrest outcome remains unclear. We hypothesized that Cerebral Performance Category score can predict the long-term outcome of postarrest survivors who received targeted temperature management during their postarrest hospital care. Retrospective chart review. Two academic medical centers from May 2005 to December 2012. The medical records of 2,417 out-of-hospital and in-hospital patients post cardiac arrest were reviewed to identify 140 of 582 survivors who received targeted temperature management. None. The Cerebral Performance Category scores at hospital discharge were determined by three independent abstractors. The 1-month, 6-month, and 12-month survival of these patients was determined by reviewing hospital records and querying the Social Security Death Index and by follow-up telephone calls. The association of unadjusted long-term survival and adjusted survival with Cerebral Performance Category was calculated. Of the 2,417 patients who were identified to have undergone cardiac arrest, 24.1% (582/2,417) were successfully resuscitated, of whom 24.1% (140/582) received postarrest targeted temperature management. Overall, 42.9% of patients (60/140) were discharged with Cerebral Performance Category 1, 27.1% (38/140) with Cerebral Performance Category 2, 18.6% (26/140) with Cerebral Performance Category 3, and 11.4% (16/140) with Cerebral Performance Category 4. Cerebral Performance Category 1 survivors had the highest long-term survival followed by Cerebral Performance Categories 2 and 3, with Cerebral Performance Category 4 having the lowest long-term survival (p < 0.001, log-rank test). We found that Cerebral Performance Category 3 (hazard ratio = 3.62, p < 0.05) and Cerebral Performance Category 4 (hazard ratio = 12.73, p < 0.001) remained associated with worse survival after adjusting for age, gender, race, shockable rhythm, time to targeted temperature management initiation, total duration of resuscitation, withdrawal of care, and location of arrest. Patients with different Cerebral Performance Category scores at discharge have significantly different survival trajectories. Favorable Cerebral Performance Category at hospital discharge predicts better long-term outcomes of survivors of cardiac arrest who received targeted temperature management than those with less favorable Cerebral Performance Category scores.

Abstract 1659: Characterizing cytokine secretion in response to dsRNA treatment in ovarian cancer cells

Abstract Ovarian cancer exhibits the lowest long-term survival rates amongst all gynecological cancers, warranting more research directed at finding novel therapies, especially for late-stage disease. Inflammation is known to affect cancer progression, with tumor-promoting or repressive effects possible in different contexts, where the types of leukocytes at the tumor site are heavily implicated in disease prognosis. Tumor-associated macrophages and T-regulatory cells, for example, are known to promote tumor growth by inhibiting the anti-cancer response and by secreting pro-angiogenic factors. Importantly, the specific processes and cellular signaling pathways leading up to leukocyte infiltration in different cancer types remain to be fully elucidated. We hypothesize that dsRNA in the vicinity of ovarian cancer cells (such as from a viral infection or cellular debris) can activate pro-inflammatory regulators in tumor cells, in particular the NF-KB transcription factor, the aberrant over-activation of which is implicated in many cancers. NF-KB activation results in increased production and secretion of numerous cytokines that can in turn recruit pro-angiogenic leukocytes to the tumor microenvironment, thus favoring cancer progression. Herewith, we evaluated the production of numerous cytokines after dsRNA treatment in mouse and human ovarian cancer cells. Additionally, we determined which of the four known dsRNA receptors contributes most to this process. Consistently with our hypothesis, we have shown an increase in several pro-inflammatory cytokines (eg. CCL5 and IL6) in response to dsRNA treatment in both human and mouse ovarian cancer cell lines. We have also determined that the dsRNA receptor MDA5 contributes the most to dsRNA-induced cytokine secretion in both human and mouse ovarian cancer cell lines employing siRNA-directed knock-down of each receptor. Altogether, these data suggest that dsRNA-induced signaling in ovarian cancer cells may facilitate a tumor-favoring environment; thus dsRNA-sensing receptors may constitute attractive therapeutic targets for cancer immunotherapy. Further studies in our lab will determine the specific signaling pathways responsible for the upregulated cytokines as well as use a mouse model to examine the effect of dsRNA receptor knock-down in the cancer cells on tumor growth, angiogenesis, and the leukocyte infiltration profile. Citation Format: Maria Muccioli, Michelle Pate, Fabian Benencia. Characterizing cytokine secretion in response to dsRNA treatment in ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1659. doi:10.1158/1538-7445.AM2014-1659

Rectal outcomes after a liver-first treatment of patients with stage IV rectal cancer.

