Predictors of Mortality in Acute Ischemic Stroke Intervention: Analysis of the North American Solitaire Acute Stroke Registry.

BACKGROUND AND PURPOSE: Failure to recanalize predicts mortality in acute ischemic stroke. In the North American Solitaire Acute Stroke registry, we investigated parameters associated with mortality in successfully recanalized patients. METHODS: Logistic regression was used to evaluate baseline characteristics and recanalization parameters for association with 90-day mortality. A multivariable model was developed based on backward selection with retention criteria of P<0.05 from factors with at least marginal significance (P≤0.10), then refit to minimize the number of excluded cases (missing data). RESULTS: Successfully recanalized patients had lower mortality (25.2% [59/234] versus 46.9% [38/81] P<0.001). There was no difference in symptomatic intracranial hemorrhage between patients with successful versus failed recanalization (9% [21/234] versus 14% [11/79]; P=0.205). However, mortality was significantly higher in patients with symptomatic intracranial hemorrhage (72% [23/32] versus 26% [73/281]; P<0.001). Proximal occlusion (internal carotid artery or vertebrobasilar), initial National Institutes of Health Stroke Scale≥18, use of rescue therapy (P<0.05), and 3+ passes (P<0.10) were associated with mortality in recanalized patients. In the multivariate model with good predictive power (c index=0.72), proximal occlusion, initial National Institutes of Health Stroke Scale≥18, and use of rescue therapy remained significant independent predictors of 90-day mortality. CONCLUSIONS: Failure to recanalize and presence of symptomatic intracranial hemorrhage resulted in increased mortality. Despite successful recanalization, proximal occlusion, high National Institutes of Health Stroke Scale, and need for rescue therapy were predictors of mortality.

A Phase I Study using low-dose fractionated whole abdominal radiotherapy as a chemopotentiator to full-dose cisplatin for optimally debulked stage III/IV carcinoma of the endometrium.

OBJECTIVE: To evaluate the feasibility of combining low-dose fractionated whole abdominal radiation (LDF-WAR) with weekly full-dose cisplatin (FD-CDDP) for patients with stage III/IV endometrial carcinoma. METHODS: Patients with optimally debulked stage III/IV carcinoma of the endometrium (without extra-abdominal disease) were eligible for the study. Postoperatively, patients received the institutional standard systemic chemotherapy and vaginal brachytherapy. Patients then underwent experimental six weekly cycles of FD-CDDP (40 mg/m², maximum 70 mg IV) followed by LDF-WAR 6-8 hours after initiation of chemotherapy. In a conservative design, 6 patients were accrued to two sequential cohorts of LDF-WAR, at 0.5 Gy/fraction [Fx] (total 3 Gy) and 0.75 Gy/Fx (total 4.5 Gy). Toxicities and laboratory studies were evaluated at each visit. RESULTS: Twelve patients were enrolled from January 2005 to June 2009 with median follow-up of 13.5 months (range: 5-27 months). Seventy-five percent of enrolled patients had uterine papillary serous histology. Eleven patients at least partially completed therapy (range: 2-6 cycles of FD-CDDP/LDF-WAR) with one additional patient opting out at the higher dose level. Combination therapy overall was well tolerated. Three patients in each cohort experienced grade 3 acute hematologic events with one recorded grade 4 toxicity in the second cohort. Of patients receiving any of the experimental treatment, five have experienced recurrences. Three of these patients were in cohort one and received 0.5 Gy/Fx LDF-WAR. CONCLUSION: Combination therapy with LDF-WAR as a novel chemopotentiator to FD-CDDP is a feasible adjuvant regimen in optimally debulked patients with stage III/IV endometrial carcinoma. Further investigation is warranted to determine treatment efficacy.

Association of Contrast and Acute Kidney Injury in the Critically Ill: A Propensity-Matched Study.

