Search

Objective: To assess the impact of a granular measure of SED on pancreatic surgical and cancer-related outcomes at a high-volume cancer center that employs a standardized clinic pathway., Summary of Background Data: Prior research has shown that low socioeconomic status leads to less treatment and worse outcomes for PDAC. However, these studies employed inconsistent definitions and categorizations of socioeconomic status, aggregated individual socioeconomic data using large geographic areas, and lacked detailed clinicopathologic variables., Methods: We conducted a retrospective cohort study of 1552 PDAC patients between 2008 and 2015. Patients were stratified using the area deprivation index, a validated dataset that ranks census block groups based on SED. Multivariable models were used in the curative surgery cohort to predict the impact of SED on (1) grade 3/4 Clavien-Dindo complications, (2) initiation of adjuvant therapy, (3) completion of adjuvant therapy, and (4) overall survival., Results: Patients from high SED neighborhoods constituted 29.9% of the cohort. Median overall survival was 28 months. The rate of Clavien-Dindo grade 3/4 complications was 14.2% and completion of adjuvant therapy was 65.6%. There was no evidence that SED impacted surgical evaluation, receipt of curative-intent surgery, postoperative complications, receipt of adjuvant therapy or overall survival., Conclusions: Although nearly one-quarter of curative-intent surgery patients were from high SED neighborhoods, this factor was not associated with measures of treatment quality or survival. These observations suggest that treatment at a high-volume cancer center employing a standardized clinical pathway may in part address socioeconomic disparities in pancreatic cancer., Competing Interests: The authors report no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

A major challenge for HIV vaccine development is to raise anti-envelope antibodies capable of recognizing and neutralizing diverse strains of HIV-1. Accordingly, a full length single chain (FLSC) of gp120-CD4 chimeric vaccine construct was designed to present a highly conserved CD4-induced (CD4i) HIV-1 envelope structure that elicits cross-reactive anti-envelope humoral responses and protective immunity in animal models of HIV infection. IHV01 is the FLSC formulated in aluminum phosphate adjuvant. We enrolled 65 healthy adult volunteers in this first-in-human phase 1a randomized, double-blind, placebo-controlled study with three dose-escalating cohorts (75 µg, 150 µg, and 300 µg doses). Intramuscular injections were given on weeks 0, 4, 8, and 24. Participants were followed for an additional 24 weeks after the last immunization. The overall incidence of adverse events (AEs) was not significantly different between vaccinees and controls. The majority (89%) of vaccine-related AE were mild. The most common vaccine-related adverse event was injection site pain. There were no vaccine-related serious AE, discontinuation due to AE, intercurrent HIV infection, or significant decreases in CD4 count. By the final vaccination, all vaccine recipients developed antibodies against IHV01 and demonstrated anti-CD4i epitope antibodies. The elicited antibodies reacted with CD4 non-liganded Env antigens from diverse HIV-1 strains. Antibody-dependent cell-mediated cytotoxicity against heterologous infected cells or gp120 bound to CD4+ cells was evident in all cohorts as were anti-gp120 T-cell responses. IHV01 vaccine was safe, well tolerated, and immunogenic at all doses tested. The vaccine raised broadly reactive humoral responses against conserved CD4i epitopes on gp120 that mediates antiviral functions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We characterize the breadth, function and phenotype of innate and adaptive cellular responses in a prevention of Mycobacterium tuberculosis infection trial. Responses are measured by whole blood intracellular cytokine staining at baseline and 70 days after vaccination with H4:IC31 (subunit vaccine containing Ag85B and TB10.4), Bacille Calmette-Guerin (BCG, a live attenuated vaccine) or placebo (n = ~30 per group). H4:IC31 vaccination induces Ag85B and TB10.4-specific CD4 T cells, and an unexpected NKT like subset, that expresses IFN-γ, TNF and/or IL-2. BCG revaccination increases frequencies of CD4 T cell subsets that either express Th1 cytokines or IL-22, and modestly increases IFNγ-producing NK cells. In vitro BCG re-stimulation also triggers responses by donor-unrestricted T cells, which may contribute to host responses against mycobacteria. BCG, which demonstrated efficacy against sustained Mycobacterium tuberculosis infection, modulates multiple immune cell subsets, in particular conventional Th1 and Th22 cells, which should be investigated in discovery studies of correlates of protection.

