ALBERT

Description: Evidence on Aboriginal and Torres Strait Islander peoples’ food security experiences and coping strategies used when food insecurity occurs is limited. Such evidence is important to inform policies that can reduce the consequences of food insecurity. This study investigated factors perceived by Aboriginal and Torres Strait Islander families with young children to influence household food security, and coping strategies used, in an urban setting. A qualitative research inductive approach was used. Data were collected through an iterative process of inquiry through initial interviews with 30 primary care-givers, followed by in-depth interviews with six participants to further explore emerging themes. Major topics explored were: influencing factors, food insecurity experiences, impact on food selection, and coping strategies. Food affordability relating to income and living expenses was a major barrier to a healthy diet with large household bills impacting food choice and meal quality. Access to family support was the main reported coping strategy. Food insecurity is experienced by Aboriginal and Torres Strait Islander families, it is largely intermittent occurring especially when large household bills are due for payment. Family support provides an essential safety net and the implications of this are important to consider in public policy to address food insecurity.

Description: In contrast to humans, many amphibians are able to rapidly and completely regenerate complex tissues, including entire appendages. Following tail amputation, Xenopus tropicalis tadpoles quickly regenerate muscle, spinal cord, cartilage, vasculature and skin, all properly patterned in three dimensions. To better understand the molecular basis of this regenerative competence, we performed a transcriptional analysis of the first 72 hours of tail regeneration using RNA-Seq. Our analysis refines the windows during which many key biological signaling processes act in regeneration, including embryonic patterning signals, immune responses, bioelectrical signaling and apoptosis. Our work provides a deep database for researchers interested in appendage regeneration, and points to new avenues for further study. This article is protected by copyright. All rights reserved.

Description: Introduction: There is no standard treatment for Mantle cell lymphoma (MCL). Intensive treatment strategies such as conventional R-hyperCVAD with alternating R-cytarabine/methotrexate or autologous stem cell transplant appear to improve PFS but the effect on OS is unclear. In addition, approximately 50% of newly diagnosed patients are not candidates for intensive therapies. Novel treatment strategies are needed. We have published the results of a study using a modified R-hyperCVAD induction followed by maintenance rituximab (Kahl et al, Ann Oncol 2006). This induction strategy yielded a complete response (CR) rate of 64% and the entire treatment program yielded a median PFS of 37 months. Bortezomib (Velcade) has demonstrated promising activity in relapsed MCL (Fisher et al, J Clin Onc, 2006). We hypothesized that the incorporation of Velcade (Vc) into the induction regimen would improve the CR rate. The new regimen, VcRCVAD, was tested for safety and efficacy in a phase II study at the University of Wisconsin and within the Wisconsin Oncology Network. Methods: Eligible patients had histologically confirmed mantle cell lymphoma, PS 0–2, and adequate end organ function. The final treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1–3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1–2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1–4. Due to excessive painful peripheral neuropathy (PN), 2 dose modifications were required during the course of the study. Patients 1–7 received 1.5 mg/m2 Velcade and 2 mg vincristine. Patients 8–14 received 1.3 mg/m2 Velcade and 2 mg vincristine. Patients 15–30 received 1.3 mg/m2 Velcade and 1 mg vincristine. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF cytokine support. Patients achieving at least a PR receive maintenance rituximab therapy for 5 years. Results: Enrollment is complete and all 30 patients are evaluable for response to VcRCVAD induction. Baseline characteristics include median age 60.5 (48–74), 24M:6F, 26/30 (87%) stage IV, and 12 (40%) low-risk, 8 (27%) int-risk, and 10 (33%) high-risk by MIPI. 3 patients (10%) experienced PD during induction therapy and 27 (90%) responded with 23 CR/CRu (77%) and 4 PR (13%). With a median follow up of approximately 18 months, the 18-month PFS and OS are 73% and 97%, respectively. The major toxicity of this treatment regimen is painful PN and expected hematologic toxicity. 5/7 patients in cohort 1 and 3/7 patients in cohort 2 developed grade 3 painful PN and 1 patient in cohort 2 developed grade 4 painful PN. Only 1/16 patients in the final cohort experienced grade 3 painful PN. All neuropathy eventually improved to ≤ grade 2, but 10 patients require chronic medication for symptom relief. 13/167 (8%) of the treatment cycles were complicated by neutropenic fever/infection. There were no treatment related deaths. Conclusion: The VcR-CVAD induction has produced high overall response (90%) and CR rate (77%) in a very representative MCL patient population. Comparing these data to our previous frontline MCL study, the CR rate appears to be enhanced (77% vs 64%) by the addition of Velcade. Longer follow up is needed before determining if the higher CR rate will translate into an improved PFS and OS. Because of the risk for painful PN, caution must be exercised when using vincristine and Velcade in combination. The MTD for this combination was 1 mg vincristine and 1.3 mg/m2 Velcade. The encouraging complete response rate provided the rationale for ECOG study E1405, which is testing the safety and efficacy of this induction regimen in a cooperative group setting.