BACKGROUND: Despite evidence that low osmolar radiocontrast media is not associated with acute kidney injury, it is important to evaluate this association in critically ill patients with normal kidney function. METHODS: This retrospective observational study included 7,333 adults with an ICU stay at a six-hospital health system in south Florida. Patients who received contrast were compared with unexposed control subjects prior to and following propensity score (PS) matching derived from baseline characteristics, admission diagnoses, comorbidities, and severity of illness. Acute kidney injury (AKI), defined as initial onset (stage I) or increased severity, was determined from serum creatinine levels according to Kidney Disease: Improving Global Outcomes guidelines. RESULTS: Based on 2,306 PS-matched pairs obtained from 2,557 patients who received IV contrast and 4,776 unexposed control subjects, the increase in AKI attributable to contrast was 1.3% (19.3% vs 18.0%; P = .273), and no association was found between contrast and the pattern of onset and recovery. Hospital mortality increased by 14.3% subsequent to AKI (18.0 vs 3.6; P < .001), but the risk ratio in relation to patients with stable AKI did not vary when stratified according to contrast. Multivariable regression identified sepsis, metabolic disorders, diabetes, history of renal disease, and severity of illness as factors that were more strongly associated with AKI. CONCLUSIONS: In critically ill adults with normal kidney function, low osmolar radiocontrast media did not substantively increase AKI. Rather than limiting the use of contrast in ICU patients, efforts to prevent AKI should focus on the susceptibility of patients with sepsis, diabetes complications, high Acute Physiology and Chronic Health Evaluation scores, and history of renal disease.

Adoptively transferred tumor-specific T cells stimulated ex vivo using herpes simplex virus amplicons encoding 4-1BBL persist in the host and show antitumor activity in vivo.

4-1BB is a T-cell costimulatory receptor which binds its ligand 4-1BBL, resulting in prolonged T cell survival. We studied the antitumor effects of adoptively transferred tumor-specific T cells expanded ex vivo using tumors transduced with herpes simplex virus (HSV) amplicons expressing 4-1BBL as a direct source of antigen and costimulation. We constructed HSV amplicons encoding either the 4-1BBL (HSV.4-1BBL) or B7.1 (HSV.B7.1) costimulatory ligands. Lewis lung carcinoma cells expressing ovalbumin (LLC/OVA) were transduced with HSV.4-1BBL, HSV.B7.1, or control HSV amplicons and used to stimulate GFP+ OVA-specific CD8+ T cells (OT-1/GFP) ex vivo. Naive or ex vivo stimulated OT-1/GFP cells were adoptively transferred into LLC/OVA tumor-bearing mice. Higher percentages of OT-1/GFP cells were seen in the peripheral blood, spleen, and tumor bed of the HSV.4-1BBL-stimulated OT-1/GFP group compared with all other experimental groups. OT-1 cells identified within the tumor bed and draining lymph nodes of the HSV.4-1BBL-stimulated OT-1 group showed enhanced bromodeoxyuridine (BrdUrd) incorporation, suggesting ongoing expansion in vivo. Mice receiving HSV.4-1BBL-stimulated OT-1/GFP had significantly decreased tumor volumes compared with untreated mice (P<0.001) or to mice receiving naive OT-1/GFP (P<0.001). Transfer of HSV.B7.1-stimulated OT-1/GFP did not protect mice from tumor. Mice that received HSV.4-1BBL-stimulated OT-1/GFP exhibited increased cytolytic activity against LLC/OVA and higher percentages of Ly-6C+ OT-1/GFP in the spleen and tumor bed compared with controls. Tumor-specific T cells stimulated ex vivo using tumor transduced with HSV.4-1BBL expand in vivo following adoptive transfer, resulting in tumor eradication and the generation of tumor-specific CD44+Ly-6C+CD62L- effector memory T cells.

Is adjuvant 5-FU-based chemoradiotherapy for resectable pancreatic adenocarcinoma beneficial? A meta-analysis of an unanswered question.