A fundamental challenge in vaccinology is learning how to induce durable antibody responses. Live viral vaccines induce antibody responses that last a lifetime, but those induced with subunit vaccines wane rapidly. Studies in mice and humans have established that long-lived plasma cells (LLPCs) in the bone marrow (BM) are critical mediators of durable antibody responses. Here, we present data that adjuvanting an HIV-1 clade C 1086.C-derived gp140 immunogen (Env) with a novel synthetic Toll-like receptor (TLR)-7/8 agonist named 3M-052 formulated in poly(lactic- co -glycolic)acid or PLGA nanoparticles (NPs) or with alum, either alone or in combination with a TLR-4 agonist GLA, induces notably high and persistent (up to ~1 year) frequencies of Env-specific LLPCs in the BM and serum antibody responses in rhesus macaques. Up to 36 and 18% of Env-specific cells among total IgG-secreting BM-resident plasma cells were detected at peak and termination, respectively. In contrast, adjuvanting Env with alum or GLA in NP induced significantly lower (~<100-fold) LLPC and antibody responses. Immune responses induced by 3M-052 were also significantly higher than those induced by a combination of TLR-7/8 (R848) and TLR-4 (MPL) agonists. Adjuvanting Env with 3M-052 also induced robust activation of blood monocytes, strong plasmablast responses in blood, germinal center B cells, T follicular helper (T FH ) cells, and persistent Env-specific plasma cells in draining lymph nodes. Overall, these results demonstrate efficacy of 3M-052 in promoting high magnitude and durability of antibody responses via robust stimulation of innate immunity and BM-resident LLPCs., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: Vaccines and biologics containing CD4 molecules or HIV-1 gp120 might induce antibodies targeting CD4. We evaluated temporal variability of CD4 levels in healthy volunteers to quantify declines that could indicate true adverse events., Design: Prospective observational cohort study of 100 healthy adults without HIV-1 infection from the Baltimore region., Methods: Participants enrolled and consented to blood draws for immunologic laboratory panels performed once every 8 weeks for 48 weeks. The primary CD4 measurements were CD4 absolute count (cells/mm) and CD4 percentage (CD4%, total CD4 cells/total lymphocyte cells). CD4 changes over time were modeled using fold changes for CD4 absolute counts and differences for CD4 percentages., Results: Variation of average CD4 cell counts and percentages were highly participant-specific (P < 0.001 for both). However, changes in both CD4 measurements over time were stable in the population. We proposed thresholds to flag unusual drops using 1.5 SD estimates, calculated as 1.5-fold declines for CD4 count and 6.4% declines for CD4 percentage. In this healthy cohort, flagging simultaneous declines in both measurements corresponded to a low false-positive rate (5.26%)., Conclusions: Normal biological variation in large lymphocytes should be taken into account to establish thresholds for adverse changes in clinical trials. The inherent subject-specific variability in CD4 levels makes establishing absolute cutoffs difficult. However, this study proposes that thresholds for declines using 1.5 SDs from these data (50% in absolute count and 6.4% for CD4 percentage) allow a small false-positive rate (∼5%) that could maintain sensitivity for true adverse events in a clinical trial.

A central tenet of reproducible research is that scientific results are published along with the underlying data and software code necessary to reproduce and verify the findings. A host of tools and software have been released that facilitate such work-flows and scientific journals have increasingly demanded that code and primary data be made available with publications. There has been little practical advice on implementing reproducible research work-flows for large 'omics' or systems biology data sets used by teams of analysts working in collaboration. In such instances it is important to ensure all analysts use the same version of a data set for their analyses. Yet, instantiating relational databases and standard operating procedures can be unwieldy, with high "startup" costs and poor adherence to procedures when they deviate substantially from an analyst's usual work-flow. Ideally a reproducible research work-flow should fit naturally into an individual's existing work-flow, with minimal disruption. Here, we provide an overview of how we have leveraged popular open source tools, including Bioconductor, Rmarkdown, git version control, R, and specifically R's package system combined with a new tool DataPackageR , to implement a lightweight reproducible research work-flow for preprocessing large data sets, suitable for sharing among small-to-medium sized teams of computational scientists. Our primary contribution is the DataPackageR tool, which decouples time-consuming data processing from data analysis while leaving a traceable record of how raw data is processed into analysis-ready data sets. The software ensures packaged data objects are properly documented and performs checksum verification of these along with basic package version management, and importantly, leaves a record of data processing code in the form of package vignettes. Our group has implemented this work-flow to manage, analyze and report on pre-clinical immunological trial data from multi-center, multi-assay studies for the past three years., Competing Interests: No competing interests were disclosed.

