Comorbidity and the Receipt of Curative Therapy for Favorable-risk Prostate Cancer Prior to and Following the Publication of PIVOT.

The publication of the randomized Prostate Cancer Intervention Versus Observation Trial (PIVOT) in July 2012, in which men with favorable-risk prostate cancer (PCa) were not found to benefit from radical prostatectomy, had the potential to shift PCa practice patterns. Using a prospectively assembled database of 5398 men with low-risk or favorable intermediate-risk PCa selected for curative treatment with brachytherapy in the years preceding and the year following the publication of PIVOT, we evaluated the odds of receiving curative treatment after adjusting for risk group (favorable intermediate vs low), race (black, Hispanic, or other), number of cardiometabolic comorbidities, and age. Following publication, the receipt of curative treatment was significantly lower (adjusted odds ratio [AOR]: 0.40; 95% confidence interval [CI], 0.16-0.99; p=0.05) among men with at least two cardiometabolic comorbidities, in contrast to the increasing trend (p=0.02) noted prior to PIVOT. Among black men, a subgroup at risk for occult high-grade disease, the odds of receiving curative treatment increased after PIVOT (AOR: 1.55; 95% CI, 1.06-2.26; p=0.02). These observations suggest that PIVOT's publication appropriately contributed to decreasing the use of curative treatment in men unlikely to benefit. PATIENT SUMMARY: The Prostate Intervention Versus Observation Trial (PIVOT) showed that radical prostatectomy did not benefit men with favorable-risk prostate cancer. Following the publication of PIVOT, the selection of men with multiple medical issues for curative treatment declined, whereas treatment of men at high risk of having aggressive prostate cancer increased.

The Impact of Reexcision and Residual Disease on Local Recurrence Following Breast-Conserving Therapy.

PURPOSE: Risk factors for local recurrence (LR) following breast-conserving therapy (BCT) inform the need for local therapy. A Danish population-based cohort study identified residual disease on reexcision as an independent risk factor for LR but was limited by incomplete data on biologic subtype (Bodilsen et al. 2015 in Ann Surg Oncol 22: S476-S485). We sought to elaborate this risk in an independent cohort with clearly defined biologic subtypes. METHODS: The study population included patients with localized invasive breast cancer with complete biologic subtype data treated with BCT with one or zero reexcisions at one institution from 1998 to 2008. Cumulative incidence of LR was calculated using competing risk analysis, and associated risk factors were evaluated using Cox proportional hazards regression. RESULTS: A total 1073 consecutive patients were included with a median follow-up of 10 years. The 10-year LR rates were 2.4% [95% confidence interval (CI) 1.4-3.9%] without reexcision, 6.0% (95% CI 3.8-8.9%) with reexcision, and 8.2% (95% CI 4.1-14.0%) with any reexcised residual disease. On univariate regression, residual disease [hazard ratio (HR) = 1.50, p = 0.31] was not significantly associated with LR. Subtype other than luminal A/luminal-HER2 (luminal B HR = 2.29, p = 0.033; HER2/triple-negative HR = 2.85, p = 0.004), age (HR = 0.95 per year, p < 0.001), and nodal involvement (HR = 1.12 per involved node, p = 0.001) remained significant on multivariate regression. The impact of residual disease was confounded by its association (p < 0.001) with nodal involvement. CONCLUSIONS: Our findings suggest that LR is associated with younger age, nodal involvement, and biologic subtype but not with residual disease at reexcision. The study's power is limited by the low incidence of LR despite detailed clinical data and long-term follow-up. Further study is required.

Selective induction of DNA repair pathways in human B cells activated by CD4+ T cells.

Greater than 75% of all hematologic malignancies derive from germinal center (GC) or post-GC B cells, suggesting that the GC reaction predisposes B cells to tumorigenesis. Because GC B cells acquire expression of the highly mutagenic enzyme activation-induced cytidine deaminase (AID), GC B cells may require additional DNA repair capacity. The goal of this study was to investigate whether normal human B cells acquire enhanced expression of DNA repair factors upon AID induction. We first demonstrated that several DNA mismatch repair, homologous recombination, base excision repair, and ATR signaling genes were overexpressed in GC B cells relative to naïve and memory B cells, reflecting activation of a process we have termed somatic hyperrepair (SHR). Using an in vitro system, we next characterized activation signals required to induce AID expression and SHR. Although AID expression was induced by a variety of polyclonal activators, SHR induction strictly required signals provided by contact with activated CD4+ T cells, and B cells activated in this manner displayed reduced levels of DNA damage-induced apoptosis. We further show the induction of SHR is independent of AID expression, as GC B cells from AID-/-mice retained heightened expression of SHR proteins. In consideration of the critical role that CD4+ T cells play in inducing the SHR process, our data suggest a novel role for CD4+ T cells in the tumor suppression of GC/post-GC B cells.