The treatment of patients with metastatic rectal cancer remains controversial. We developed a reverse strategy, the liver-first approach, to optimize the chance of a curative resection. The aim of this study was to assess rectal outcomes after reverse treatment of patients with metastatic rectal cancer. From May 2000 to November 2013, a total of 34 consecutive selected patients with histology-proven adenocarcinoma of the rectum and liver metastases were prospectively entered into a dedicated computerized database. All patients were treated via our reverse strategy. Rectal and overall survival outcomes were analyzed. Most patients presented with advanced disease (median Fong clinical risk score of 3; range 2-5). One patient failed to complete the whole treatment (3%). Rectal surgery was performed after a median of 3.9 months (range 0.4-17.8 months). A total of 73.3% patients received preoperative radiotherapy. Perioperative mortality and morbidity rates were 0 and 27.3% after rectal surgery. Severe complications were reported in two patients (6.1%): one anastomotic leak and one systemic inflammatory response syndrome. The median hospital stay was 11 days (range 5-23 days). Complete local pathological response was observed in three patients (9.1%). The median number of lymph nodes collected was 14. The R0 rate was 93.9%. There was no positive circumferential margin. After a mean follow-up of 36 months after rectal surgery, 5-year overall survival was 52.5%. Five patients experienced pelvic recurrence. In our cohort of selected patients with stage IV rectal cancer, the reverse strategy was not only safe and effective, but also oncologically promising, with a low morbidity rate and high long-term survival.

Survival outcomes following norwood procedure for hypoplastic left heart.

Prior studies evaluating the association of HLHS anatomic variants and mortality report conflicting results. Our objective was to determine if antegrade flow across the mitral within variants of HLHS with aortic atresia is associated with increased mortality compared to ventricular hypoplasia variants without antegrade mitral flow. All patients with HLHS born between 2002 and 2011 year who underwent stage I Norwood palliation with complete history and echocardiograms for patency of the mitral and aortic valves were studied. The cohort was divided into three groups: aortic atresia-mitral atresia (AA-MA), aortic stenosis-mitral stenosis (AS-MS), and aortic atresia-mitral stenosis (AA-MS). Demographic, comorbidities, and operative variables were analyzed. Analysis of variance techniques was applied for continuous variables and categorical variables. Survival analysis was performed using the Kaplan-Meier method with log-rank testing. A total of 70 consecutive patients who underwent Norwood Procedure were analyzed. There were no statistical differences in gender, birth weight, and age at time of Norwood procedure. Thirty patients had AA-MA variant, 23 had AA-MS, and 17 had AS-MS. Long-term Norwood survival was 60% for AA-MA, 65% for AS-MS, and 26% for AA-MS (p = 0.043). Use of extracorporeal membrane oxygenation as well as shunt revisions was more frequent for the AA-MS compared to other variants (p < 0.05). Patient weight at time of Norwood and length of regional perfusion were the highest predictors for hospital death following Norwood procedure. The Norwood procedure for mitral stenosis and aortic atresia is more often associated with use of extracorporeal membrane oxygenation and shunt revision compared to other variants. This HLHS variant has lowest long-term survival.

Long-Term Survival of a Patient with Jejunal Somatostatin-Producing Tumour and Liver Metastases

Extrapancreatic somatostatinomas are uncommon neuroendocrine tumours. Information related to its long-term prognosis is scarce. The prognosis of patients with advanced somatostatinoma is expected to be poor, but some tumours show low malignant potential and long-term survival rates have been described, even in the presence of metastases. We present a case of a 30-year-old patient, diagnosed with jejunal somatostatinoma. Multiple liver metastases were present at diagnosis. The primary tumour was removed and somatostatin analogues were prescribed. The patient survived for 12 years, with acceptable quality of life, although he suffered from repeated episodes of abdominal pain, diarrhea and vomiting along with severe hyperglycaemia followed by hypoglycaemia. Finally, he died because of severe ascitis and dyspnea due to tumour progression.

Small Acute Increases in Serum Creatinine Are Associated with Decreased Long-Term Survival in the Critically Ill

Long-term outcomes after acute kidney injury (AKI) are poorly described. We hypothesized that one single episode of minimal (stage 1) AKI is associated with reduced long-term survival compared with no AKI after recovery from critical illness. A prospective cohort of 2,010 intensive care unit (ICU) patients admitted to the ICU between years 2000 and 2009 at a provincial tertiary care hospital. Development of AKI was determined according to the KDIGO classification and mortality up to 10 years after ICU admission was recorded. Of the 1,844 eligible patients, 18.4% had AKI stage 1, 12.1% had stage 2, 26.5% had stage 3, and 43.0% had no AKI. The 28-day, 1-year, 5-year, and 10-year survival rates were 67.1%, 51.8%, 44.1%, and 36.3% in patients with mild AKI, which was significantly worse compared with the critically ill patients with no AKI at any time (P < 0.01). The unadjusted 10-year mortality hazard ratio was 1.53 (95% confidence interval, 1.2-2.0) for 28-day survivors with stage 1 AKI compared with critically ill patients with no AKI. Adjusted 10-year mortality risk was 1.26 (1.0-1.6). After propensity matching stage 1 AKI with no AKI patients, mild AKI was still significantly associated with decreased 10-year survival (P = 0.036). Patients with one episode of mild AKI have significantly lower long-term survival rates than critically ill patients with no AKI. Close medical follow-up of these patients may be warranted and mechanistic research is required to understand how AKI influences long-term events.

