A non-human primate model of acute liver failure suitable for testing liver support systems.

Acute hepatic failure is associated with high morbidity and mortality for which the only definitive therapy is liver transplantation. Some fraction of those who undergo emergency transplantation have been shown to recover native liver function when transplanted with an auxiliary hepatic graft that leaves part of the native liver intact. Thus, transplantation could have been averted with the development and use of some form of hepatic support. The costs of developing and testing liver support systems could be dramatically reduced by the availability of a reliable large animal model of hepatic failure with a large therapeutic window that allows the assessment of efficacy and timing of intervention. Non-lethal forms of hepatic injury were examined in combination with liver-directed radiation in non-human primates (NHPs) to develop a model of acute hepatic failure that mimics the human condition. Porcine hepatocyte transplantation was then tested as a potential therapy for acute hepatic failure. After liver-directed radiation therapy, delivery of a non-lethal hepatic ischemia-reperfusion injury reliably and rapidly generated liver failure providing conditions that can enable pre-clinical testing of liver support or replacement therapies. Unfortunately, in preliminary studies, low hepatocyte engraftment and over-immune suppression interfered with the ability to assess the efficacy of transplanted porcine hepatocytes in the model. A model of acute liver failure in NHPs was created that recapitulates the pathophysiology and pathology of the clinical condition, does so with reasonably predictable kinetics, and results in 100% mortality. The model allowed preliminary testing of xenogeneic hepatocyte transplantation as a potential therapy.

Interhospital variability in localization techniques for small pulmonary nodules in children: A pediatric surgical oncology research collaborative study.

BACKGROUND: Pulmonary nodules that are deep within lung parenchyma and/or small in size can be challenging to localize for biopsy. This study describes current trends in performance of image-guided localization techniques for pulmonary nodules in pediatric patients. METHODS: A retrospective review was performed on patients < 21 years of age undergoing localization of pulmonary nodules at 15 institutions. Localization and resection success, time in interventional radiology (IR), operating room (OR) and total anesthesia time, complications, and technical problems were compared between techniques. RESULTS: 225 patients were included with an average of 1.3 lesions (range 1-5). Median nodule size and depth were 4 mm (range 0-30) and 5.4 mm (0-61), respectively. The most common localization techniques were: wire + methylene blue dye (MBD) (28%), MBD only (25%), wire only (14%), technetium-99 only (11%), coil + MBD (7%) and coil only (5%). Localization technique was associated with institution (p < 0.01); technique and institution were significantly associated with mean IR, OR, and anesthesia time (all p < 0.05). Comparing techniques, there was no difference in successful IR localization (range 92-100%, p = 0.75), successful resection (94-100%, p = 0.98), IR technical problems (p = 0.22), or operative complications (p = 0.16). CONCLUSIONS: Many IR localization techniques for small pulmonary nodules in children can be successful, but there is wide variability in application by institution and in procedure time. LEVEL OF EVIDENCE: Retrospective review, Level 3.

Microcoil localization as an effective adjunct to thoracoscopic resection of pulmonary nodules in children.

BACKGROUND/PURPOSE: Thoracoscopic excision of pulmonary nodules is often required for diagnostic or therapeutic purposes, however subpleural and sub-centimeter nodules can be difficult to visualize. Various CT-guided localization techniques have been described, though there is minimal published pediatric data regarding the use of microcoils. We hypothesize that microcoil localization facilitates thoracoscopic resection of pulmonary nodules in children. METHODS: A multi-institutional retrospective review of children who underwent preoperative CT-guided localization of lung nodules was conducted from 2012 to 2019. A combination of methylene blue dye (MBD), wires, and microcoils were utilized for CT-guided localization. When microcoils were utilized, fluoroscopy assisted in lesion identification and resection. RESULTS: Eighteen patients (mean age 13 years, range 2-21 years) underwent thoracoscopic resection of 24 preoperatively localized pulmonary nodules. Mean size and depth of the lesions were 5.5 mm and 10 mm, respectively. Microcoil placement was successful 95% of the time and assisted in lesion localization in 88% of cases. Wire localization was not a durable technique, as 3 of 5 wires became dislodged upon lung  isolation. CONCLUSIONS: Preoperative CT-guided localization with microcoils can assist in fluoroscopic-guided resection of pulmonary nodules in children. This technique avoids the pitfall of wire dislodgement, and provides surgeons an additional technique to localize sub-centimeter, subpleural nodules. TYPE OF STUDY: Retrospective Review. LEVEL OF EVIDENCE: Level III.