Transcriptional and post-transcriptional mechanisms of BAFF-receptor dysregulation in human B lineage malignancies.

Together, circulating BAFF and dominant receptor BAFF-R homeostatically regulate the humoral immune system. Consistently aberrant BAFF-R expression in leukemic cells reveals an intimate connection of these cells' malignant physiology to the BAFF/BAFF-R axis and also provides an additional survival mechanism to the expressing cells. In this study, we used primary cells and cell lines to interrogate the mechanisms underlying aberrant BAFF-R expression in precursor B acute lymphoblastic leukemia (precursor B-ALL) and mature B chronic lymphocytic leukemia (CLL). Here we demonstrate the aberrant expression of BAFF-R in precursor B-ALL cell lines and reveal that these cells acquire BAFF-R expression through premature transcriptional activation of the BAFF-R promoter in coordination with regulatory transcription factor c-Rel. Investigations using primary CLL cells provide a crucial counterpoint through their paucity of BAFF-R relative to their benign mature B cell counterparts, which we establish as functionally significant in its depletion of the CLL cells' BAFF-binding capacity. Furthermore, BAFF-R downregulation in CLL patients is revealed here to be restricted to the malignant compartment and mediated post-transcriptionally in order to compensate for the consistently unchanged levels of transcription factor c-Rel and BAFF-R mRNA. Finally, we present evidence that CLL cells retain endogenous mechanisms of BAFF-R regulatory control despite active receptor dysregulation.

The structure of the TNFRSF13C promoter enables differential expression of BAFF-R during B cell ontogeny and terminal differentiation.

The B cell-activating factor of the TNF family receptor (BAFF-R), encoded by the TNFRSF13C gene, is critically important for transitional B cell survival to maturity. Thus, ligation of BAFF-R by BAFF delivers a potent survival signal. Reports implicating the BAFF/BAFF-R signaling axis in the pathogenesis of autoimmune human diseases and B lineage malignancies have largely prompted studies focusing on BAFF expression; however, there is an equally critical need to better understand BAFF-R expression. Initial BAFF-R expression, although characterized in murine B cells, has not yet been reported in human B lymphopoiesis. In this study, we first demonstrate that BAFF-R expression is absent from early precursors and is acquired by bone marrow B cells newly expressing the BCR. We next focused on identifying the specific genomic region that controls BAFF-R expression in mature B cells (i.e., the TNFRSF13C promoter). To accomplish this, we used in silico tools examining interspecies genomic conservation in conjunction with reporter constructs transfected into malignant B and plasma cell lines. DNase protection assays using nuclear extracts from BAFF-R-expressing cells suggested potential regulatory sites, which allowed the generation of EMSA probes that bound NFs specific to BAFF-R-expressing cells. With a more stringent analysis of interspecies homology, these assays identified a site at which a single nucleotide substitution could distinctly impact promoter activity. Finally, chromatin immunoprecipitation assays revealed the in vivo binding of the specific transcription factor c-Rel to the most proximal genomic region, and c-Rel small interfering RNA transfections in BAFF-R-expressing lines demonstrated a coincident knockdown of both c-Rel and BAFF-R mRNA.

B lymphocyte stimulator regulates adaptive immune responses by directly promoting dendritic cell maturation.

B lymphocyte stimulator (BLyS) is a well-known direct costimulator of adaptive immune cells, particularly B lineage cells. However, we have reported recently that BLyS is also able to activate monocytes. Other innate immune cells, such as dendritic cells (DCs), play a key role in the initiation of adaptive immune responses and the purpose of the current study was to assess whether there is a direct role for BLyS in modulating human DC functions. In this study, we show that BLyS induces DC activation and maturation. Thus, BLyS strongly induced up-regulation of surface costimulatory molecule expression and secretion of specific cytokines and chemokines in DCs. BLyS-stimulated DCs (BLyS-DCs) were also able to augment allogeneic CD4 T cell proliferation to a greater extent than control DCs. BLyS-DCs secreted elevated levels of the major Th1-polarizing cytokine, IL-12p70, and they promoted naive CD4 T cell differentiation into Th1 T cells. Regarding BLyS receptor expression, DCs primarily express cytoplasmic transmembrane activator and CAML interactor; however, low levels of cell surface transmembrane activator and CAML interactor are expressed as well. Collectively, our data suggest that BLyS may modulate adaptive immune cells indirectly by inducing DC maturation.