Citations

Abstract Background: With over 13 million cancer survivors in the United States today, second cancers are of rapidly growing importance. However, data on nontreatment risk factors for second cancers are sparse. We explored the feasibility of pooling data from cohort studies of cancer incidence to investigate second cancer etiology. Methods: We combined data from five prospective studies including more than 800,000 individuals. We compared study designs and populations; evaluated availability of and ability to harmonize risk factor data; compared incidence and survival for common first primary malignancies and incidence of second primary malignancies; and estimated sample size requirements. Results: Overall, 96,513 incident, first primary malignancies were diagnosed during 1985 to 2009. Incidence rates and survival following the first primary varied among the cohorts, but most of the heterogeneity could be explained by characteristics of the study populations (age, sex, smoking, and screening rates). A total of 7,890 second primary cancers (excluding original primary site) were identified, yielding sufficient statistical power (≥80%) for detecting modest associations with risk of all second cancers among survivors of common first primary malignancies (e.g., colorectal cancer); however, there were insufficient events for studying survivors of rarer cancers or identifying risk factors for specific second cancers. Conclusions: Pooling data from cohort studies to investigate nontreatment risk factors for second primary cancers seems feasible but there are important methodologic issues—some of which are barriers to specific research questions—that require special attention. Impact: Increased understanding of nontreatment risk factors for second cancers will provide valuable prevention and surveillance information. Cancer Epidemiol Biomarkers Prev; 23(8); 1598–608. ©2014 AACR.

Key PointsCD28 delivers a pro-survival signal to MM cells via regulation of PI3K/Akt, FoxO3a, and Bim. Blockade of CD28:CD80/CD86 in vivo resensitizes MM cells to chemotherapy and significantly reduces tumor burden.

Abstract Immunostimulatory CpG motifs in synthetic oligonucleotides can be effective adjuvants for the priming of CTLs. We first observed that a single male-specific peptide (KCSRNRQYL) (HY2) was more efficient than another male-specific peptide (WMHHNMDLI) (HY1) at priming IFN-γ-secreting CTLs in vivo when combined with lipid A and CpG and that it also visibly precipitated CpG. The addition of the six N-terminal residues (KCSRNR) from HY2 to HY1 yielded a peptide, KCSRNR-HY1, that both precipitated CpG and primed increased numbers of HY1-specific CTLs. We refer to this type of peptide as a primotope that includes a class I binding peptide tailed with amino acids that increase priming. Ala residues were substituted for the Arg/Lys residues (ACSANA-HY1), and these substitutions did not reduce in vivo priming potential. However, the substitution of Ala for Cys (KASRNR-HY1) resulted in the complete loss of priming, demonstrating the importance of Cys for in vivo priming when mixed with CpG. This result suggested that increased priming was based in disulfide bonding between Cys residues and internal phosphorothioate groups of synthetic CpG. The addition of Cys-bearing primotopes to radiolabeled CpG with a single thioate group resulted in the appearance of a new band that was inhibited by 1) Cys > Ala substitution and 2) reduction and alkylation of CpG. These results reveal a novel mechanism for complexing class I binding peptides and CpG adjuvant for development of new peptide-adjuvant combinations for vaccines for cancer and infectious diseases.

Abstract Androgen has been implicated as a negative regulator of host immune function and a factor contributing to the gender dimorphism of autoimmunity. Conversely, androgen deprivation has been suggested to potentiate male host immunity. Studies have shown that removal of androgen in postpubertal male mice produces an increase in size and cellularity of primary and peripheral lymphoid organs, and enhances a variety of immune responses. Yet, few details are known about the effect of androgen removal on T cell-mediated immunity. In this study, we demonstrate two pronounced and independent alterations in T cell immunity that occur in response to androgen deprivation, provided by castration, in postpubertal male mice. First, we show that levels of T cells in peripheral lymphoid tissues of mice are increased by androgen deprivation. Second, T cells from these mice transiently proliferate more vigorously to TCR- and CD28-mediated costimulation as well as to Ag-specific activation. In addition, androgen deprivation accelerates normalization of host T and B cell levels following chemotherapy-induced lymphocyte depletion. Such alterations induced by androgen deprivation may have implications for enhancing immune responses to immunotherapy and for accelerating the recovery of the immune system following chemotherapy.