Phase II Trial of Carfilzomib Plus Irinotecan in Patients With Small-cell Lung Cancer Who Have Progressed on Prior Platinum-based Chemotherapy.

INTRODUCTION: The purpose of this study was to evaluate the efficacy and tolerability of carfilzomib plus irinotecan (C/I) in patients with relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with SCLC who progressed after 1 platinum-containing regimen for recurrent or metastatic disease were eligible. Patients were stratified as: sensitive (SS) (progressive disease > 90 days after chemotherapy) or refractory (RS) (progressive disease 30 to 90 days after chemotherapy) and received up to 6 cycles of C/I; imaging was performed every 2 cycles. The primary endpoint was 6-month overall survival (OS). RESULTS: All 62 patients enrolled were evaluable for efficacy and adverse events. 6-month OS was 59% in the platinum SS and 54% in the platinum RS. The overall response rate was 21.6% (2.7% complete response, 18.9% partial response) in SS (n = 37) and 12.5% (all partial response) in RS (n = 25). The disease control rate was 68% (SS) and 56% (RS). Progression-free survival and OS were 3.6 months (95% confidence interval [CI], 2.6-4.6 months) and 6.9 months (95% CI, 4.3-12.3 months) in SS, and 3.3 months (95% CI, 1.8-3.9 months) and 6.8 months (95% CI, 4.1-11 months) in RS. Twenty-nine (47%) patients experienced ≥ grade 3 adverse events; 8 (12.9%) subjects had grade 4 toxicities. Three treatment-related deaths occurred: myocardial infarction (possible), lung infection (possible), and sepsis (probable). CONCLUSION: In patients with relapsed SCLC, C/I was effective in the treatment of SS and RS. With 4.8% grade 5 toxicity, C/I is a viable option for relapsed patients with SCLC with performance status 0 to 1, particularly in platinum-resistant patients, or subjects who cannot receive immunotherapy.

The IASLC Lung Cancer Staging Project: A Renewed Call to Participation.

Over the past two decades, the International Association for the Study of Lung Cancer (IASLC) Staging Project has been a steady source of evidence-based recommendations for the TNM classification for lung cancer published by the Union for International Cancer Control and the American Joint Committee on Cancer. The Staging and Prognostic Factors Committee of the IASLC is now issuing a call for participation in the next phase of the project, which is designed to inform the ninth edition of the TNM classification for lung cancer. Following the case recruitment model for the eighth edition database, volunteer site participants are asked to submit data on patients whose lung cancer was diagnosed between January 1, 2011, and December 31, 2019, to the project by means of a secure, electronic data capture system provided by Cancer Research And Biostatistics in Seattle, Washington. Alternatively, participants may transfer existing data sets. The continued success of the IASLC Staging Project in achieving its objectives will depend on the extent of international participation, the degree to which cases are entered directly into the electronic data capture system, and how closely externally submitted cases conform to the data elements for the project.

The IASLC Lung Cancer Staging Project: External Validation of the Revision of the TNM Stage Groupings in the Eighth Edition of the TNM Classification of Lung Cancer.

INTRODUCTION: Revisions to the TNM stage classifications for lung cancer, informed by the international database (N = 94,708) of the International Association for the Study of Lung Cancer (IASLC) Staging and Prognostic Factors Committee, need external validation. The objective was to externally validate the revisions by using the National Cancer Data Base (NCDB) of the American College of Surgeons. METHODS: Cases presenting from 2000 through 2012 were drawn from the NCDB and reclassified according to the eighth edition stage classification. Clinically and pathologically staged subsets of NSCLC were analyzed separately. The T, N, and overall TNM classifications were evaluated according to clinical, pathologic, and "best" stage (N = 780,294). Multivariate analyses were carried out to adjust for various confounding factors. A combined analysis of the NSCLC cases from both databases was performed to explore differences in overall survival prognosis between the two databases. RESULTS: The databases differed in terms of key factors related to data source. Survival was greater in the IASLC database for all stage categories. However, the eighth edition TNM stage classification system demonstrated consistent ability to discriminate TNM categories and stage groups for clinical and pathologic stage. CONCLUSIONS: The IASLC revisions made for the eighth edition of lung cancer staging are validated by this analysis of the NCDB database by the ordering, statistical differences, and homogeneity within stage groups and by the consistency within analyses of specific cohorts.

