Search

Supplementary Tables. Supplemental Table 1: Frequency of specific MET, NRAS, and KRAS mutations Supplemental Table 2. Distribution of patients with BRAF mutations

Drugs Approved by the U.S. Food and Drug Administration by April 30, 2014, That Were Included in the Analysis

Purpose:The prognosis of metastatic osteosarcoma continues to be poor. We hypothesized that alpha-emitting, bone-targeting radium 223 dichloride (223RaCl2) can be safely administered to patients with osteosarcoma and that early signals of response or resistance can be assessed by quantitative and qualitative correlative imaging studies and biomarkers.Patients and Methods:A 3+3 phase I, dose-escalation trial of 223RaCl2 (50, 75, and 100 kBq/kg) was designed in patients with recurrent/metastatic osteosarcoma aged ≥15 years. Objective measurements included changes in standardized uptake values of positron emission tomography (PET; 18FDG and/or NaF-18) and single-photon emission CT/CT (99mTc-MDP) as well as alkaline phosphatase and bone turnover markers at baseline, midstudy, and the end of the study.Results:Among 18 patients enrolled (including 15 males) aged 15–71 years, tumor locations included spine (n = 12, 67%), pelvis (n = 10, 56%), ribs (n = 9, 50%), extremity (n = 7, 39%), and skull (n = 2, 11%). Patients received 1–6 cycles of 223RaCl2; cumulative doses were 6.84-57.81 MBq. NaF PET revealed more sites of metastases than did FDG PET. One patient showed a metabolic response on FDG PET and NaF PET. Four patients had mixed responses, and one patient had a response in a brain metastasis. Bronchopulmonary hemorrhage from Grade 3 thrombocytopenia (N = 1) was a DLT. The median overall survival time was 25 weeks.Conclusions:The first evaluation of the safety and efficacy of an alpha particle in high-risk osteosarcoma shows that the recommended phase II dose for 223RaCl2 in osteosarcoma is 100 kBq/kg monthly (twice the dose approved for prostate cancer), with minimal hematologic toxicity, setting the stage for combination therapies.

Table S1 - Histologies and tumor grade by site according to MET amplification status. Table S2- Type of BRAF mutations by tumor site. Table S3 - List of phase I trials included as best trials for MET amplified patients.

Purpose: Evaluate the association between the use of phase I expansion cohorts (ECs) and drug performance in phase II as well as time to approval by the FDA.Experimental Design: We performed a systematic search of MEDLINE for single-agent dose-finding adult oncology phase I trials published in 2006 to 2011 and subsequent phase II trials. Successful phase II trials were those that met their primary endpoints. Dates of approval were obtained from the Drugs@FDA website in April 2014. A logistic regression model was used to determine the associations between variables and success in phase II.Results: We identified 533 phase I trials evaluating 381 drugs; 112 drugs had at least one phase I trial with an expansion cohort. Phase I trials with expansion cohorts of two to 20 patients were associated with a higher rate of successful phase II trials than those with no expansion cohort [48% vs. 27%; OR, 2.1; 95% confidence interval (CI), 1.1–4.0; P = 0.037]. Phase II success rates were the same for expansion cohort with two to 20 and more than 20 patients (48% vs. 52%). Other positive associations were disease-specific trials (OR, 1.7; 95% CI, 1.0–2.9; P = 0.037), industry sponsorship (OR, 2.9; 95% CI, 1.5–5.7; P = 0.0024), and response rate of 6% to 20% (OR, 2.89; 95% CI, 1.6–5.2; P = 0.0007). Drugs tested in phase I trials with expansion cohorts had a higher rate of 5-year approval (19% vs. 5%; HR, 4.4; 95% CI, 2.2–8.8; P < 0.001).Conclusions: The use of expansion cohorts in phase I trials was associated with success of subsequent phase II trials. However, confounders may play a role in this association. Clin Cancer Res; 23(15); 4020–6. ©2017 AACR.