The objective of this study was to determine the effect, if any, on survival of adjuvant 5-FU-based chemoradiotherapy following pancreaticoduodenectomy for pancreatic carcinoma. A systematic review of the published literature was undertaken. Survival estimates were derived from published reports. Five prospective studies (4 level I, 1 level II) with a total of 607 (229 surgery only; 378 surgery-adjuvant) patients followed for survival met selection criteria. Two-year survival ranged from 15%-37% in the surgery only group and 37%-43% in the surgery and adjuvant groups. The survival advantage (absolute difference) ranged from 3%-27% and no individual study achieved statistical significance (5%). Although clinical heterogeneity existed in surgery-alone control groups with regard to trial date, no statistical heterogeneity was detected (P = 0.459, chi2 test), allowing pooling of survival data. Using a fixed effects model, the summary estimate showed an absolute 2-year survival benefit with adjuvant therapy of 12% (95% CI, 3%-21%, P = 0.011). Trials after 1997 (n = 3) indicated a survival benefit of 8% to patients receiving adjuvant therapy (95% CI, -3-18%, P = 0.145). The result was not statistically significant, and there was no evidence of heterogeneity (P = 0.626, chi2 test). Summary estimates were unchanged when the analysis was performed with a random effects model. 5-FU based chemotherapy with radiotherapy given after resection imparts a small overall survival benefit of 2 years. The benefit of 5-FU-based adjuvant therapy, however, has declined in recent years, and its significance remains unproven in the context of current diagnostic and surgical practice.

Predictors of poor outcome despite recanalization: a multiple regression analysis of the NASA registry.

BACKGROUND: Mechanical thrombectomy with stent-retrievers results in higher recanalization rates compared with previous devices. Despite successful recanalization rates (Thrombolysis in Cerebral Infarction (TICI) score ≥2b) of 70-83%, good outcomes by 90-day modified Rankin Scale (mRS) score ≤2 are achieved in only 40-55% of patients. We evaluated predictors of poor outcomes (mRS >2) despite successful recanalization (TICI ≥2b) in the North American Solitaire Stent Retriever Acute Stroke (NASA) registry. METHODS: Logistic regression was used to evaluate baseline characteristics and recanalization outcomes for association with 90-day mRS score of 0-2 (good outcome) vs 3-6 (poor outcome). Univariate tests were carried out for all factors. A multivariable model was developed based on backwards selection from the factors with at least marginal significance (p≤0.10) on univariate analysis with the retention criterion set at p≤0.05. The model was refit to minimize the number of cases excluded because of missing covariate values; the c-statistic was a measure of predictive power. RESULTS: Of 354 patients, 256 (72.3%) were recanalized successfully. Based on 234 recanalized patients evaluated for 90-day mRS score, 116 (49.6%) had poor outcomes. Univariate analysis identified an increased risk of poor outcome for age ≥80 years, occlusion site of internal carotid artery (ICA)/basilar artery, National Institute of Health Stroke Scale (NIHSS) score ≥18, history of diabetes mellitus, TICI 2b, use of rescue therapy, not using a balloon-guided catheter or intravenous tissue plasminogen activator (IV t-PA), and >30 min to recanalization (p≤0.05). In multivariable analysis, age ≥80 years, occlusion site ICA/basilar, initial NIHSS score ≥18, diabetes, absence of IV t-PA, ≥3 passes, and use of rescue therapy were significant independent predictors of poor 90-day outcome in a model with good predictive power (c-index=0.80). CONCLUSIONS: Age, occlusion site, high NIHSS, diabetes, no IV t-PA, ≥3 passes, and use of rescue therapy are associated with poor 90-day outcome despite successful recanalization.

Volumetric spectroscopic imaging of glioblastoma multiforme radiation treatment volumes.