Description: Background: Diffuse large B-cell lymphoma (DLBCL) is comprised of multiple diseases with different outcomes, cell of origin and molecular pathogenesis. DLBCL derived from germinal center B-cells (GCB) and activated B-cells (ABC) constitutes over 80% of DLBCL. A small number of DLBCL tumors harbor MYC translocations, which are associated with a poorer prognosis. Primary mediastinal B-cell lymphoma (PMBL) occurs in younger patients and is typically treated with intensive or combined modality therapy. R-CHOP is the standard of care for DLBCL but has not been prospectively studied within DLBCL molecular subtypes. DA-EPOCH-R is an alternative and more dose-intensive regimen that showed a PFS of 81% at 4-years in a phase II multicenter CALGB study (Haematologica 2012; 97:758). CALGB/Alliance undertook a phase III randomized study to compare R-CHOP and DA-EPOCH-R in DLBCL and specifically within the GCB and ABC subtypes. Methods: Patients had stage II or higher newly diagnosed DLBCL, age ≥ 18 years and were HIV negative. Subjects were randomized 1:1 to receive R-CHOP or DA-EPOCH-R as previously published. Central nervous system prophylaxis in at-risk patients was 12 mg intrathecal methotrexate in cycles 3-6 (4 doses total). All subjects with accessible tumor were required to have a biopsy or waiver. Subjects received a total of 6 treatment cycles. The primary study endpoints were EFS of R-CHOP (Arm A) versus DA-EPOCH-R (Arm B) and to develop a molecular predictor of outcome based on GCB and ABC DLBCL. Additional analyses include toxicity, pharmacogenomics and analysis of tumor genetics by next generation sequencing, and. Results: 524 patients registered (262 on each arm) between May 2005 and May 2013. Efficacy analysis includes R-CHOP (n=233) and R-EPOCH (n=231) assigned patients with confirmed eligibility who received any treatment. Characteristics of patients registered to Arm A and B did not differ with median age (58; 56), male sex (53.2%; 53.7%), high-intermediate/high IPI (33.6%; 38.2%) and primary mediastinal B-cell lymphoma histology (6.9%; 5.2%). Therapy was completed per protocol in 89% and 83%, respectively, for Arm A and B, and disease progression on therapy was 2.6% and 1.7%. Adverse side effects leading to treatment discontinuation were 1.7% and 5.6%, respectively, for Arm A and B. Arm B compared to Arm A was associated with more grade 4 neutropenia (90%; 56%), grade 4 thrombocytopenia (35%; 6%), grade 3/4 febrile neutropenia (37%; 19%) and grade 3 neuropathy (motor: 8%;1% and sensory: 15%; 3%). Grade 5 events on study were the same in both arms. Preliminary analysis of EFS in confirmed eligible subjects shows no difference between Arm A and B with hazard ratio of 1.02 and p=0.89 at a median follow-up of 4.9 years. Overall survival is also similar with hazard ratio of 1.19 and p=0.40 at median 5.0 years. Additional analyses of EFS and OS by age (=60) and by GCB versus ABC DLBCL are in process. Conclusions: There was no difference in EFS or OS between R-CHOP and DA-EPOCH-R when considering all patients. DA-EPOCH-R showed increased toxicity consistent with higher dose-intensity but not increased grade 5 toxicity. Compared to R-CHOP, more patients on DA-EPOCH-R did not complete treatment, which may reflect patterns of care or toxicity. Due to the clinical and genetic diversity of DLBCL, subset analyses are necessary to determine the effect of CNS relapse, GCB and ABC subtypes, age and IPI on outcomes of the two arms. These data do not address the efficacy of these regimens in PMBL or MYC+ DLBCL due to their low frequency, and where more dose-intense regimens appear to be important. Full molecular analyses are ongoing. Support: U10CA180821, U10CA180882, U10CA180888, CA180799, CA180820, CA180833, CA21076, CA21115.ClinicalTrials.gov Identifier: NCT00118209. Disclosures Hsi: Cellerant Therapeutics: Honoraria, Research Funding; Eli Lilly: Research Funding; Abbvie: Honoraria, Research Funding; Seattle Genetics: Honoraria, Speakers Bureau; HTG Molecular Diagnostics: Consultancy, Honoraria. Friedberg:Bayer: Honoraria, Other: Data Safety Monitoring Board. Cheson:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding. Bartlett:Gilead: Consultancy. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Zelenetz:Gilead Sciences: Research Funding.