Supplementary Appendices. Supplemental Appendix 1: List of Trials by NCT numbers Supplementary Appendix 2: Synergy and antagonism interaction examples

Purpose: We hypothesized that chemotherapy synergizes with VEGF/VEGFR (VEGF/R) inhibitors in patients with advanced solid malignancies.Experimental Design: Patients treated on phase I protocols between December 2004 and July 2013 (n = 1,498) were included in this analysis. The primary outcome was clinical benefit, defined as stable disease ≥6 months, complete response, or partial response. Two odds ratios (OR) for achieving clinical benefit were calculated: one for patients treated with VEGF/R inhibitors (OR with VEGF/R) and another for patients treated without (OR without VEGF/R). To compare these two ORs, an interaction term was included in the multivariate model: (chemotherapy/factor of interest)×(VEGF/R). We took significant interaction terms (Pinteraction < 0.05) to suggest effect modification (either synergy or antagonism) with VEGF/R inhibitors.Results: All patients treated with VEGF/R inhibitors exhibited higher OR for clinical benefit than those who were not [OR = 1.9; 95% confidence interval (CI), 1.5–2.4; P < 0.0001]. Use of chemotherapy agents concomitant with VEGF/R inhibitors was associated with significantly higher OR for clinical benefit compared with chemotherapy use without VEGF/R inhibitors [OR with VEGF/R = 1.6 (95% CI, 1.1–2.5) vs. OR without VEGF/R = 0.4 (95% CI, 0.3–0.6), Pinteraction = 0.02]. Specifically, the antimetabolite class was associated with the greatest increase in OR for clinical benefit [OR with VEGF/R = 2.7 (95% CI, 1.5–4.7) vs. OR without VEGF/R = 0.2 (95% CI 0.1–0.3), Pinteraction = 0.004].Conclusions: VEGF/R inhibitor was found to synergize with chemotherapeutics. This effect was most pronounced with the antimetabolite class. Clin Cancer Res; 20(23); 5956–63. ©2014 AACR.

Supplementary file: Previous therapies, Overall survival S1 : Prior therapies of patients with osteosarcoma enrolled on the Radium 223 trial. Supplementary Table S2: Adverse events in patients with osteosarcoma enrolled on the Radium 223 trial. Supplementary Figure 1: Overall survival of patients with osteosarcoma enrolled on the Radium 223 trial. Supplementary Figure 2: Correlation of % change in RECIST with relative change in LDH. Table 3: Table 1. Ra-223 dichloride Dose Escalation scheme (N=3/cohort)

Purpose: This study aimed to assess MET amplification among different cancers, association with clinical factors and genetic aberrations and targeted therapy response modifications.Experimental Design: From May 2010 to November 2012, samples from patients with advanced tumors referred to the MD Anderson Phase I Clinic were analyzed for MET gene amplification by FISH. Patient demographic, histologic characteristics, molecular characteristics, and outcomes in phase I protocols were compared per MET amplification status.Results: Of 1,115 patients, 29 (2.6%) had MET amplification. The highest prevalence was in adrenal (2 of 13; 15%) and renal (4 of 28; 14%) tumors, followed by gastroesophageal (6%), breast (5%), and ovarian cancers (4%). MET amplification was associated with adenocarcinomas (P = 0.007), high-grade tumors (P = 0.003), more sites of metastasis, higher BRAF mutation, and PTEN loss (all P < 0.05). Median overall survival was 7.23 and 8.62 months for patients with and without a MET amplification, respectively (HR = 1.12; 95% confidence intervals, 0.83–1.85; P = 0.29). Among the 20 patients with MET amplification treated on a phase I protocol, 4 (20%) achieved a partial response with greatest response rate on agents targeting angiogenesis (3 of 6, 50%). No patient treated with a c-MET inhibitor (0 of 7) achieved an objective response.Conclusion:MET amplification was detected in 2.6% of patients with solid tumors and was associated with adenocarcinomas, high-grade histology, and higher metastatic burden. Concomitant alterations in additional pathways (BRAF mutation and PTEN loss) and variable responses on targeted therapies, including c-MET inhibitors, suggest that further studies are needed to target this population. Clin Cancer Res; 20(24); 6336–45. ©2014 AACR.