PURPOSE: Magnetic resonance (MR) imaging and computed tomography (CT) are used almost exclusively in radiation therapy planning of glioblastoma multiforme (GBM), despite their well-recognized limitations. MR spectroscopic imaging (MRSI) can identify biochemical patterns associated with normal brain and tumor, predominantly by observation of choline (Cho) and N-acetylaspartate (NAA) distributions. In this study, volumetric 3-dimensional MRSI was used to map these compounds over a wide region of the brain and to evaluate metabolite-defined treatment targets (metabolic tumor volumes [MTV]). METHODS AND MATERIALS: Volumetric MRSI with effective voxel size of ∼1.0 mL and standard clinical MR images were obtained from 19 GBM patients. Gross tumor volumes and edema were manually outlined, and clinical target volumes (CTVs) receiving 46 and 60 Gy were defined (CTV46 and CTV60, respectively). MTVCho and MTVNAA were constructed based on volumes with high Cho and low NAA relative to values estimated from normal-appearing tissue. RESULTS: The MRSI coverage of the brain was between 70% and 76%. The MTVNAA were almost entirely contained within the edema, and the correlation between the 2 volumes was significant (r=0.68, P=.001). In contrast, a considerable fraction of MTVCho was outside of the edema (median, 33%) and for some patients it was also outside of the CTV46 and CTV60. These untreated volumes were greater than 10% for 7 patients (37%) in the study, and on average more than one-third (34.3%) of the MTVCho for these patients were outside of CTV60. CONCLUSIONS: This study demonstrates the potential usefulness of whole-brain MRSI for radiation therapy planning of GBM and revealed that areas of metabolically active tumor are not covered by standard RT volumes. The described integration of MTV into the RT system will pave the way to future clinical trials investigating outcomes in patients treated based on metabolic information.

Lack of survival improvement in patients with peripheral T-cell lymphoma: a Surveillance, Epidemiology, and End Results analysis.

In patients with aggressive non-Hodgkin lymphomas (NHLs), T-cell lymphoma (TCL) confers a poor prognosis. Since rituximab has increased survival for patients with diffuse large B-cell lymphoma (DLBCL), we hypothesized that the difference in outcome by phenotype became more pronounced recently and evaluated these changes using the Surveillance, Epidemiology, and End Results (SEER) Program. Cases diagnosed in 1992-1997 (era 1) and 1998-2003 (era 2) were evaluated for outcomes according to immunophenotype and era. A total of 22,252 patients with DLBCL and 2222 with TCL were included. In both eras, patients with TCL were more likely to die from their disease than those with DLBCL. Death from NHL decreased significantly from era 1 to era 2 for all DLBCL patients grouped by age and stage but in none of the TCL groups. Improved outcomes for DLBCL after the introduction of rituximab-based therapies in 1997 have no counterpart in patients with TCL, pointing to the need for new therapies to treat TCL.

Efficacy and toxicity of chemoradiotherapy with carboplatin and irinotecan followed by consolidation docetaxel for unresectable stage III non-small cell lung cancer.

INTRODUCTION: In 2003, consolidation docetaxel was a promising concept for unresectable stage IIIA/B nonsmall cell lung cancer (NSCLC). To test the hypothesis that chemoradiotherapy with carboplatin and irinotecan followed by consolidation docetaxel would be feasible and clinically active, we conducted a phase II study. METHODS: Thirty-two patients with unresectable stage IIIA/B NSCLC received irinotecan (30 mg/m) and carboplatin dosed to a target area under the concentration curve of 2, each administered weekly for 7 weeks. Concurrent radiotherapy was administered more than 7 weeks to a total dose of 63 Gy in 35 fractions. Consolidation docetaxel (75 mg/m) was administered every 3 weeks for 3 doses 4 weeks after chemoradiotherapy. The primary end point was objective response rate by RECIST. RESULTS: Complete responses occurred in 4 patients and partial responses occurred in 14, for an objective response rate of 56.3% (95% confidence interval [CI], 37.7-73.6%). Median progression-free survival was 6.5 months (95% CI, 4.6-13.5); median duration of survival was 14.8 months (95% CI, 6.9-27.3). The most common hematologic toxicity was leukopenia, which were grade 3 or 4 in 16 patients (50%). Radiation pneumonitis (grade >or=2) occurred in 13 of 31 treated patients (42%). CONCLUSIONS: These findings suggested that concurrent chemoradiotherapy with carboplatin and irinotecan followed by consolidation docetaxel is clinically active based on median survival in patients with unresectable stage III NSCLC; however, the 42% incidence of clinical radiation pneumonitis was unexpected and warrants further investigation to determine the mechanism and preventive strategies.

High rate and prolonged duration of complete remissions induced by rituximab, methotrexate, doxorubicin, cyclophosphamide, vincristine, ifosfamide, etoposide, cytarabine, and thalidomide (R-MACLO-IVAM-T), a modification of the National Cancer Institute 89-C-41 regimen, in patients with newly diagnosed mantle cell lymphoma.

