Citations

Abstract Destruction of tumor cells is a key function of lymphocytes, but the molecular processes driving it are unclear. Analysis of signal molecules indicated that mitogen-activated protein kinase (MAPK)/extracellular regulated kinase 2 critically controlled lytic function in human NK cells. We now have evidence to indicate that target ligation triggers a Ras-independent MAPK pathway that is required for lysis of the ligated tumor cell. Target engagement caused NK cells to rapidly activate MAPK within 5 min, and PD098059 effectively blocked both MAPK activation and tumoricidal function in NK cells. Target engagement also rapidly activated Ras, detected as active Ras-GTP bound to GST-Raf-RBD, a GST fusion protein linked to the Raf protein fragment containing the Ras-GTP binding domain. However, Ras inactivation by pharmacological disruption with the farnesyl transferase inhibitor, FTI-277, had no adverse effect on the ability of NK cells to lyse tumor cells or to express MAPK activation upon target conjugation. Notably, MAPK inactivation with PD098059, but not Ras inactivation with FTI-277, could interfere with perforin and granzyme B polarization within NK cells toward the contacted target cell. Using vaccinia delivery of N17 Ras into NK cells, we demonstrated that IL-2 activated a Ras-dependent MAPK pathway, while target ligation used a Ras-independent MAPK pathway to trigger lysis in NK cells.

Objective To demonstrate sarcomatoid differentiation is an independent prognostic feature for patients with grade 4 renal cell carcinoma ( RCC ) with or without distant metastases. To identify independent predictors of survival, evaluate the correlation between the amount of sarcomatoid differentiation and cancer‐specific survival ( CSS ), and to design a multivariate prognostic model for patients with sarcomatoid RCC . Patients and Methods We used the Mayo Clinic Nephrectomy Registry to identify 204 post‐nephrectomy patients with sarcomatoid‐variant RCC , as well as 207 patients with unilateral grade 4 RCC without sarcomatoid features for comparison. All slides were reviewed by one pathologist. CSS was estimated using the K aplan– M eier method. The associations of clinical and pathological features with death from RCC were evaluated using Cox proportional hazards regression models. Results For all patients with grade 4 RCC , the presence of sarcomatoid differentiation was associated with a 58% increased risk of death from RCC ( P < 0.001). For patients with grade 4 non‐metastatic ( M0 ) RCC , the presence of sarcomatoid differentiation was associated with an 82% increased risk of death from RCC ( P < 0.001). For patients with sarcomatoid RCC , the 2009 primary tumour classifications, presence of regional lymph nodes and distant metastases, coagulative tumour necrosis, and the amount of sarcomatoid differentiation were each significantly associated with death from RCC in a multivariate setting. After adjusting for other prognostic variables, each 10% increase in the amount of sarcomatoid differentiation was associated with a 6% increased risk of death from RCC ( P = 0.028). Patients whose tumours contained ≥30% (median amount) sarcomatoid differentiation were 52% more likely to die from RCC compared with patients whose tumours contained <30% sarcomatoid differentiation (hazard ratio 1.52; P = 0.018). Conclusions Among patients with grade 4 RCC , either with or without distant metastases at surgery, sarcomatoid differentiation is significantly associated with adverse survival in a multivariate setting. We also suggest for the first time that the percentage of sarcomatoid differentiation is an independent prognostic feature in a multivariate setting. The 2009 primary tumour classifications, regional lymph node status, the presence of distant metastases classifications, coagulative tumour necrosis, and the amount of sarcomatoid differentiation are independent predictors of survival for patients with sarcomatoid RCC .