Antibiotic resistance among Helicobacter pylori clinical isolates in Lima, Peru.

OBJECTIVES: Gastric carcinoma is the most common cancer and cause of cancer mortality in Peru. Helicobacter pylori, a bacterium that colonizes the human stomach, is a Group 1 carcinogen due to its causal relationship to gastric carcinoma. While eradication of H. pylori can help prevent gastric cancer, characterizing regional antibiotic resistance patterns is necessary to determine targeted treatment for each region. Thus, we examined primary antibiotic resistance in clinical isolates of H. pylori in Lima, Peru. MATERIALS AND METHODS: H. pylori strains were isolated from gastric biopsies of patients with histologically proven H. pylori infection. Primary antibiotic resistance among isolates was examined using E-test strips. Isolates were examined for the presence of the cagA pathogenicity island and the vacA m1/m2 alleles via polymerase chain reaction. RESULTS: Seventy-six isolates were recovered from gastric biopsies. Clinical isolates showed evidence of antibiotic resistance to 1 (27.6%, n=21/76), 2 (28.9%, n=22/76), or ≥3 antibiotics (40.8%). Of 76 isolates, eight (10.5%) were resistant to amoxicillin and clarithromycin, which are part of the standard triple therapy for H. pylori infection. No trends were seen between the presence of cagA, vacA m1, or vacA m2 and antibiotic resistance. CONCLUSION: The rate of antibiotic resistance among H. pylori isolates in Lima, Peru, is higher than expected and presents cause for concern. To develop more targeted eradication therapies for H. pylori in Peru, more research is needed to better characterize antibiotic resistance among a larger number of clinical isolates prospectively.

Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results: Analysis of Phase 3 SWOG Intergroup Trial S0033.

IMPORTANCE: After identification of activating mutations of the KIT gene in gastrointestinal stromal tumor (GIST)-the most common sarcomaof the gastrointestinal tract-a phase 2 study demonstrated efficacy of imatinib mesylate in patients with metastatic GIST harboring a KIT exon 11 mutation. Initial results of long-term follow-up have found a survival benefit in this subgroup of patients. OBECTIVE: To assess the long-term survival of patients with GIST who were treated in SWOG study S0033 and to present new molecular data regarding treatment outcomes. DESIGN, SETTING, AND PARTICIPANTS: In this follow-up of randomized clinical trial participants (from December 15, 2000, to September 1, 2001), patients were required to have advanced GIST that was not surgically curable. Postprotocol data collection occurred from August 29, 2011, to July 15, 2015. Using modern sequencing technologies, 20 cases originally classified as having wild-type tumors underwent reanalysis. This intergroup study was coordinated by SWOG, a cooperative group member within the National Clinical Trials Network, with participation by member/affiliate institutions. This follow-up was not planned as part of the initial study. INTERVENTIONS: Patients were randomized to 1 of 2 dose levels of imatinib mesylate, including 400 mg once daily (400 mg/d) vs 400 mg twice daily (800 mg/d), and were treated until disease progression or unacceptable toxic effects of the drug occurred. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. Updated survival data were correlated with clinical and molecular factors, and patterns of postprotocol therapies were enumerated and described in long-term survivors. RESULTS: Of 695 eligible patients (376 men [54.1%]; 319 women [45.9%]; mean [SD] age, 60.1 [14.0] years), 189 survived 8 years or longer, including 95 in the 400-mg/d dose arm and 94 in the 800-mg/d arm. The 10-year estimate of overall survival was 23% (95% CI, 20%-26%). Among 142 long-term survivors, imatinib was the sole therapy administered in 69 (48.6%), with additional systemic agents administered to 54 patients (38.0%). Resequencing studies of 20 cases originally classified as KIT/PDGFRA wild-type GIST revealed that 17 (85.0%) harbored a pathogenic mutation, most commonly a mutation of a subunit of the succinate dehydrogenase complex. CONCLUSIONS AND RELEVANCE: A subset of patients with metastatic GIST experiences durable, long-term overall survival with imatinib treatment. Although this study provides guidance for management of GIST harboring the most common KIT and PDGFRA mutations, optimal management of other genotypic subtypes remains unclear. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00009906.

