Search

Prior meta-analysis of stem-cell transplantation trials for renal-cell carcinoma observed that clinical outcomes vary by subjects' order of entry, specifically their quartile of accrual. We test this hypothesis using meta-analysis of individual patient data from diverse Phase II trials conducted by an oncology consortium. Eligible were all Phase II trials in hematologic or solid tumors opened and closed by California Cancer Consortium during 2005–2020. Excluded were trials closed in first quartile or currently embargoed pending publication and subjects ineligible per protocol or untreated on study. The primary risk factor was entry by quartile of planned sample size. As a cross-protocol endpoint, primary outcome was time to discontinuation of intervention. One-stage meta-analysis used a shared frailty model with trial as random effect. As covariates, stepwise selection retained tumor type, obesity, their interaction, calendar year, entry at least 3 years post-diagnosis, and performance status but rejected age, sex, randomized design, and class of drug. Twenty trials (including 8 terminated early, 2 not published) included n = 923 subjects. Most (90.6%) subjects discontinued intervention, usually for disease progression or toxicity. Independently of covariates, risk of discontinuation increased (p < 0.0001) with each quartile of entry (Hazards Ratio 1.13, 95% CI 1.06–1.22), culminating at Quartile 4 (HR 1.46, 1.36–1.57). The 95% prediction interval for the Hazards Ratio in future trials was (1.04–1.24). Progression-free survival similarly worsened by quartile of entry. In Phase II trials, clinical outcome worsens with quartile of entry. This finding merits independent replication, and the cause of this phenomenon merits investigation. [ABSTRACT FROM AUTHOR]

Abstract: Despite 2 randomized trials reporting no reduction in operations or local recurrence at 1 year, preoperative magnetic resonance imaging (MRI) is increasingly used in diagnostic workup of breast cancer. We evaluated 5 utilization criteria recently proposed by experts. Of women (n = 340) newly diagnosed with unilateral breast cancer who underwent bilateral MRI, most (69.4%) met at least 1 criterion before MRI: mammographic density (44.4%), under consideration for partial breast irradiation (PBI) (19.7%), genetic-familial risk (12.9%), invasive lobular carcinoma (11.8%), and multifocal/multicentric disease (10.6%). MRI detected occult malignant lesion or extension of index lesion in 21.2% of index, 3.3% of contralateral, breasts. No expert criterion was associated with MRI-detected malignant lesion, which associated instead with pre-MRI plan of lumpectomy without PBI (48.2% of subjects): Odds Ratio 3.05, 95% CI 1.57–5.91 (p adjusted for multiple hypothesis testing = 0.007, adjusted for index-vs-contralateral breast and covariates). The expert guidelines were not confirmed by clinical evidence. [Copyright &y& Elsevier]

Abstract: In the era of cytomegalovirus (CMV)-preemptive therapy, it is unclear whether CMV serostatus of donor or recipient affects outcome of allogeneic hematopoietic stem cell transplantation (HSCT) among children with leukemia. To investigate, consecutive patients aged 0-18 who underwent primary HSCT for acute leukemia in 1997-2007 (HLA-matched sibling or unrelated donor, myeloablative conditioning, unmanipulated bone marrow or peripheral blood, preemptive therapy, no CMV prophylaxis) were followed retrospectively through January 2008. Treatment failure (relapse or death) was analyzed using survival-based proportional hazards regression. Competing risks (relapse and nonrelapse mortality, NRM) were analyzed using generalized linear models of cumulative incidence-based proportional hazards. Excluding 4 (2.8%) patients lacking serostatus of donor or recipient, there were 140 subjects, of whom 50 relapsed and 24 died in remission. Pretransplant CMV seroprevalence was 55.7% in recipients, 57.1% in donors. Thirty-five (25.0%) grafts were from seronegative donor to seronegative recipient (D−/R−). On univariate analysis, D−/R− grafts were associated with shorter relapse-free survival (RFS) than other grafts (median 1.06 versus 3.15 years, P < .05). Adjusted for donor type, diagnosis, disease stage, recipient and donor age, female-to-male graft, graft source, and year, D−/R− graft was associated with relapse (hazards ratio 3.15, 95% confidence interval 1.46-6.76) and treatment failure (2.45, 1.46-4.12) but not significantly with NRM (2.00, 0.44-9.09). In the current era, children who undergo allogeneic HSCT for acute leukemia have reduced risk of relapse and superior RFS when recipient and/or donor is CMV-seropositive before transplantation. However, no net improvement in RFS would be gained from substituting seropositive unrelated for seronegative sibling donors. [Copyright &y& Elsevier]