Sa1011 Obesity Is Associated With Significantly Lower Long-Term Survival Among Patients With Acute Liver Failure Undergoing Liver Transplantation in the United States

Background: Over 2,000 cases of acute liver failure (ALF) are reported in the U.S. on an annual basis. Previous studies have demonstrated that the prevalence of obesity in patients with ALF is comparable to general U.S. population. However, obese patients that developed ALF had significantly poorer survival. The validity of these studies was limited by the fact that body mass index (BMI) data was missing in over 25% of ALF patients. Our study aims to evaluate the impact of obesity on post-liver transplantation (LT) survival among ALF patients in the U.S. Methods: Adult patients with ALF undergoing LT in the U.S. from 20032012 were evaluated using data from the United Network for Organ Sharing registry. Patient demographics and clinical characteristics (including the etiology of ALF) were evaluated using chi square testing for categorical variables and Student's t-test for continuous variables. Non-parametric methods were used for non-normally distributed variables. Analyses were stratified by obesity status (BMI > 30 kg/m2) and race/ethnicity. Overall long term post-LT survival was evaluated with KaplanMeier methods and multivariate Cox proportional hazards models (adjusted for age, sex, race/ethnicity, etiology of ALF, obesity, year of LT, MELD score, ascites and presence of diabetes). Results: A total of 2,924 patients with ALF underwent LT from 2003-2012. Overall, 31.8% of ALF patients undergoing LT were obese (mean BMI: 27.1 ± 6.1) and 9.2% (n=246) had diabetes. When stratified by race/ethnicity, blacks had the highest rates of obesity (44.0%, n=210), followed by non-Hispanic whites (30.4%, n= 556), Hispanics (30.3%, n=100), and Asians (17.5%, n=43), p<0.001. Compared to nonobese patients, there was a trend towards lower 5-year post-LT survival among obese ALF patients (73.4% vs. 76.0%, p=0.18). However, when compared with non-obese, non-diabetic patients, there was a stronger trend towards lower post-LT survival among obese diabetic ALF patients (66.9% vs. 77.3%, p=0.08). In the multivariate Cox proportional hazards model, obesity was independently associated with lower post-LT survival in ALF patients (HR 1.20, 95% CI 1.00-1.43, p<0.01) (Table). Presence of diabetes was also associated with significantly lower post-LT survival (HR 1.45, 95% CI 1.09-1.93, p=0.01). Conclusions: Among patients with ALF undergoing LT, obesity is associated with significantly lower post-LT survival. Concurrent diabetes among obese ALF patients may confer an additional survival disadvantage. Multivariate Cox Proportional Hazards Model

Human papillomavirus, p16INK4A, and Ki-67 in relation to clinicopathological variables and survival in primary carcinoma of the vagina

Background:This study aimed to determine human papillomavirus (HPV) status and to investigate p16INK4A and Ki-67 expression and their correlation with clinical parameters and survival in women with primary carcinoma of the vagina (PCV).Methods:The presence of HPV DNA was evaluated by PCR. Genotyping was performed by Luminex in 68 short-term (⩽2 years) and long-term (⩾8 years) PCV survivors. p16INK4A and Ki-67 expression was evaluated by immunohistochemistry.Results:Human papillomavirus DNA was detected in 43% of patients, the majority (63%) of whom were HPV16 positive. High p16INK4A expression was significantly correlated with low histopathological grade (P=0.004), HPV positivity (P=0.032), and long-term survival (P=0.045). High Ki-67 expression was negatively correlated with histopathological grade (P<0.001) and tumour size (P=0.047). There was an association between HPV positivity and low histopathological grade, but not between HPV positivity and survival.Conclusion:High p16INK4A expression was associated with long-term survival, but the only independent predictors for survival were tumour size and histopathological grade. Our results indicate that p16INK4A and Ki-67 expression might be useful in tumour grading, and that it might be possible to use p16INK4A expression as a marker for HPV positivity, but this has to be further elucidated.

Effect Evaluation of Vascular Resection for Patients with Hilar Cholangiocarcinoma: Original Data and Meta-analysis

To evaluate the effect of vascular resection (VR) in surgical management of hilar cholangiocarcinoma (HCCA), this report is used in a clinical analysis and conducted a systematic review, combined other studies, based on meta-analysis. 238 HCCA patients underwent hepatectomy in the Eastern Hepatobiliary Surgery Hospital. Binary logistic regression analysis was performed to investigate the potentially complicated associated factors. Kaplan-Meier test was employed to compare the long-term survival of patients in four groups (R0+PVR-free, R0+PVR, R1, and R2). Meta-analysis was performed using RevMan 4.3.2 software. The results suggested that hepatectomy and HAR were important negative factors from complications (p < 0.01). Compared with patients in other groups, survival of patients in R0+PVR group was worse than R0+PVR-free group, better than R2 group, and similar to R1group with p = 0.001, 0.047, and 0.606, respectively. The results of meta-analysis suggested patients who underwent VR had higher complications rate and mortality rate than patients who did not. Moreover, patients with vascular resection had lower long-term survival rate. VR used to be considered effective to the patients with vascular invasion. However, our study suggests that the surgical decision of undergoing VR should be made cautiously, since VR could diminish the survival time in some cases.