Anaplastic thyroid cancer (ATC) is a deadly form of thyroid cancer.The ddPCR assay was evaluated for its sensitivity, specificity for detection ofForty-four patients with ATC who were tested for thecfDNA detection by ddPCR is highly sensitive, specific, and concordant with mutation status on ATC tumors. ddPCR also can be used for monitoring cfDNA levels in conjunction with imaging scans in patients with ATC.

Ocular toxicities are among the most common adverse events resulting from targeted anticancer agents and are becoming increasingly relevant in the management of patients on these agents. The purpose of this study is to provide a framework for management of these challenging toxicities based on objective data from FDA labels and from analysis of the literature. All oncologic drugs approved by the FDA up to March 14, 2015, were screened for inclusion. A total of 16 drugs (12 small-molecule drugs and 4 monoclonal antibodies) were analyzed for ocular toxicity profiles based on evidence of ocular toxicity. Trials cited by FDA labels were retrieved, and a combination search in Medline, Google Scholar, the Cochrane database, and the NIH Clinical Trials Database was conducted. The majority of ocular toxicities reported were low severity, and the most common were conjunctivitis and “visual disturbances.” However, severe events including incidents of blindness, retinal vascular occlusion, and corneal ulceration occurred. The frequency and severity at which ocular toxicities occur merits a more multidisciplinary approach to managing patients with agents that are known to cause ocular issues. We suggest a standardized methodology for referral and surveillance of patients who are potentially at risk of severe ocular toxicity.

PURPOSE Human epidermal growth factor receptor 2 (HER2) is an effective therapeutic target in breast and gastric and gastroesophageal junction cancers. However, less is known about the prevalence of ERBB2 (HER2) amplification and the efficacy of HER2-targeted treatment in other tumors. PATIENTS AND METHODS We assessed HER2 amplification status among 5,002 patients with advanced disease (excluding breast cancer) who underwent next-generation sequencing. We evaluated the clinical benefit of HER2-targeted therapy by measuring the time-dependent overall survival (OS) from the genomic testing results, progression-free survival (PFS), and PFS during HER2-targeted therapy (PFS2) compared with PFS during prior therapy (PFS1). RESULTS Overall, 122 patients (2.4%) had HER2 amplification, including patients with endometrial (5.3%), bladder (5.2%), biliary or gallbladder (4.9%), salivary (4.7%), and colorectal cancer (3.6%). Forty patients (38%) with nongastric, nongastroesophageal junction, or nonesophageal cancers received at least one line of HER2-targeted therapy. Patients receiving HER2-targeted therapy had a median OS of 18.6 months, compared with 10.9 months for patients who did not receive HER2-targeted therapy (P = .070). On multivariable analysis, HER2-targeted therapy was significantly associated with increased OS (hazard ratio, 0.5; 95% CI, 0.27 to 0.93; P = .029), regardless of sex, age, or number of prior lines of treatment. The PFS2-to-PFS1 ratio was 1.3 or greater in 21 (57%) of 37 patients who received HER2-targeted therapy not in the first line of systemic treatment, and the median PFS2 and PFS1 times were 24 and 13 weeks, respectively (P < .001). CONCLUSION HER2 amplifications using next-generation sequencing can be identified in a variety of tumor types. HER2-targeted therapy may confer clinical benefit in tumor types other than those for which HER2 inhibitors are approved.

The Richmond Agitation-Sedation Scale (RASS) is commonly used to assess psychomotor activity; however, to the authors' knowledge, its minimal clinically important difference (MCID) has not been determined to date. The objective of the current study was to identify the MCID for RASS using 2 anchor-based approaches.The current study was a secondary analysis of a randomized controlled trial to compare the effect of lorazepam versus placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium. The primary outcome was change in RASS (10-point numeric rating scale ranging from -5 [unarousable] to +4 [combative]) from baseline to 8 hours after treatment administration. The sensitivity-specificity and within-patient change methods were used to identify the MCID, with the anchor being patient comfort after the study intervention as perceived by caregivers and nurses.A total of 90 patients were randomized and 58 (64%) received the study medication for restlessness/agitation (mean baseline RASS, 1.6). A total of 23 caregivers (61%) and 23 nurses (55%) perceived that the patient was more comfortable after treatment. Using the sensitivity-specificity method, the optimal RASS reduction was ≥4 points according to both caregivers (sensitivity of 61% and specificity of 80%; area under the curve, 0.71) and nurses (sensitivity of 73% and specificity of 84%; area under the curve, 0.78). The RASS cutoff value based on the within-patient change method was similar (-4.2 for caregivers and -4.0 for nurses).For patients with persistent restlessness/agitation, a reduction of ≥4 points in RASS was considered to be the MCID for both nurses and caregivers. These preliminary findings may have implications for sample size calculation and the interpretation of treatment effect in future delirium trials. Cancer 2018;124:2246-52. © 2018 American Cancer Society.

Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.

Seizures are a potentially devastating complication of resection of brain tumors. Consequently, many neurosurgeons administer prophylactic antiepileptic drugs (AEDs) in the perioperative period. However, it is currently unclear whether perioperative AEDs should be routinely administered to patients with brain tumors who have never had a seizure. Therefore, the authors conducted a prospective, randomized trial examining the use of phenytoin for postoperative seizure prophylaxis in patients undergoing resection for supratentorial brain metastases or gliomas.Patients with brain tumors (metastases or gliomas) who did not have seizures and who were undergoing craniotomy for tumor resection were randomized to receive either phenytoin for 7 days after tumor resection (prophylaxis group) or no seizure prophylaxis (observation group). Phenytoin levels were monitored daily. Primary outcomes were seizures and adverse events. Using an estimated seizure incidence of 30% in the observation arm and 10% in the prophylaxis arm, a Type I error of 0.05 and a Type II error of 0.20, a target accrual of 142 patients (71 per arm) was planned.The trial was closed before completion of accrual because Bayesian predictive probability analyses performed by an independent data monitoring committee indicated a probability of 0.003 that at the end of the study prophylaxis would prove superior to observation and a probability of 0.997 that there would be insufficient evidence at the end of the trial to choose either arm as superior. At the time of trial closure, 123 patients (77 metastases and 46 gliomas) were randomized, with 62 receiving 7-day phenytoin (prophylaxis group) and 61 receiving no prophylaxis (observation group). The incidence of all seizures was 18% in the observation group and 24% in the prophylaxis group (p = 0.51). Importantly, the incidence of early seizures (30 days after surgery) was 8% in the observation group compared with 10% in the prophylaxis group (p = 1.0). Likewise, the incidence of clinically significant early seizures was 3% in the observation group and 2% in the prophylaxis group (p = 0.62). The prophylaxis group experienced significantly more adverse events (18% vs 0%, p0.01). Therapeutic phenytoin levels were maintained in 80% of patients.The incidence of seizures after surgery for brain tumors is low (8% [95% CI 3%-18%]) even without prophylactic AEDs, and the incidence of clinically significant seizures is even lower (3%). In contrast, routine phenytoin administration is associated with significant drug-related morbidity. Although the lower-than-anticipated incidence of seizures in the control group significantly limited the power of the study, the low baseline rate of perioperative seizures in patients with brain tumors raises concerns about the routine use of prophylactic phenytoin in this patient population.

Acute rupture was confirmed at operation in 117 patients treated for descending thoracic or thoracoabdominal aortic aneurysm. Descending thoracic (n = 80) aortic rupture occurred into lung or esophagus in 8, the pleural cavity in 49, and the mediastinum in 23. Upper abdominal aortic (n = 37) rupture occurred into peritoneal cavity in 3 and into retroperitoneal tissues in 34. Aneurysmal size (range, 5 to 17 cm; median, 8 cm) could be determined retrospectively in 86 patients; 59 (74%) descending thoracic and 27 (73%) abdominal aorta. Size (external diameter) in the former was 8 (14%), 5 to 6 cm; 21 (36%), 6 to 8 cm; 23 (39%), 8 to 10 cm; and 7 (12%) greater than 10 cm. Size at the abdominal site was similar. Thus size was not greater than 10 cm in 52 (88%) (range, 5 to 10 cm), which contradicts opinions that thoracic aneurysms rupture only when size exceeds 10 cm. Twenty-nine patients (25%) were hypotensive (systolic blood pressure less than 100 mmHg), of whom 16 (55%) had cardiac arrest before operation. Associated conditions included advanced age (greater than or equal to 75 years) in 26 (22%), coronary artery disease in 41 (35%), chronic obstructive pulmonary disease in 46 (39%), renal insufficiency in 25 (21%), and cardiovascular disease in 22 (18%). The overall early survival rate (30-day) was 89 of 117 patients (76%); 69% in patients with hypotension, 56% of patients with cardiac arrest, 88% in good-risk patients. Five-year (Kaplan-Meier) survival was 28%. Because elective operation is associated with 92% survival, this should be considered before rupture when aneurysm is 5 cm or larger in good-risk patients, in patients with symptomatic aneurysms, and in most patients with larger aneurysms.