The RV144 Phase III clinical trial with ALVAC-HIV prime and AIDSVAX B/E subtypes CRF01&#95;AE (A244) and B (MN) gp120 boost vaccine regime in Thailand provided a foundation for the future development of improved vaccine strategies that may afford protection against the human immunodeficiency virus type 1 (HIV-1). Results from this trial showed that immune responses directed against specific regions V1V2 of the viral envelope (Env) glycoprotein gp120 of HIV-1, were inversely correlated to the risk of HIV-1 infection. Due to the low production of gp120 proteins in CHO cells (2-20 mg/L), cleavage sites in V1V2 loops (A244) and V3 loop (MN) causing heterogeneous antigen products, it was an urgent need to generate CHO cells harboring A244 gp120 with high production yields and an additional, homogenous and uncleaved subtype B gp120 protein to replace MN used in RV144 for the future clinical trials. Here we describe the generation of Chinese Hamster Ovary (CHO) cell lines stably expressing vaccine HIV-1 Env antigens for these purposes: one expressing an HIV-1 subtype CRF01&#95;AE A244 Env gp120 protein (A244.AE) and one expressing an HIV-1 subtype B 6240 Env gp120 protein (6240.B) suitable for possible future manufacturing of Phase I clinical trial materials with cell culture expression levels of over 100 mg/L. The antigenic profiles of the molecules were elucidated by comprehensive approaches including analysis with a panel of well-characterized monoclonal antibodies recognizing critical epitopes using Biacore and ELISA, and glycosylation analysis by mass spectrometry, which confirmed previously identified glycosylation sites and revealed unknown sites of O-linked and N-linked glycosylations at non-consensus motifs. Overall, the vaccines given with MF59 adjuvant induced higher and more rapid antibody (Ab) responses as well as higher Ab avidity than groups given with aluminum hydroxide. Also, bivalent proteins (A244.AE and 6240.B) formulated with MF59 elicited distinct V2-specific Abs to the epitope previously shown to correlate with decreased risk of HIV-1 infection in the RV144 trial. All together, these results provide critical information allowing the consideration of these candidate gp120 proteins for future clinical evaluations in combination with a potent adjuvant.