Abstract Purpose. The Oncotype DX colon cancer assay is a clinically validated predictor of recurrence risk in stage II colon cancer patients. This prospective study evaluated the impact of recurrence score (RS) results on physician recommendations regarding adjuvant chemotherapy in T3, mismatch repair-proficient (MMR-P) stage II colon cancer patients. Patients and Methods. Stage IIA colon cancer patients were enrolled in 17 centers. Patient tumor specimens were assessed by the RS test (quantitative reverse transcription-polymerase chain reaction) and mismatch repair (immunohistochemistry). For each patient, the physician's recommended postoperative treatment plan of observation, fluoropyrimidine monotherapy, or combination therapy with oxaliplatin was recorded before and after the RS and mismatch repair results were provided. Results. Of 221 enrolled patients, 141 patients had T3 MMR-P tumors and were eligible for the primary analysis. Treatment recommendations changed for 63 (45%; 95% confidence interval: 36%–53%) of these 141 T3 MMR-P patients, with intensity decreasing for 47 (33%) and increasing for 16 (11%). Recommendations for chemotherapy decreased from 73 patients (52%) to 42 (30%), following review of RS results by physician and patient. Increased treatment intensity was more often observed at higher RS values, and decreased intensity was observed at lower values (p = .011). Conclusion. Compared with traditional clinicopathological assessment, incorporation of the RS result into clinical decision making was associated with treatment recommendation changes for 45% of T3 MMR-P stage II colon cancer patients in this prospective multicenter study. Use of the RS assay may lead to overall reduction in adjuvant chemotherapy use in this subgroup of stage II colon cancer patients.

AbstractRenal retransplantation after a failed prior kidney and pancreas transplant is being increasingly performed. In these complex cases, both iliac fossae have been used for prior transplants, and the placement of the new allograft can be problematic. We describe our experience with an alternative technique for renal retransplantation (RRTx) in the setting of severe bilateral aortoiliac atherosclerosis or scarring and fibrosis on the iliac vessels. Nephrectomy of the failed allograft is performed, and the renal vessels of the failed allograft (RVFA) are preserved. The new kidney is implanted on RVFA at the same operative time. This technique was attempted and successfully accomplished in a total of six patients (mean operative time = 240 ± 63 min). One postoperative complication occurred: poor arterial inflow to the allograft, being corrected reoperatively. Hospitalizations ranged from five to eight d. Five of the six patients were alive with a functioning allograft at last follow‐up (a single graft failure occurred 21 months postoperatively in the setting of post‐transplant lymphoproliferative disease that also led to patient death). Renal vessels of the failed allograft seem to be suitable alternative vascular conduits for renal retransplantation after prior kidney and pancreas transplants.

Variable survival outcomes are seen following treatment for aggressive non‐Hodgkin lymphoma (NHL). This study examined whether outcomes for aggressive B‐cell NHL are associated with single nucleotide polymorphisms (SNPs) in oxidative stress‐related genes, which can alter drug metabolism and immune responses. Genotypes for 53 SNPs in 29 genes were determined for 337 patients given anthracycline‐based therapies. Their associations with progression‐free survival (PFS) and overall survival (OS) were estimated by Cox proportional hazard regression; associations with hematologic toxicity were estimated by logistic regression. To validate the findings, the top three SNPs were tested in an independent cohort of 572 DLBCL patients. The top SNPs associated with PFS in the discovery cohort were the rare homozygotes for MPO rs2243828 (hazard ratio [HR] = 1.87, 95% confidence interval [CI] = 1.14–3.06, P = 0.013), AKR1C3 rs10508293 (HR = 2.09, 95% CI = 1.28–3.41, P = 0.0032) and NCF4 rs1883112 (HR = 0.66, 95% CI = 0.43–1.02, P = 0.06). The association of the NCF4 SNP with PFS was replicated in the validation dataset (HR = 0.66, 95% CI = 0.44–1.01, P = 0.05) and the meta‐analysis was significant (HR = 0.66, 95% CI = 0.49–0.89, P < 0.01). The association of the MPO SNP was attenuated in the validation dataset, while the meta‐analysis remained significant (HR = 1.64, 95% CI = 1.12–2.41). These two SNPs showed similar trends with OS in the meta‐analysis (for NCF4, HR = 0.72, 95% CI = 0.51–1.02, P = 0.07 and for MPO, HR = 2.06, 95% CI = 1.36–3.12, P < 0.01). In addition, patients with the rare homozygote of the NCF4 SNP had an increased risk of hematologic toxicity. We concluded that genetic variations in NCF4 may contribute to treatment outcomes for patients with aggressive NHL. Am. J. Hematol. 89:639–645, 2014. © 2014 Wiley Periodicals, Inc.