Abstract Rationale Provider decisions about patients to be discharged from the intensive care unit (ICU) are often based on subjective intuition, sometimes leading to premature discharge and early readmission. The Stability and Work Load Index for Transfer (SWIFT) score, as a risk stratification tool, has moderate ability to predict patients at risk of ICU readmission. Objectives To describe findings following the incorporation of the SWIFT score into the discharge workflow of a medical ICU. Methods The study involved 5,293 consecutive patients discharged alive from the medical ICU of an academic medical center. The SWIFT score and associated percentage risk for readmission were incorporated into daily rounds for purpose of discharge decision-making. We measured readmission rates before and after implementation and observed changes in provider discharge decisions for individual patients after SWIFT discussions. Measurements and Main Results Baseline (n = 1,906) and implementation (n = 1,938) cohorts differed with respect to APACHE III scores (P = 0.03). In the implementation cohort, 26.2% of subjects had SWIFT scores greater than 15 and thus were predicted to have a higher risk of unplanned readmissions. In this high-risk group, 25% had SWIFT discussed in their discharge planning. There was modification of provider discharge decisions in 108 (30%) of cases in which the SWIFT was discussed. SWIFT score values above a prespecified cutoff of 15 were associated with physician tendency to prolong ICU stay or to discharge to a monitored setting (P &lt; 0.001). There was no difference in 24-hour or 7-day readmission rates between the baseline and implementation cohorts (1.9 vs. 2.4%, P = 0.24; 6.5 vs. 7.4%, P = 0.26, respectively) even after adjustment for severity of illness. Conclusions Using the SWIFT score as an adjunct to clinical judgment, physicians modified their discharge decisions in one-third of subjects. Introducing such tools into the discharge workflow may present change management challenges that limit the evaluation of their impact on readmission rates and other relevant ICU outcomes.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab‐containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short‐duration regimen combining pentostatin, alemtuzumab, and low‐dose high‐frequency rituximab designed to decrease the risk of treatment‐associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13−) (n = 3). Thirteen (33%) patients had both 17p13− and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty‐six (67%) patients completed therapy, with only five (13%) patients having treatment‐limiting toxicity and no treatment‐related deaths. Twenty‐two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression‐free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B‐cell lymphoma (n = 6). Correlative studies showed that low‐dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low‐dose high‐frequency rituximab is a tolerable and effective therapy for CLL and that low‐dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. Am. J. Hematol. 89:757–765, 2014. © 2014 Wiley Periodicals, Inc.

ABSTRACTBackgroundDobutamine stress echocardiography (DSE) is commonly used to risk stratify patients in the cardiac evaluation prior to orthotopic liver transplantation (OLT). Data remain limited regarding the accuracy to predict obstructive coronary artery disease (CAD) using this approach.HypothesisWe hypothesize that DSE may have limitations in the investigation of underlying CAD in patients with end‐stage liver disease.MethodsA retrospective chart review of all patients who underwent OLT at Mayo Clinic in Florida between 1998 and 2010 was performed. Sixty‐six underwent invasive coronary angiography (ICA) within 1 year of DSE and were included in our study. Based on DSE results, patients were stratified into 1 of 3 groups: nonischemic, ischemic, and indeterminate. The relationship between DSE, ICA, and death from all cause and cardiac‐related cause with a minimum 3‐year follow‐up period were analyzed.ResultsA total of 66 patients were included in our cohort. There was no difference in age, gender, severity of liver disease, and echocardiographic findings among the groups. Forty‐three percent of patients (n = 12) with an abnormal result on DSE were found to have moderate or severe obstructive CAD on cardiac catheterization, whereas 49% of patients (n = 17) with a normal finding on DSE had moderate or severe CAD. Of 5 patients who died from a documented cardiac etiology, 3 had normal stress test results, 1 had abnormal findings, and 1 had an indeterminate DSE result. When compared with ICA, our study demonstrated that DSE has a sensitivity of 41.4% (95% confidence interval [CI]: 0.24‐0.61), specificity of 47.1% (95% CI: 0.30‐0.65), positive predictive value of 40.0% (95% CI: 0.23‐0.59), and negative predictive value of 48.0% (95% CI: 0.31‐0.66) in identification of underlying CAD.ConclusionsAlthough widely used, DSE may not always accurately reflect the severity of obstructive CAD in patients undergoing OLT.