Abstract: Using data from the Third National Health and Nutrition Examination Survey (United States, 1988–1994), we compared clinical phenotypes of hepatitis C virus (HCV)-seropositive and seronegative adults aged 20–89 years with hyperglycemia (impaired fasting glucose (IFG) or type 2 diabetes, n =3566 including 86 with HCV). Seroprevalence was higher among younger persons (3.4% for ages 20–59 versus 0.9% for ages 60–89, p =0.002), while traditional correlates of diabetes (hypertension, coronary heart disease) were more prevalent among older persons (both comparisons, p <0.0001). To prevent confounding by age, younger and older persons were analyzed separately. In both age groups, HCV was associated with signs of hepatic impairment and B-cell clonal expansion (higher alanine aminotransferase (ALT) and serum globulin, lower total cholesterol and platelet count). Only among younger persons, however, was HCV also associated with a marker for advanced hepatic fibrosis (elevated serum ferritin) and absence of the classical diabetic phenotype (overweight, coronary heart disease). In addition, among younger persons, HCV was currently associated with family history of diabetes, positively in persons with diabetes and inversely in those with IFG, suggesting that family history of diabetes may serve as a cofactor for progression from HCV-associated IFG to diabetes. [Copyright &y& Elsevier]

Background: Precision oncology can identify patient-specific molecular signatures to better inform the prognosis and management of surgical cancer patients. Specifically, microRNAs (miRs) hold promise as prognostic biomarkers because dysregulation of individual miRs is implicated in tumorigenesis, progression, and metastases of various malignancies, including gastric adenocarcinoma (GC).Study Design: To identify miRs prognostic of survival after radical gastrectomy, we studied GC patients within The Cancer Genome Atlas (TCGA) who had undergone R0 or R1 resection and had data on clinical characteristics, overall survival (OS), and tumor miR expression. The miRs expressed by at least 15% of tumors were eligible for study. From 10 replicate samples, each with 80% of patients, miRs were selected using age-adjusted proportional hazards regression with stepwise selection. Cross-validated miRs (selected by multiple replicates) were retained if they optimized an accelerated failure-time model of OS using all patients.Results: In this GC cohort (n = 270), half (916/1,870) of miRs screened met our criteria for evaluation. Cross-validation identified 20 miRs as prognostic, of which 14 (miR-129-1, miR-373, miR-490, miR-597, miR-1185-2, miR-3943, miR-4756, miR-5683, miR-6510, miR-6733, miR-6808, miR-6855, miR-6882, miR-8072) were independently informative. The age-adjusted 14-miRNA panel remained significantly associated with OS after adjustment for pathologic prognostic factors (number of lymph nodes examined, number of positive lymph nodes) and other clinical covariates (TNM stage, residual tumor, tumor microsatellite instability, targeted molecular therapy, sex, race, ethnicity). Panel-predicted survival estimates below the upper tertile cut-off were associated with worse outcome (30% vs 74% OS at 3 years, p < 0.0001).Conclusions: In surgically resected GC patients, an epigenetic signature of miRs associated with survival has the potential to improve prognostication. [ABSTRACT FROM AUTHOR]

Abstract: Phase II trial designs that ignore between-patient heterogeneity and do not allow for treatment–subgroup interactions may produce very large false positive and false negative error rates if efficacy varies by subgroup. Recent discussions of this problem were illustrated with scenarios and computer simulations. In this short communication, we reanalyzed a published phase II trial to highlight the need to consider between-patient heterogeneity and the possibility of treatment–subgroup interaction when designing and analyzing phase II studies. The single-arm trial evaluated amsacrine plus cytosine arabinoside, vincristine, and prednisone (a combination abbreviated as OAP) for adult acute leukemia, when standard treatment was adriamycin plus OAP. We carried out an analysis of covariance (ANCOVA) incorporating data from historical control patients who met eligibility criteria for the trial and received standard treatment at the study center in the years immediately preceding the trial. Patients administered experimental treatment and control patients were classified as having favorable or unfavorable prognosis according to their predicted probability of response to standard treatment. When the prognostic subgroup of patients was ignored, the response rates for experimental and standard treatment appeared similar. However, fitting an ANCOVA model determined that the effects of subgroup, treatment, and their interaction were statistically significant: experimental treatment was superior to standard treatment in patients with unfavorable prognosis and inferior to standard treatment in patients with favorable prognosis. This real-world example of treatment–subgroup interaction highlights the need to employ phase II designs that consider between-patient heterogeneity and the possibility that efficacy differs by subgroup. [Copyright &y& Elsevier]