Glioblastoma multiforme (GBM) is one of the most therapeutically refractory human cancers. Elevated cellular polyamine levels are a common feature of cancer cells, including GBM cells, and the polyamine pathway has been explored as a potential therapeutic target to inhibit polyamine biosynthesis or activate polyamine catabolism. In this study, we investigated the effect of N1,N11-diethyl-norspermine (DENSPM), a spermine analog that activates polyamine catabolism, in GBM cells. The in vitro cell culture experiments showed that DENSPM increased the sub-G1 apoptotic cell population in GBM cell lines but caused minimal cytotoxicity in normal astrocytes. Prior to apoptosis induction, DENSPM caused the elevation of spermidine/spermine N1-acetyltransferase (SSAT) expression accompanied by a decrease in polyamine levels and an increase of acetylated polyamine levels, which temporally coincided with the onset of hydrogen peroxide (H2O2) induction in the cells. The cytotoxic effects of DENSPM in the GBM cells could be partially attenuated by either turning down SSAT mRNA with small interference RNA or inhibiting H2O2 production with N1-acetylpolymine oxidase (APAO)/spermine oxidase (SMO) inhibitor. Though mitochondrial damage was induced, neither activation of the caspase cascade nor cytochrome c redistribution between the mitochondria and cytoplasm was observed. Systemic DENSPM treatment of mice with intracerebral GBM led to longer survival. Taken together, our studies indicate that DENSPM kills GBM cells through induction of SSAT coupled with H2O2 production, which is a potential target for GBM therapy.

The anatomical distribution of sensory-evoked activity recorded from the hippocampal long-axis can shift depending on prior experience. In accordance with Marr's computational model of hippo- campal function, CA3 NMDA receptors have been hypothesized to mediate this experience-dependent shift in hippocampal activity. Here we tested this hypothesis by investigating genetically-modified mice in which CA3 NMDA receptors are selectively knocked-out (CA3-NR1 KO). First, we were required to develop an fMRI protocol that can re- cord sensory-evoked activity from the mouse hippocampal long-axis. This goal was achieved in part by using a dedicated mouse scanner to image odor-evoked activity, and by using non-EPI (echo planer imaging) pulse sequences. As in humans, odors were found to evoke a ventral- predominant activation pattern in the mouse hippocampus. More impor- tantly, odor-evoked activity shifted in an experience-dependent manner. Finally, we found that the experience-dependent shift in hippocampal long-axis activity is blocked in CA3-NR1 knock-out mice. These findings establish a cellular mechanism for the plasticity imaged in the hippo- campal long-axis, suggesting how experience-dependent modifications of hippocampal activity can contribute to its mnemonic function. V C 2007 Wiley-Liss, Inc.