Description: Abstract 3601 Richter syndrome (RS) represents the development of diffuse large B-cell lymphoma (DLBCL) in the context of chronic lymphocytic leukemia (CLL). Despite the availability of clinical predictors, the identification of RS patients projected to experience long survival represents an unresolved issue that may benefit from the development of novel RS prognosticators. The study was based on 86 RS classified as DLBCL after pathological review. Clonal relationship between CLL/RS pairs was assessed by immunoglobulin gene analysis. RS was clonally related to the CLL phase in 49/59 (83.1%) cases, and clonally unrelated in 10/59 (16.9%). In 27 cases, clonal relationship remained undetermined because of unavailability of paired CLL samples. Out of the molecular features investigated, the prevalence of TP53 disruption by mutations and/or deletion was significantly higher in clonally related RS (23/36, 63.9%) compared to clonally unrelated cases (1/8, 12.5%) (p=.015). Among immunogenetic features, usage of stereotyped VH CDR3 occurred in 25/49 (51.0%) clonally related RS, while was very rare among clonally unrelated cases (1/10, 10.0%) (p=.032). The difference in stereotyped VH CDR3 frequency occurred irrespective of IGHV gene mutation status. All clonally unrelated RS tested negative for EBV infection and none received alemtuzumab before DLBCL development. Clonally related and clonally unrelated RS were indistinguishable in terms of clinical features at presentation. However, RS survival was significantly shorter in clonally related (median: 14.2 months) versus clonally unrelated cases (median: 62.5 months) (p=.017) (Fig. 1A). This survival difference was observed even though clonally related RS received SCT in 8/48 (16.7%) cases, while clonally unrelated RS received in all cases conventional chemotherapy without SCT consolidation. Other variables that were associated with poor RS survival were TP53 disruption (p60 years (p=.005), ECOG PS 〉1 (p5 cm (p=.001), platelets 1.5 ULN (p=.002), and having received SCT (p=.027). None of the pathologic features of DLBCL diagnostic biopsies correlated with RS prognosis. After adjusting for clinical variables associated with RS survival, diagnosis of clonally unrelated RS translated into a 80% reduction in risk of death when compared to clonally related RS (HR: 0.22; p=.036). By recursive-partitioning analysis, clonal relationship, TP53 disruption and ECOG PS were the major determinants of RS survival, and classified RS patients according to risk of death (Fig. 1B). All clonally unrelated RS displayed a low risk of death (median survival 62.5 months; 95% CI: 33.7–91.3), irrespective of TP53 disruption and ECOG PS (Fig. 1B; Group 1). Among clonally related RS and RS with undetermined clonal relationship, patients presenting with ECOG PS ≤1 and no TP53 disruption had a low risk of death (median survival: 55.4 months) (Fig. 1B; Group 2). Patients presenting with ECOG PS ≤1 in the presence of TP53 disruption had an intermediate risk of death (median survival: 27.0 months) (Fig. 1B; Group 3). Patients presenting with ECOG PS 〉1 had a high risk of death, irrespective of TP53 disruption (median survival: 7.8 months) (Fig. 1B; Group 4). Based on c-statistics, the model including clonal relationship, ECOG PS and TP53 status had a 90% probability of correctly discriminating a priori RS survival (c-statistic=.90±.07). These observations suggest that clonally related and clonally unrelated RS are biologically and clinically distinct disorders, and that clonally unrelated RS should be considered as a secondary DLBCL arising de novo in the context of CLL, rather than a true RS. Therefore, we propose that the diagnosis of RS should be restricted to clonally related cases. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Interim positron-emission tomography (PET) following 1-3 cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in newly-diagnosed, non-bulky stage I and II HL patients (pts) is a useful biomarker that predicts relapse rates of ≤10% for PET- pts. Relapse rates are higher in pts who are PET+ (J Clin Oncol 2014 32: 2705-11; N Engl J Med 2015 372: 1598-607). Interim PET thus provides an opportunity to minimize treatment for the majority of pts who are interim PET - and only intensify treatment for those who are PET+. This strategy could reduce short and long term treatment toxicity for the majority of pts. To test this hypothesis, the US Intergroup conducted a phase II clinical trial, CALGB/Alliance 50604, for newly-diagnosed non-bulky stage I and II HL pts. Methods Between 5/15/10 and 5/4/12, 164 previously untreated pts with non-bulky stages I/II HL were enrolled. Pts received 2 cycles of ABVD followed by PET. Deauville scores 1-3 were negative (≤ liver uptake), while scores of 4-5 were positive, based on central review. PET- pts received 2 more cycles of ABVD, and PET+ pts received 2 cycles of dose-intense bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (escalated BEACOPP) + 3060 cGy involved-field radiation therapy (IF RT). Prophylactic growth factor use was permitted only after grade 3/4 febrile neutropenic events, with or without infection. Results Median age was 31 years (18-58). There were 88 males and 76 females. Pt. stages were IA (16), IB (4), IIA (90), IIB (35), IIAE 4, and IIBE (3). All pts were PET+ prior to treatment. 144/164 patients had cycle 2 PET and adequate follow-up for assessment: 131 (91%) were PET- and 13 (9%) PET+. Of 20 not analyzed, 13 were excluded (6 never treated and 2 treated with 〈 2 cycles) and 7 had insufficient follow up. At a median follow-up time of 2 years, 8/131 (6%) PET- pts relapsed or progressed with an estimated 3-year progression-free-survival (PFS) of 92%. 4/13 (31%) PET+ pts. failed (3 relapsed, 1 suicide) with an estimated 3-year PFS of 66%. By Cox model, observed hazard ratio comparing PET- and PET+ PFS for pts is 6.04 (1.82, 20.08). It is likely that the trial will meet the primary objective of 3-year PFS of at least 85% (79%, 92%) for PET- pts treated with 2 additional cycles of ABVD. It is unlikely that the results will meet secondary objective of improving the 3-year PFS of PET+ pts treated with 2 cycles of escalated BEACOPP + IF RT to the pre-set level considered to be of clinical interest in comparison with PET- pts treated with 2 additional cycles of ABVD (HR〈 3.84). There was 1 death (suicide). Toxicity for all pts was minimal: Neutropenia: 29% grade 3 and 42% grade 4; Febrile neutropenia: 5% grade 3; Decreased CO diffusing capacity: 1% grade 3; Decreased left ventricular ejection fraction: 1% grade 3; Sensory neuropathy: 2% grade 3 and 1% grade 4; Motor neuropathy: 1% grade 4. Conclusions These early results confirm interim PET as a potential biomarker for prediction of relapse with ABVD in patients with non-bulky, stages I/II HL. Importantly, this study demonstrates that defining PET- as Deauville scores of 1-3 results in only 9% of pts. remaining PET+ after 2 ABVD cycles and excellent PFS for the PET-majority. More intensive treatment with 2 cycles of escalated BEACOPP and IF RT for the 9% of pts who are interim PET+ will be unlikely to improve 3-year PFS to the level considered to be of clinical interest in this trial. Interpretation may be limited by small numbers and lack of randomized control comparison. Fortunately, exciting new treatment approaches may provide an opportunity to improve outcomes for the minority of interim PET+ pts in the future. Kaplan Meier Plot of PFS for PET-negative and PET-positive patients For Alliance for Clinical Trials in Oncology, Eastern Cooperative Oncology Group, and Southwest Oncology Group; Supported in part by U10CA180821, U10CA180820, and U10CA180888 Figure 1. Figure 1. Disclosures Straus: Millenium Pharmaceuticals: Research Funding. Hsi:Abbvie: Research Funding; Cellerent Therapeutics: Research Funding; Eli Lilly: Research Funding; Onyx: Honoraria; Seattle Genetics: Honoraria. Kahl:Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Cheson:Gilead: Consultancy, Research Funding; Teva: Research Funding; Celgene: Consultancy, Research Funding; Ascenta: Research Funding; Astellas: Consultancy; Pharmacyclics: Consultancy, Research Funding; Spectrum: Consultancy; AstraZeneca: Consultancy; Roche/Genentech: Consultancy, Research Funding; MedImmune: Research Funding. Bartlett:Janssen: Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Research Funding; ImaginAB: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Medimmune: Research Funding; Millenium: Research Funding; Celgene: Research Funding; Gilead: Consultancy; Seattle Genetics: Consultancy, Research Funding.