Purpose: Our goal was to determine whether tumour radiosensitivity is associated with activation of the immune system across all tumour types as measured by two gene expression signatures (GESs)., Methods: We identified 10,240 genomically profiled distinct solid primary tumours with gene expression analysis available from an institutional de-identified database. Two separate GESs were included in the analysis, the radiosensitivity index (RSI) GES (a 10-gene GES as a measure of radiosensitivity) and the 12-chemokine (12-CK) signature (a 12-gene GES as a measure of immune activation). We tested whether the RSI and 12-CK were associated with each other across all tumour samples and, in an exploratory analysis, their prognostic significance in predicting distant metastasis-free survival (DMFS) among a well-characterised, independent cohort of 282 early-stage breast cancer cases treated with surgery and post-operative radiation alone without systemic therapy. The lower the RSI score, the higher the tumour radiosensitivity; whereas, the higher the 12-CK score the higher the immune activation., Results: Using an RSI cut-point of ≤0.3745, RSI-low tumours (n = 4,291, 41.9%) had a significantly higher median 12-CK GES value (0.54 [-0.136, 1.095]) compared with RSI-high tumours (-0.17 [-0.82, 0.42]; p < 0.001) across all tumour samples, indicating that radiosensitivity is associated with immune activation. In an exploratory analysis of early-stage breast cancer cases, a multivariable model with patient age, RSI and 12-CK provided a strong composite model for DMFS (p = 0.02), with RSI (hazard ratio [HR] 0.63 [95% confidence interval 0.36, 1.09]) and 12-CK (HR 0.66 [0.41, 1.04]) each providing comparable contributions., Conclusions: Tumour radiosensitivity is associated with immune activation as measured by the two GESs., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We compared the HIV-1-specific immune responses generated by targeting HIV-1 envelope protein (Env gp140) to either CD40 or LOX-1, two endocytic receptors on dendritic cells (DCs), in rhesus macaques primed with a poxvirus vector (NYVAC-KC) expressing Env gp140. The DC-targeting vaccines, humanized recombinant monoclonal antibodies fused to Env gp140, were administered as a boost with poly-ICLC adjuvant either alone or coadministered with the NYVAC-KC vector. All the DC-targeting vaccine administrations with poly-ICLC increased the low-level serum anti-Env IgG responses elicited by NYVAC-KC priming significantly more (up to a P value of 0.01) than in a group without poly-ICLC. The responses were robust and cross-reactive and contained antibodies specific to multiple epitopes within gp140, including the C1, C2, V1, V2, and V3, C4, C5, and gp41 immunodominant regions. The DC-targeting vaccines also elicited modest serum Env-specific IgA responses. All groups gave serum neutralization activity limited to tier 1 viruses and antibody-dependent cytotoxicity responses (ADCC) after DC-targeting boosts. Furthermore, CD4 + and CD8 + T cell responses specific to multiple Env epitopes were strongly boosted by the DC-targeting vaccines plus poly-ICLC. Together, these results indicate that prime-boost immunization via NYVAC-KC and either anti-CD40.Env gp140/poly-ICLC or anti-LOX-1.Env gp140/poly-ICLC induced balanced antibody and T cell responses against HIV-1 Env. Coadministration of NYVAC-KC with the DC-targeting vaccines increased T cell responses but had minimal effects on antibody responses except for suppressing serum IgA responses. Overall, targeting Env to CD40 gave more robust T cell and serum antibody responses with broader epitope representation and greater durability than with LOX-1. IMPORTANCE An effective vaccine to prevent HIV-1 infection does not yet exist. An approach to elicit strong protective antibody development is to direct virus protein antigens specifically to dendritic cells, which are now known to be the key cell type for controlling immunity. In this study, we have tested in nonhuman primates two prototype vaccines engineered to direct the HIV-1 coat protein Env to dendritic cells. These vaccines bind to either CD40 or LOX-1, two dendritic cell surface receptors with different functions and tissue distributions. We tested the vaccines described above in combination with attenuated virus vectors that express Env. Both vaccines, but especially that delivered via CD40, raised robust immunity against HIV-1 as measured by monitoring potentially protective antibody and T cell responses in the blood. The safety and efficacy of the CD40-targeted vaccine justify further development for future human clinical trials., (Copyright © 2017 American Society for Microbiology.)

Risk of subsequent primary malignancies (SPMs) associated with lenalidomide therapy in multiple myeloma (MM) patients, outside the context of melphalan-based therapy is not established. We assessed the risk of SPMs in lenalidomide treated MM patients (n = 1653) at Moffitt Cancer Center (2004-2012) outside the context of melphalan-based induction therapy and post-melphalan maintenance therapy, via (1) cohort analysis and (2) nested case-control study. Incident SPMs (n = 51) were matched to controls (n = 102) on age at MM diagnosis, gender, follow-up time, and date of diagnosis. Incidence of SPM differed significantly (p = 0.0038) between MM patients treated with and without lenalidomide (5-year incidence estimates of 3.2 and 6.2%, respectively), although not significant after adjustment for age and year of diagnosis (HR = 0.82, 95%CI = 0.43-1.57). Lenalidomide treatment was inversely associated with SPM in the nested case-control analysis (OR = 0.03, 95%CI = 0.002-0.34). In this large cohort of MM patients, lenalidomide treatment was not associated with an increased risk of SPM.

Background: Following wide excision of Merkel cell carcinoma (MCC), postoperative radiation therapy (RT) is typically recommended. Controversy remains as to whether RT can be avoided in selected cases, such as those with negative margins. Additionally, there is evidence that RT can influence survival., Methods: We included 171 patients treated for non-metastatic MCC from 1994 through 2012 at a single institution. Patients without pathologic nodal evaluation (clinical N0 disease) were excluded to reflect modern treatment practice. The endpoints included local control (LC), locoregional control (LRC), disease-free survival (DFS), overall survival (OS), and disease-specific survival (DSS)., Results: Median follow-up was 33 months. Treatment with RT was associated with improved 3-year LC (91.2 vs. 76.9 %, respectively; p = 0.01), LRC (79.5 vs. 59.1 %; p = 0.004), DFS (57.0 vs. 30.2 %; p < 0.001), and OS (73 vs. 66 %; p = 0.02), and was associated with improved 3-year DSS among node-positive patients (76.2 vs. 48.1 %; p = 0.035), but not node-negative patients (90.1 vs. 80.8 %; p = 0.79). On multivariate analysis, RT was associated with improved LC [hazard ratio (HR) 0.18, 95 % confidence interval (CI) 0.07-0.46; p < 0.001], LRC (HR 0.28, 95 % CI 0.14-0.56; p < 0.001), DFS (HR 0.42, 95 % CI 0.26-0.70; p = 0.001), OS (HR 0.53, 95 % CI 0.31-0.93; p = 0.03), and DSS (HR 0.42, 95 % CI 0.26-0.70; p = 0.001). Patients with negative margins had significant improvements in 3-year LC (90.1 vs. 75.4 %; p < 0.001) with RT. Deaths not attributable to MCC were relatively evenly distributed between the RT and no RT groups (28.5 and 29.3 % of patients, respectively)., Conclusions: RT for MCC was associated with improved LRC and survival. RT appeared to be beneficial regardless of margin status.