Host conditioning and rejection monitoring in hepatocyte transplantation in humans.

BACKGROUND & AIMS: Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver-directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. METHODS: Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. RESULTS: Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343±48µM (normal 30-119µM) to 854±25µM (treatment goal ≤360µM) after transplant (36% decrease; p<0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900µM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. CONCLUSIONS: Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. LAY SUMMARY: Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients.

Opportunities and challenges in incorporating ancillary studies into a cancer prevention randomized clinical trial.

BACKGROUND: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was a randomized, double-blind, placebo-controlled, prostate cancer prevention study funded by the National Cancer Institute and conducted by SWOG (Southwest Oncology Group). A total of 35,533 men were assigned randomly to one of four treatment groups (vitamin E + placebo, selenium + placebo, vitamin E + selenium, placebo + placebo). At the time of the trial's development, NIH had invested substantial resources in evaluating the potential benefits of these antioxidants. To capitalize on the knowledge gained from following a large cohort of healthy, aging males on the effects of selenium and/or vitamin E, ancillary studies with other disease endpoints were solicited. METHODS: Four ancillary studies were added. Each drew from the same population but had independent objectives and an endpoint other than prostate cancer. These studies fell into two categories: those prospectively enrolling and following participants (studies of Alzheimer's disease and respiratory function) and those requiring a retrospective medical record review after a reported event (cataracts/age-related macular degeneration and colorectal screening). An examination of the challenges and opportunities of adding ancillary studies is provided. The impact of the ancillary studies on adherence to SELECT was evaluated using a Cox proportional hazards model. RESULTS: While the addition of ancillary studies appears to have improved participant adherence to the primary trial, this did not come without added complexity. Activation of the ancillary studies happened after the SELECT randomizations had begun resulting in accrual problems to some of the studies. Study site participation in the ancillary trials varied greatly and depended on the interest of the study site principal investigator. Procedures for each were integrated into the primary trial and all monitoring was done by the SELECT Data and Safety Monitoring Committee. The impact of the early closure of the primary trial was different for each of the ancillary trials. CONCLUSIONS: The ancillary studies allowed study sites to broaden the research opportunities for their participants. Their implementation was efficient because of the established infrastructure of the primary trial. Implementation of these ancillary trials took substantial planning and coordination but enriched the overall primary trial. TRIAL REGISTRATION: NCT00006392-S0000 : Selenium and Vitamin E in Preventing Prostate Cancer (SELECT) (4 October 2000). NCT00780689-S0000A :  Prevention of Alzheimer's Disease by Vitamin E and Selenium (PREADVISE) (25 June 2002). NCT00784225-S0000B : Vitamin E and/or Selenium in Preventing Cataract and Age-Related Macular Degeneration in Men on SELECT SWOG-S0000 (SEE) (31 October 2008). NCT00706121-S0000D : Effect of Vitamin E and/or Selenium on Colorectal Polyps in Men Enrolled on SELECT Trial SWOG-S0000 (ACP) (26 June 2008). NCT00063453-S0000C : Vitamin E and/or Selenium in Preventing Loss of Lung Function in Older Men Enrolled on SELECT Clinical Trial SWOG-S0000 (26 June 2003).

Prospective analysis of antigen-specific immunity, stem-cell antigens, and immune checkpoints in monoclonal gammopathy.