Abstract Objective: This study aims to evaluate cardiac function in fetuses with intrauterine growth restriction (IUGR) compared with healthy fetuses, using the left modified myocardial performance index (MPI) and the association between MPI and perinatal outcome. Methods: Pregnant women between 34 and 39 weeks of gestation, who met the criteria for IUGR and were scheduled for delivery at an Egyptian tertiary medical center, were prospectively enrolled in the study. Women in the same gestational-age group with uncomplicated pregnancies were included as a control group. MPI was measured in all fetuses. The IUGR group was analyzed based on normal and abnormal umbilical artery (UA) Doppler. Perinatal outcomes were recorded. Results: The mean left MPI was significantly higher in IUGR fetuses with abnormal UA Doppler (mean 0.58±SD 0.093) compared with healthy fetuses (mean 0.45±SD 0.070) (P<0.001). IUGR fetuses with abnormal left MPI showed significantly worse perinatal outcome and increased morbidity compared with the control group. IUGR fetuses with abnormal left MPI also showed significantly worse perinatal outcome compared with IUGR fetuses with normal MPI (whether the UA Doppler was normal or abnormal). The fetal MPI was associated with the severity of fetal compromise in IUGR fetuses based on the perinatal outcome. Conclusion: MPI is a potentially useful tool in evaluating fetuses with suspected IUGR, which is crucial in classifying IUGR pregnancies into critical and non-critical cases and in predicting neonatal outcome.

BACKGROUNDThe authors examined the “real‐world” effectiveness of rituximab (R) maintenance therapy (R‐maintenance) compared with observation after R‐based induction therapy in patients with previously untreated follicular lymphoma (FL) in the United States.METHODSThe National LymphoCare Study is a prospective, multicenter, observational study that enrolled > 2700 untreated patients with FL diagnosed from 2004 to 2007 at 265 sites in the United States. Among these, patients who achieved at least stable disease after R‐based induction therapy were eligible for the current analysis. Patients who initiated R‐maintenance within 215 days of completing induction therapy were categorized as the R‐maintenance group, and those who did not initiate therapy during this period were categorized as the observation group. The objective of the current study was to determine the effect of R‐maintenance on progression‐free survival (PFS), time to next treatment (TTNT), and overall survival (OS).RESULTSA total of 1439 patients completed R‐based induction therapy, 1186 of whom met all inclusion criteria (541 patients received R‐maintenance and 645 patients were observed). Characteristics that were found to be predictive of receiving R‐maintenance were histology grade (1/2), Ann Arbor stage of disease (III/IV), geographic region (region other than the West), and practice setting (community practice). With a median follow‐up of 5.7 years, R‐maintenance was associated with superior PFS (hazards ratio [HR], 0.68; 95% confidence interval [95% CI], 0.56‐0.84 [P = .0003]) and TTNT (HR, 0.66; 95% CI, 0.52‐0.84 [P = .0007]). No significant difference in OS was observed (HR, 0.81; 95% CI, 0.58‐1.14 [P = .23]).CONCLUSIONSR‐maintenance in patients with FL and at least stable disease after R‐based induction therapy provided significantly longer PFS and TTNT in comparison with observation, but no significant difference in OS was observed with 5‐years of follow‐up. This comparative effectiveness study aligns with the results of randomized trials suggesting that similar outcomes occur with R‐maintenance in FL with the treatment variations observed in clinical practice. Cancer 2014;120:1830–1837. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Background Exercise testing provides valuable information in addition to ST ‐segment changes. The present study evaluated the associations among exercise test parameters and all‐cause mortality in a referral population. Methods and Results We examined conventional cardiovascular risk factors and exercise test parameters in 6546 individuals (mean age 49 years, 58% men) with no known cardiovascular disease who were referred to our clinic for exercise stress testing between 1993 and 2003. The association of exercise parameters with mortality was assessed during a follow‐up of 8.1±3.7 years. A total of 285 patients died during the follow‐up period. Adjusting for age and sex, the variables associated with mortality were: smoking, diabetes, functional aerobic capacity ( FAC ), heart rate recovery ( HRR ), chronotropic incompetence, and angina during the exercise. Adjusting for cardiovascular risk factors (diabetes, smoking, body mass index, blood pressure, serum total, HDL , LDL cholesterol, and triglycerides) and other exercise variables in a multivariable model, the only exercise parameters independently associated with mortality were lower FAC (adjusted hazard ratio [ HR ] per 10% decrease in FAC , 1.21; 95% confidence interval [ CI ], 1.13 to 1.29; P <0.001), and abnormal HRR , defined as failure to decrease heart rate by 12 beats at 1 minute recovery (adjusted HR per 1‐beat decrease, 1.05; 95% CI , 1.03 to 1.07; P <0.001). The additive effects of FAC and HRR on mortality were also highly significant when considered as categorical variables. Conclusion In this cohort of patients with no known cardiovascular disease who were referred for exercise electrocardiography, FAC and HRR were independently associated with all‐cause mortality.