The purpose of this study was to determine whether comprehensive transcriptional profiles (TPs) can be obtained from single-passage fine-needle aspirations (FNAs) of breast cancer and to explore whether profiles capture routine clinicopathological parameters.Expression profiles were available on 38 patients with stage I-III breast cancer who underwent FNA at the time of diagnosis. [(33)P]dCTP-labeled cDNA probes were generated and hybridized to cDNA membrane microarrays that contained 30,000 human sequence clones, including 10,890 expressed sequence tags.The median total RNA yield from the biopsies was 2 micro g (range, 1-25 micro g). The cellular composition of each biopsy was examined and, on average, 79% of the cells were cancer cells. TP was successfully performed on all 38 of the biopsies. Unsupervised complete-linkage hierarchical clustering with all of the biopsies revealed an association between estrogen receptor (ER) status and gene expression profiles. There was a strong correlation between ER status determined by TP and measured by routine immunohistochemistry (P = 0.001). A similar strong correlation was seen with HER-2 status determined by fluorescent in situ hybridization (P = 0.0002). Using the first 18 cases as the discovery set, we established a cutoff of 2.0 and 18.0 for ER and HER-2 mRNA levels, respectively, to distinguish clinically-negative from -positive cases. We also identified 105 genes (excluding the ER gene) the expression of which correlated highly with clinical ER status. Twenty tumors were used for prospective validation. HER-2 status was correctly identified in all 20 of the cases, based on HER-2 mRNA content detected by TP. ER status was correctly identified in 19 of 20 cases. When the marker set of 105 genes was used to prospectively predict ER status, TP-based classification correctly identified 9 of 10 of the ER-positive and 7 of 10 of the ER-negative tumors. We also explored supervised cluster analysis using various functional categories of genes, and we observed a clear separation between ER-negative and ER-positive tumors when genes involved in signal transduction were used for clustering.These results demonstrate that comprehensive TP can be performed on FNA biopsies. TPs reliably measure conventional single-gene prognostic markers such as ER and HER-2. A complex pattern of genes (not including ER) can also be used to predict clinical ER status. These results demonstrate that needle biopsy-based diagnostic microarray tests may be developed that could capture conventional prognostic information but may also contain additional clinical information that cannot currently be measured with other methods.

This phase II study in recurrent high-grade glioma evaluated the response rate, toxicities, and time to treatment failure of high-dose carboplatin modulated by a 24-h infusion of thymidine (75 g/m(2)). The trial was based on preclinical data and a prior phase I study ( J. Clin. Oncol. 17, 2922-2931, 1999); a phase II recurrent high-grade glioma study was initiated in July of 1998. Thymidine was given over 24 h; carboplatin was given over 20 min at hour 20 of the thymidine infusion. The starting dose of carboplatin had a value of 7 for the area under the curve (AUC), with allowance for dose escalation of 1 AUC unit per cycle if grade 2 toxicity was observed. Treatment cycles were repeated every 4 weeks. Accrual as of September 1999 was 45 patients [4 were unevaluable]: 76% with glioblastoma multiforme (GBM), 20% with anaplastic oligodendroglioma, 2% with mixed type, and 2% with anaplastic astrocytoma. Most patients had prior chemotherapy (78%). As observed in the earlier phase I study (in which carboplatin pharmacokinetics were unaltered by thymidine or antiseizure medications), thymidine was myeloprotective, resulting in a minimal need for dose reduction for patients having a >2 grade toxicity (in only 4% of the courses of treatment). Of 101 total courses, the number of courses (at the AUCs) was 3 (5), 4 (6), 58 (7), 20 (8), 11 (9), and 5 (10). Grade 3 nonhematologic toxicities included headache (4%), altered consciousness (3%), fatigue (1%), and nausea (3%). Responses included 2 partial (1 oligodendroglioma, 1 GBM; 5%); 3 minor (1 anaplastic astrocytoma, 2 GBM; 7.3%); 6 stable disease (14.6%); and 30 progressive disease (73.2%). For GBM patients, median survival was 23 weeks (with a 95% confidence interval of 20 to 50 weeks), and progression-free survival was 8 weeks (with a 95% confidence interval of 7-16 weeks). These results in GBM were comparable to other phase II GBM trials and thus do not represent a therapeutic advance in the treatment of GBM. Taken collectively, however, results are consistent with continued investigation of thymidine in combination with chemotherapeutic agents for high-grade glioma and other malignant diseases. The significant myeloprotection afforded by thymidine may have particular relevance to polychemotherapeutic regimens.