The role of antibody-mediated immunity in preventing newly acquired oral human papillomavirus (HPV) is not well understood. Among 1618 men participating in the HPV Infection in Men (HIM) Study, we evaluated oral rinses for HPV DNA and baseline sera for HPV-6, -11, -16, and -18 L1 antibodies. Thirty percent of men (486) were seropositive for ≥1 HPV type, and 25 men developed incident oral HPV infection (HPV-6 was detected in 7, HPV-11 in 0, HPV-16 in 17, and HPV-18 in 1). Cox models revealed that men with circulating antibodies to HPV-6, -11, -16, or -18 were not less likely to acquire type-specific oral HPV than men without antibodies (hazard ratio for the risk of acquiring HPV-6, -11, -16, or -18, 1.63; 95% confidence interval, .56-4.76)., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

The few studies that have examined rates of acute myeloid leukemia (AML) transformation in lenalidomide-treated myelodysplastic syndrome (MDS) patients have been limited to deletion 5q MDS. The association between lenalidomide and subsequent primary malignancies (SPMs) in MDS patients has not been evaluated previously. We conducted a retrospective cohort study to evaluate the risk of both SPM and AML in association with lenalidomide. A cohort of MDS patients (n = 1248) treated between 2004 and 2012 at Moffitt Cancer Center were identified, and incident cases of SPM and AML transformation were ascertained. Using a nested case-control design, MDS controls were 1:1 matched to SPM (n = 41) and AML (n = 150) cases, on age and date of MDS diagnosis, gender, follow-up time, IPSS, and del (5q). Associations between lenalidomide and (1) SPM incidence and (2) AML transformation were estimated with hazards ratios (HR) and 95% confidence intervals (CIs) in the cohort and odds ratios (OR) in the case-control analysis. SPM incidence did not differ significantly between cohort MDS patients treated with (0.7 per 100 person-years) or without lenalidomide (1.4 per 100 person-years) (HR = 1.04, 95% CI = 0.40-2.74), whereas a significantly reduced SPM risk was observed in the case-control sample (OR = 0.03, 95% CI = <0.01-0.63). Lenalidomide was not associated with AML transformation in the cohort analysis (HR = 0.75, 95% CI = 0.44-1.27) or in the case-control analyses (OR = 1.16, 95% CI = 0.52-2.56), after adjustment for potential confounders. Lenalidomide was not associated with increased risk of SPM or AML transformation in a large cohort of MDS patients mostly including nondeletion 5q MDS., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Transformation of essential thrombocythemia (ET) to myelodysplastic syndromes or acute myeloid leukemia is infrequent, comprising 1-5% of cases with dismal clinical outcome. Studies on prognosis in ET patients with leukemic transformation are limited. The large cohort included 40 patients (1990-2014) with ET transformation (median age of 59 years, M:F of 1:1). Median time from ET diagnosis to transformation was 76 months (26-481) with median follow-up time of 15 years. Advanced age, myelofibrosis (grade 2-3), and leukocytosis at the time of transformation were associated with inferior OS from transformation (p<0.05). Given rarity of the clinical scenario, multicenter efforts are encouraged., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Survival in patients with metastatic esophageal and gastric cancer is dismal. No standard treatment has been established. Carboplatin/paclitaxel is active in both advanced gastric and esophageal cancer. Here we retrospectively present our single center experience. Between 1998 and 2013, a total of 134 patients with metastatic esophageal and gastric adenocarcinoma treated with carboplatin/paclitaxel (carboplatin predominantly area under the curve 5 and paclitaxel predominantly 175 mg/m(2)) every 3 weeks as first-line therapy were identified. Baseline characteristics, response to therapy, toxicities, and survival in this patient population were evaluated. Overall survival was defined as date from diagnosis to death or last follow up, and progression-free survival was defined at time from cycle 1 to, progression or last follow up. Kaplan-Meier curves were fit to estimate overall and progression-free survival. Of the 134 patients evaluated, the median age at diagnosis was 65 years. Disease control rate was 62.6% (complete response: 11%, partial response: 28%, stable disease: 33%). Median overall survival from date of initial diagnosis was 15.5 months (95% confidence interval [CI] 1.06-1.5). Median progression-free survival from date of initiation of carboplatin and paclitaxel was 5.3 months (95% CI 0.34-0.5). Grade III or greater toxicity occurred in 26.1% of patients. The most common grade III toxicities were neutropenia and neuropathy, present in 14.2% and 3.7% of the total study population, respectively. In patients with metastatic or unresectable esophageal or gastric cancer, the combination of carboplatin and paclitaxel is well tolerated with comparable overall survival and progression-free survival to existing regimens in this population., (© 2014 International Society for Diseases of the Esophagus.)