Blockade of immune checkpoints (ICPs) has led to impressive responses in cancer patients. However, the impact of preexisting immunity and ICPs on the risk of malignant transformation in human preneoplasia has not been prospectively studied. We prospectively analyzed antigen-specific B/T-cell immunity, immune composition of the tumor microenvironment, and the expression of a panel of ICPs on tumor and tumor-infiltrating immune cells in 305 patients with asymptomatic monoclonal gammopathy enrolled in S0120 under the auspices of SWOG. T-cell immunity against stem-cell antigen SOX2 and preserved humoral responses at study entry independently correlated with reduced risk of progression to clinical myeloma. Among the ICPs analyzed, expression of programmed death-ligand 1 (PD-L1) on tumor and infiltrating T cells correlated with increased risk of clinical malignancy, and blockade of this pathway boosted anti-SOX2 immunity in culture. These data suggest that stem-cell antigens and PD-L1 may be targeted for immunoprevention of myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00900263.

A randomized controlled trial of vitamin E and selenium on rate of decline in lung function.

BACKGROUND: The intake of nutrients with antioxidant properties is hypothesized to augment antioxidant defenses, decrease oxidant damage to tissues, and attenuate age-related rate of decline in lung function. The objective was to determine whether long-term intervention with selenium and/or vitamin E supplements attenuates the annual rate of decline in lung function, particularly in cigarette smokers. METHODS: The Respiratory Ancillary Study (RAS) tested the single and joint effects of selenium (200 µg/d L-selenomethionine) and vitamin E (400 IU/day all rac-α-tocopheryl acetate) in a randomized double-blind placebo-controlled trial. At the end of the intervention, 1,641 men had repeated pulmonary function tests separated by an average of 3 years. Linear mixed-effects regression models estimated the effect of intervention on annual rate of decline in lung function. RESULTS: Compared to placebo, intervention had no main effect on either forced expiratory volume in the first second (FEV1) or forced expiratory flow (FEF25-75). There was no evidence for a smoking by treatment interaction for FEV1, but selenium attenuated rate of decline in FEF25-75 in current smokers (P = 0.0219). For current smokers randomized to selenium, annual rate of decline in FEF25-75 was similar to the annual decline experienced by never smokers randomized to placebo, with consistent effects for selenium alone and combined with vitamin E. CONCLUSIONS: Among all men, there was no effect of selenium and/or vitamin E supplementation on rate of lung function decline. However, current smokers randomized to selenium had an attenuated rate of decline in FEF25-75, a marker of airflow. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00241865 .

Age-related cataract in men in the selenium and vitamin e cancer prevention trial eye endpoints study: a randomized clinical trial.

IMPORTANCE: Observational studies suggest a role for dietary nutrients such as vitamin E and selenium in cataract prevention. However, the results of randomized clinical trials of vitamin E supplements and cataract have been disappointing and are not yet available for selenium. OBJECTIVE: To test whether long-term supplementation with selenium and vitamin E affects the incidence of cataract in a large cohort of men. DESIGN, SETTING, AND PARTICIPANTS: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) Eye Endpoints Study was an ancillary study of the Southwest Oncology Group-coordinated SELECT, a randomized placebo-controlled 4-arm trial of selenium and vitamin E conducted among 35,533 men, 50 years and older for African American participants and 55 years and older for all other men, at 427 participating sites in the United States, Canada, and Puerto Rico. A total of 11,267 SELECT participants from 128 SELECT sites participated in the SELECT Eye Endpoints ancillary study. INTERVENTIONS: Individual supplements of selenium (200 µg per day from L-selenomethionine) and vitamin E (400 IU per day of all rac-α-tocopheryl acetate). MAIN OUTCOMES AND MEASURES: Incident cataract was defined as a lens opacity, age related in origin, and responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-reports confirmed by medical record review. Cataract extraction was defined as the surgical removal of an incident cataract. RESULTS: During a mean (SD) of 5.6 (1.2) years of treatment and follow-up, 389 cases of cataract were documented. There were 185 cataracts in the selenium group and 204 in the no selenium group (hazard ratio, 0.91; 95 % CI, 0.75-1.11; P = .37). For vitamin E, there were 197 cases in the treated group and 192 in the placebo group (hazard ratio, 1.02; 95 % CI, 0.84-1.25; P = .81). Similar results were observed for cataract extraction. CONCLUSIONS AND RELEVANCE: These data from a large cohort of apparently healthy men indicate that long-term daily supplementation with selenium and/or vitamin E is unlikely to have a large beneficial effect on age-related cataract. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00784225.