Novel therapeutic approaches are needed in mantle cell lymphoma (MCL). We conducted a phase II study in MCL testing an intensive regimen, R-MACLO-IVAM-T, a modification of the NCI 89-C-41 protocol. Newly diagnosed patients were treated with rituximab, methotrexate, doxorubicin, cyclophosphamide, and vincristine (cycle 1) followed by rituximab, ifosfamide (and mesna), etoposide, and cytarabine (cycle 2). These two cycles were repeated once, and patients achieving complete response (CR) received maintenance thalidomide. Among the 22 patients enrolled, 21 completed two or more cycles and achieved a CR. Three patients relapsed, while 17 are alive and relapse-free after a median follow-up of 37 months (range 19-65 months). Two patients died: one from sepsis during cycle 1 and another at 38 months while in remission from MCL. The progression-free survival at 3 years was 78% (95% CI: 51-91%). These results compare favorably with previously reported outcomes suggesting that durable remissions can be achieved without myeloablative therapy.

Family history of cancer, oral contraceptive use, and ovarian cancer risk.

OBJECTIVE: The purpose of this study was to determine whether women with a family history of ovarian cancer are at reduced risk of ovarian cancer from the use of oral contraceptives and to compare their risk with that of women with no family history of ovarian cancer. STUDY DESIGN: A population-based case-controlled study was conducted from May 1994 through July 1998 in which 767 women aged 20 to 69 years with a diagnosis of epithelial ovarian cancer were ascertained from 39 hospitals in 3 northeastern states. Personal interviews with the women and 1367 control subjects provided data that allowed us to estimate the relative risk of ovarian cancer in relation to a family history of cancer and total duration of oral contraception. RESULTS: Among the 33 case patients and 24 control subjects with a first-degree family history of ovarian cancer, risk of ovarian cancer declined with increasing duration of oral contraception (P =.01). Risk reduction from short-term use of oral contraceptives (< or = 48 months) did not differ significantly by family history (combined estimate of odds ratio, 0.72; 90% CI, 0.59%-0.87%). Risk reduction from long-term use of oral contraceptives (>48 months) was greater in women with a positive family history of ovarian cancer (odds ratio, 0.12) than in women with a negative family history of ovarian cancer (odds ratio, 0.51; test of interaction, P =.04; 692 case patients, 1279 control subjects). CONCLUSION: Four to 8 years of oral contraception may substantially reduce the risk of ovarian cancer by age 70 years in women with a family history of the disease, from approximately 4 women per 100 women who did not use oral contraceptives to only 2 women per 100 women who did use oral contraceptives.

Neoadjuvant treatment for resectable cancer of the esophagus and the gastroesophageal junction: a meta-analysis of randomized clinical trials.

BACKGROUND: There is no general agreement on the effect of neoadjuvant treatment for esophageal cancer on patient survival. METHODS: A meta-analysis was performed to determine the effect of preoperative treatment on survival of patients with resectable esophageal cancer and the effect of preoperative treatment on patient mortality. A standard variance-based method was used to derive summary estimates of the absolute difference in both 2-year survival and treatment-related mortality. RESULTS: Eleven randomized trials involving 2311 patients were analyzed. Preoperative chemotherapy improved 2-year survival compared with surgery alone: the absolute difference was 4.4% (95% confidence interval [CI],.3%-8.5%). Marginal evidence of heterogeneity was eliminated by restricting attention to the four most recent studies, which increased the estimate to 6.3% (95% CI, 1.8%-10.7%). For combined chemoradiotherapy, the increase was 6.4% (nonsignificant; 95% CI, -1.2%-14.0%). Treatment-related mortality increased by 1.7% with neoadjuvant chemotherapy (95% CI, -.9%-4.3%) and by 3.4% with chemoradiotherapy (95% CI, -.1%-7.3%), compared with surgery alone. CONCLUSIONS: There seems to be a modest survival advantage for patients who receive neoadjuvant chemotherapy followed by surgery, as compared with surgery alone. There is an apparent increase in treatment-related mortality, mainly for patients who receive neoadjuvant chemoradiotherapy.