Background: Despite the impact of proteasome inhibitors and immunomodulatory agents, infusional chemotherapy regimens continue to be used for patients with multiple myeloma. To the authors' knowledge, contemporary data regarding salvage chemotherapy regimens are sparse, with no direct comparisons., Methods: The authors performed a single-institution study comparing 3 salvage chemotherapy regimens in 107 patients with recurrent/refractory multiple myeloma: dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) in 52 patients; bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide (VTD-PACE) in 22 patients; and cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) in 33 patients., Results: Differences between treatment groups existed, including higher baseline creatinine for patients treated with CVAD (P<.001) and greater prior use of infusional chemotherapy for those receiving VTD-PACE (P<.001). There was no significant difference in response noted among the 3 regimens: 55% overall (P = .18). For the intent-to-transplant population, a similar percentage were successfully bridged to transplant without further therapy (62%; P = .9). There was no difference in survival observed across the 3 regimens, with an overall median progression-free survival of 4.5 months (95% confidence interval, 3.6-5.5 months [P = .8]) and a median overall survival of 8.5 months (95% confidence interval, 6.1-11 months [P = .8]). Furthermore, there was no statistically significant difference noted among clinically relevant adverse events, although there was a suggestion of fewer adverse events with DCEP. Patients treated with the intent to transplant had superior outcomes for response (odds ratio, 3.40; P = .01), progression-free survival (hazard ratio, 0.28; P<.001), and overall survival (hazard ratio, 0.19; P<.001)., Conclusions: The 3 salvage regimens demonstrated similar responses, survival, and adverse events. Given the short response durations observed in the recurrent/refractory disease setting, infusional chemotherapy is best suited for cytoreduction before more definitive therapy is administered., (© 2015 American Cancer Society.)

Background: Eligibility criteria for intraoperative radiation therapy (IORT) for breast cancer are being established. Impact of age, one criterion, on short-term complications/outcomes was evaluated., Methods: Institutional Review Board approved retrospective review of early-stage breast cancer patients undergoing breast conserving surgery and IORT from January 2011 to June 2013 were reviewed. Data collected were demographics, comorbidities, histopathology, intraoperative data, adjuvant treatment, and outcomes. Local recurrence (LR), re-excision rates, and complications were evaluated by age group using descriptive statistics., Results: The total number of patients was 100 (43 patients <70, 57 patients ≥70). No significant differences existed between groups in tumor size, operative time, estrogen receptor status, nodal status, tumor grade, or margin excision. Wound infection rates were low for both groups (P = .21). Two LR occurred (both patients ≥70). Median follow-up time was 24 months., Conclusion: IORT with its low rate of LR and wound complications may be a reasonable alternative to whole breast irradiation for early-stage breast cancer, regardless of age., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Pasireotide (SOM230) is a somatostatin analog with high binding affinity for somatostatin receptors including sst1, 2, 3 and 5 and inhibit insulin like growth factor-1. Blocking of IGF-1 receptor (IGF-1R) in combination with cytotoxic chemotherapy has demonstrated additive or synergistic activity in pre-clinical models. This study aimed to evaluate the maximum tolerated dose (MTD) of pasireotide in combination with standard FOLFIRI (5-fluorouracil, leucovorin and irinotecan) regimen in patients with gastrointestinal malignancies., Methods: This was a phase 1, 3 + 3 design, open-label dose escalation study conducted in sequential cohorts to determine the MTD of pasireotide in combination with FOLFIRI. All patients had gastrointestinal malignancies and were previously treated. Sixteen patients enrolled in five dose cohorts at pasireotide doses of 40, 60, 80, 100 and 120 mg were evaluated for safety and tolerability of the combination., Results: The tumor types of the enrolled subjects included esophageal (n = 5), biliary tract (n = 3), colon (n = 3), gastric (n = 2), pancreatic (n = 1), anal (n = 1) and small bowel (n = 1). No dose limiting toxicities were observed. The most common adverse events related to the study treatment included hyperglycemia (81 %), neutropenia (62 %), thrombocytopenia (44 %), anorexia (44 %), dehydration (25 %) and elevated alkaline phosphatase (25 %). Two patients had partial response and 7 patients had stable disease. Plasma levels of IGF-1 and IGFBP-3 were significantly reduced after treatment with pasireotide., Discussion: Combination of pasireotide and FOLFIRI has manageable safety profile and is feasible in patients with gastrointestinal malignancies. Preliminary signals of activity were observed. Larger phase II trials are warranted.