Neurofibromas with imaging characteristics resembling vascular anomalies.

OBJECTIVE: Although neurofibromas are rare, their initial clinical and imaging presentation can mimic those of vascular anomalies, particularly if the characteristic clinical features of neurofibromatosis are not present. The diagnostic challenges encountered in five cases of histologically proven neurofibromas, initially diagnosed as vascular anomalies, are reviewed and discussed. CONCLUSION: The clinical and imaging differences between neurofibromas and vascular anomalies are detailed with the histopathologic features to better understand why some neurofibromas are diagnosed as vascular anomalies.

A phase 2 trial of R1507, a monoclonal antibody to the insulin-like growth factor-1 receptor (IGF-1R), in patients with recurrent or refractory rhabdomyosarcoma, osteosarcoma, synovial sarcoma, and other soft tissue sarcomas: results of a Sarcoma Alliance for Research Through Collaboration study.

BACKGROUND: Insulin-like growth factor-1 receptor (IGF-1R) is implicated in the pathogenesis of rhabdomyosarcoma (RMS), osteosarcoma (OS), and synovial sarcoma (SS). The authors conducted a multi-institutional phase 2 trial of the monoclonal antibody R1507 in patients with various subtypes of recurrent or refractory sarcomas. METHODS: Eligibility criteria included age ≥ 2 years and a diagnosis of recurrent or refractory RMS, OS, SS, and other soft tissue sarcomas. Patients received a weekly dose of 9 mg/kg R1507 intravenously. The primary endpoint was the best objective response rate using World Health Organization criteria. Tumor imaging was performed every 6 weeks × 4 and every 12 weeks thereafter. RESULTS: From December 2007 through August 2009, 163 eligible patients from 33 institutions were enrolled. The median patient age was 31 years (range, 7-85 years). Histologic diagnoses included OS (n = 38), RMS (n = 36), SS (n = 23), and other sarcomas (n = 66). The overall objective response rate was 2.5% (95% confidence interval, 0.7%-6.2%). Partial responses were observed in 4 patients, including 2 patients with OS, 1 patient with RMS, and 1 patient with alveolar soft part sarcoma. Four additional patients (3 with RMS and 1 with myxoid liposarcoma) had a ≥ 50% decrease in tumor size that lasted for <4 weeks. The median progression-free survival was 5.7 weeks, and the median overall survival was 11 months. The most common grade 3/4 toxicities were metabolic (12%), hematologic (6%), gastrointestinal (4%), and general constitutional symptoms (8%). CONCLUSIONS: R1507 is safe and well tolerated but has limited activity in patients with recurrent or refractory bone and soft tissue sarcomas. Additional studies to help identify the predictive factors associated with clinical benefit in selected histologies such as RMS appear to be warranted.

Overview: progression-free survival as an endpoint in clinical trials with solid tumors.

Progression-free survival (PFS) is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with solid tumors for both practical and clinical considerations. Although in its simplest form, PFS is the time from randomization to a predefined endpoint, there are many factors that can influence the exact moment of when disease progression is recorded. In this overview, we review the circumstances that can devalue the use of PFS as a primary endpoint and attempt to provide a pathway for a future desired state when PFS will become not just a secondary alternative to overall survival but rather an endpoint of choice.

Risk of recurrent Helicobacter pylori infection 1 year after initial eradication therapy in 7 Latin American communities.