The life expectancy of patients with aortic aneurysm is significantly prolonged by graft replacement therapy. Regardless, a significant predictor of late death is complications of either residual aortic aneurysmal disease or the development of additional aortic aneurysm. This paper reviews a personal experience in the treatment of 4170 patients with aneurysmal disease of either dissection or medial degenerative origin, indicating that multiple segment involvement was or became present in 1262 (30%) patients, 463 (67%) of 694 patients with dissection, and 799 (23%) of 3476 patients without dissection. Regardless of etiology, multiple involvement varied with the location of the presenting involved segment, i.e., ascending aorta (38%), ascending and arch (70%), descending thoracic aorta (73%), and abdominal aorta (26%). This study was limited in detail to 811 patients who had ascending and ascending and aortic arch replacement for aneurysm. These patients were divided into 3 subgroups: (1) 524 patients with no distal disease; (2) 135 patients with distal disease treated by subtotal replacement in 82 and total replacement in 53; and (3) 152 patients with distal disease not treated. The 5-year survival rate from the time of first operation, including early death from operation was 75% in group 1, 65% in group 2, and 39% in group 3. The causes of death in group 3 patients were aneurysmal rupture and/or associated disease. It is concluded that initial total aortic study and regular postoperative monitoring with computed tomographic scanning is indicated to detect extensive disease or recurrence of disease and that aggressive replacement is indicated except in patients with associated disease that does not permit operation.

Background: Colorectal cancer is the second leading cause of cancer deaths in the United States. Fecal occult blood testing has become a standard screening test for large-bowel cancers in the average asymptomatic population. Performance characteristics of the test and physician and participant compliance are the 2 major elements that impact the success of screening and early detection. Objectives: To evaluate the nonhydrated Hemoccult, rehydrated Hemoccult, and Hemoccult SENSA tests (SmithKline Diagnostics Inc, Palo Alto, Calif) and to assess participant and physician compliance. Methods: A mass community-based screening study in an urban setting. Kits were distributed by a local pharmacy and at community sites. Diagnostic tests were completed through physicians' offices and clinics. Participants were asymptomatic and aged 50 years or older. Those who tested positive were advised to follow up with a physician. Results: An overall positivity rate of 16% was reported for the 8293 kits that were processed. Rehydrated Hemoccult had a positivity rate of 15%; Hemoccult SENSA, 7%; and nonhydrated Hemoccult, 5%. The positive predictive value of nonhydrated Hemoccult was 14%; rehydrated Hemoccult, 7%; and Hemoccult SENSA, 11%. Of those who tested positive, 59% had a colonoscopy or flexible sigmoidoscopy and double-contrast barium enema examination on follow-up. Recommended follow-up was more frequent for those who consulted a gastroenterologist. Conclusions: Rehydrated Hemoccult yielded a higher positivity rate and lower positive predictive value than either Hemoccult SENSA or nonhydrated Hemoccult. Hemoccult SENSA approached the positive predictive value of nonhydrated Hemoccult. Adequacy of follow-up of patients testing positive for fecal occult blood needs improvement. Arch Intern Med. 1997;157:970-976

We evaluated 1525 consecutive patients who had undergone thoracic or thoracoabdominal aortic surgery to ascertain the factors associated with the development of acute renal failure. Complete data were available in 1233 patients who were treated recently, and these were analyzed. Acute renal failure, severe enough to require dialysis, developed in 5.5% of this group (68/1233): 2.3% and 7%, respectively, for descending (9/391) and thoracoabdominal repairs (59/842). Of interest, on multivariate analysis, both renal artery endarterectomy for occlusive disease (p = 0.0006) and chronic dissection (p = 0.03) were associated with significantly less acute renal failure. On multivariate analysis, the significant independent predictors (p < 0.05) of acute renal failure were preexistent renal dysfunction, evidence of diffuse atherosclerosis, the use of the pump bypass, and markers of hemodynamic instability. Contrary to earlier reports based on a smaller number of patients, we found that neither the use of pump bypass (7% acute renal failure), atriorenal bypass (8% acute renal failure), nor cold Ringer's lactate (3% acute renal failure) appeared to significantly avert the complication of acute renal failure. Indeed, pump bypass appeared to be deleterious (p = 0.0146) and perfusion with cold Ringer's lactate was not without risk. Furthermore, in a prospective evaluation of angiotensin converting enzyme blockers, we were unable to show that they afforded renal protection after transient renal ischemia. This study has clarified the clinical problems associated with acute renal failure and lays the foundation for future research. (J Vasc Surg 1989;10:230–9.)