Background and Purpose: Adjuvant radiation therapy for resectable pancreatic cancer remains controversial. Sub-populations of radiosensitive tumors might exist given the genetic heterogeneity of pancreatic cancers. We evaluated whether RSI is predictive of survival in pancreatic cancer treated with radiation., Materials and Methods: We identified 73 genomically-profiled pancreas cancer patients treated with upfront surgery between 2000 and 2011 (48 radiation, 25 no radiation). Briefly, RSI score is derived from the expression of 10 specific genes and a linear regression algorithm modeled on SF2 of 48 cancer cells. The primary endpoint was to assess the association of RSI with overall survival., Results: Median follow-up was 67months for surviving patients. On multivariate analysis, patients with radioresistant tumors had a trend toward worse survival (Hazard ratio [HR] 2.1 [95% CI 1.0-4.3], p=0.054). Among high-risk, irradiated patients (positive margins, positive lymph nodes, or a post-operative CA19-9 >90; n=31), radiosensitive patients had significantly improved survival compared with radioresistant patients (median 31.2 vs. 13.2months; HR 0.42 [0.19, 0.94], p=0.04). Among irradiated patients (n=48), low-risk patients lived longer than both high-risk patients with radiosensitive tumors and radioresistant tumors (HR 2.7 [1.0, 7.2], p=0.04 and HR 6.3 [2.3, 17.0], p<0.001, respectively)., Conclusions: Integrating RSI with standard high-risk variables has the potential to refine the classification of high-risk resected pancreatic cancer patients treated with radiation therapy., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Adjuvant treatment for early stage, estrogen receptor (ER) positive invasive breast cancer has been based on prognosticators such as menopausal status. The recurrence score (RS) from the 21-gene assay Oncotype DX (ODX) is predictive of a 10-y distant recurrence in this population but is rarely applied to premenopausal patients. The relationship between menopausal status and RS was evaluated., Materials and Methods: An institutional review board-approved retrospective review was conducted of invasive breast cancer patients with known RS. ODX eligibility was based on National Comprehensive Cancer Network guidelines or physician discretion. Perimenopausal women were classified as premenopausal for statistical analyses. Comparisons of menopausal status and RS were made using general linear regression model and the exact Wilcoxon rank-sum test., Results: Menopausal status was available for 575 patients (142 premenopausal, 433 postmenopausal). Median age was 46 y for premenopausal and 62 y for postmenopausal. Median invasive tumor size was 1.5 cm for both cohorts. Mastectomy rate was higher in the premenopausal group (54.8%) than postmenopausal (42%; P = 0.0001). Premenopausal women had a higher local-regional recurrence rate (2.8% versus 0%; P = 0.0384) but distant recurrence and overall survival were not statistically different (P = 0.6808). Median ER H-score was lower in premenopausal (H-score = 270) than postmenopausal women (H-score = 280; P < 0.0001). Median RS was 16 for both premenopausal (range, 0-54) and postmenopausal (range, 0-63) women. Menopausal status as a categorical variable was not predictive of RS (P-value = 0.6780)., Conclusions: Menopausal status has limited predictive power for distant recurrence. Therefore, menopausal status alone should not preclude performance of ODX in ER-positive, early stage breast cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)