IMPORTANCE: The long-term effectiveness of Helicobacter pylori eradication programs for preventing gastric cancer will depend on recurrence risk and individual and community factors. OBJECTIVE: To estimate risk of H. pylori recurrence and assess factors associated with successful eradication 1 year after treatment. DESIGN, SETTING, AND PARTICIPANTS: Cohort analysis of 1463 randomized trial participants aged 21 to 65 years from 7 Latin American communities, who were treated for H. pylori and observed between September 2009 and July 2011. INTERVENTIONS: Randomization to 1 of 3 treatment groups: 14-day lansoprazole, amoxicillin, and clarithromycin (triple therapy); 5-day lansoprazole and amoxicillin followed by 5-day lansoprazole, clarithromycin, and metronidazole (sequential); or 5-day lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant). Participants with a positive (13)C-urea breath test (UBT) 6 to 8 weeks posttreatment were offered voluntary re-treatment with 14-day bismuth-based quadruple therapy. MEASUREMENTS: Recurrent infection after a negative posttreatment UBT and factors associated with successful eradication at 1-year follow-up. RESULTS: Among participants with UBT-negative results who had a 1-year follow-up UBT (n=1091), 125 tested UBT positive, a recurrence risk of 11.5% (95% CI, 9.6%-13.5%). Recurrence was significantly associated with study site (P = .03), nonadherence to initial therapy (adjusted odds ratio [AOR], 2.94; 95% CI, 1.31-6.13; P = .01), and children in the household (AOR, 1.17; 95% CI, 1.01-1.35 per child; P = .03). Of the 281 with positive posttreatment UBT results, 138 completed re-treatment, of whom 93 tested UBT negative at 1 year. Among the 1340 who had a 1-year UBT, 80.4% (95% CI, 76.4%-83.9%), 79.8% (95% CI, 75.8%-83.5%), and 77.8% (95% CI, 73.6%-81.6%) had UBT-negative results in the triple, sequential, and concomitant groups, respectively (P = .61), with 79.3% overall effectiveness (95% CI, 77.1%-81.5%). In a single-treatment course analysis that ignored the effects of re-treatment, the percentage of UBT-negative results at 1 year was 72.4% (95% CI, 69.9%-74.8%) and was significantly associated with study site (P < .001), adherence to initial therapy (AOR, 0.26; 95% CI, 0.15-0.42; P < .001), male sex (AOR, 1.63; 95% CI, 1.25-2.13; P < .001), and age (AOR, 1.14; 95% CI, 1.02-1.27 per decade; P = .02). One-year effectiveness among all 1463 enrolled participants, considering all missing UBT results as positive, was 72.7% (95% CI, 70.3%-74.9%). CONCLUSIONS AND RELEVANCE: One year after treatment for H. pylori infection, recurrence occurred in 11.5% of participants who had negative posttreatment UBT results. Recurrence determinants (ie, nonadherence and demographics) may be as important as specific antibiotic regimen in determining the long-term success of H. pylori eradication interventions. Study findings are relevant to the feasibility of programs for the primary prevention of gastric cancer in high-incidence regions of Latin America. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01061437.

Patient income level and cancer clinical trial participation.

PURPOSE: Studies have shown an association between socioeconomic status (SES) and quality of oncology care, but less is known about the impact of patient SES on clinical trial participation. PATIENTS AND METHODS: We assessed clinical trial participation patterns according to important SES (income, education) and demographic factors in a large sample of patients surveyed via an Internet-based treatment decision tool. Logistic regression, conditioning on type of cancer, was used. Attitudes toward clinical trials were assessed using prespecified items about treatment, treatment tolerability, convenience, and cost. RESULTS: From 2007 to 2011, 5,499 patients were successfully surveyed. Forty percent discussed clinical trials with their physician, 45% of discussions led to physician offers of clinical trial participation, and 51% of offers led to clinical trial participation. The overall clinical trial participation rate was 9%. In univariate models, older patients (P = .002) and patients with lower income (P = .001) and education (P = .02) were less likely to participate in clinical trials. In a multivariable model, income remained a statistically significant predictor of clinical trial participation (odds ratio, 0.73; 95% CI, 0.57 to 0.94; P = .01). Even in patients age ≥ 65 years, who have universal access to Medicare, lower income predicted lower trial participation. Cost concerns were much more evident among lower-income patients (P < .001). CONCLUSION: Lower-income patients were less likely to participate in clinical trials, even when considering age group. A better understanding of why income is a barrier may help identify ways to make clinical trials better available to all patients and would increase the generalizability of clinical trial results across all income levels.