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The National Center for Advancing Translational Science (NCATS) seeks to improve upon the translational process to advance research and treatment across all diseases and conditions and bring these interventions to all who need them. Addressing the racial/ethnic health disparities and health inequities that persist in screening, diagnosis, treatment, and health outcomes (e.g., morbidity, mortality) is central to NCATS’ mission to deliver more interventions to all people more quickly. Working toward this goal will require enhancing diversity, equity, inclusion, and accessibility (DEIA) in the translational workforce and in research conducted across the translational continuum, to support health equity. This paper discusses how aspects of DEIA are integral to the mission of translational science (TS). It describes recent NIH and NCATS efforts to advance DEIA in the TS workforce and in the research we support. Additionally, NCATS is developing approaches to apply a lens of DEIA in its activities and research – with relevance to the activities of the TS community – and will elucidate these approaches through related examples of NCATS-led, partnered, and supported activities, working toward the Center’s goal of bringing more treatments to all people more quickly.

This chapter grapples with the question: How do Buddhist Vietnamese American home altar practices organize domestic life? In the following analysis, domestic altars materialize as shifting positions in the realms of the diasporic, the political, and the civic. First, the author argues that Vietnamese American home altar practices are organic, material spaces that practitioners manipulate to invoke the intersections between the homeland and a new home. Second, domestic altars enact an individualized moral or spiritual orientation and also express a complex and politically engaged imaginary through the particular positioning of objects and imagery. And third, they can reveal a creative, adaptable, and civically engaged Vietnamese American spirituality and subjectivity. In sum, home altar practices organize and manifest religious embodiment, political and civic proclivities, and an appeal to diasporic and national belonging.

Background aims Autologous cell therapy (AuCT) is an emerging therapeutic treatment that is undergoing transformation from laboratory- to industry-scale manufacturing with recent regulatory approvals. Various challenges facing the complex AuCT manufacturing and supply chain process hinder the scale out and broader application of this highly potent treatment. Methods We present a multiscale logistics simulation framework, AuCT-Sim, that integrates novel supply chain system modeling algorithms, methods, and tools. AuCT-Sim includes a single facility model and a system-wide network model. Unique challenges of the AuCT industry are analyzed and addressed in AuCT-Sim. Decision-supporting tools can be developed based on this framework to explore “what-if” manufacturing and supply chain scenarios of importance to various cell therapy stakeholder groups. Results Two case studies demonstrate the decision-supporting capability of AuCT-Sim where one investigates the optimal reagent base stocking level, and the other one simulates a reagent supply disruption event. These case studies serve as guidelines for designing computational experiments with AuCT-Sim to solve specific problems in AuCT manufacturing and supply chain. Discussion This simulation framework will be useful in understanding the impact of possible manufacturing and supply chain strategies, policies, regulations, and standards informing strategies to increase patient access to AuCT.

This phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2 to 4. In part 3, both study drugs were dosed, same day, for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (ORR; N = 91) was 85%, with 67% achieving a complete response (CR). At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI], 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow-up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns. This trial was registered at www.clinicaltrials.gov as #NCT02572167.

Background Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) composed of a CD30-directed monoclonal antibody, a protease-cleavable linker, and the microtubule-disrupting agent, monomethyl auristatin E (MMAE). Direct cytotoxicity, driven by MMAE, is at the heart of the multifaceted anticancer activity of BV (Sutherland 2006). BV was the first ADC to be approved in multiple cancer types, including treatment-naïve Stage III or IV classical Hodgkin lymphoma (cHL) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) (Connors 2017). Nivolumab is a fully humanized monoclonal antibody that targets programmed cell death protein 1 and is approved for the treatment of adults with relapsed/refractory (R/R) cHL. Both agents have been well tolerated with encouraging activity when combined with multi-agent chemotherapy. BV plus nivolumab was evaluated as a frontline treatment option for patients with cHL who are ≥60 years of age and ineligible for, or declined, conventional combination chemotherapy. The ongoing study reported an objective response rate (ORR) of 82% in 11 evaluable patients, and BV appears to be well tolerated in this population (Friedberg 2018). The combination of BV and nivolumab produced a 67% complete response (CR) rate and an estimated 3-year progression-free survival (PFS) rate of 77% in 93 patients with R/R cHL treated in the first-line salvage setting (Advani 2021). BV plus doxorubicin and dacarbazine (AD) without radiation therapy was evaluated in 34 patients with non-bulky Stage I or II cHL. BV-AD treatment resulted in interim and end of treatment (EOT) CR rates of 94% and 97%, respectively. The 4-year PFS and overall survival (OS) estimates were 91% and 100%, respectively. Peripheral sensory neuropathy (PSN) was low grade and only 1 patient had persistent PSN at the last follow-up (Abramson 2021). Part C of this study will evaluate BV, nivolumab, doxorubicin, and dacarbazine (AN+AD) in patients with Stage I or II cHL without bulky disease, a patient population similar to that studied in Abramson 2021. Based on the results of the trials summarized above, it is reasonable to expect that the combination of AN+AD will result in high response rates and be well tolerated, with potentially less toxicity compared with A+AVD. Study Design and Methods SGN35-027 (NCT03646123) is an open-label, multiple part, multicenter, phase 2 clinical trial of BV in patients with Stage III or IV cHL evaluating the efficacy and safety of A+AVD when administered with growth factor prophylaxis (Part A). Part B will evaluate the combination of AN+AD in patients with Stage I or II cHL with bulky mediastinal disease or Stage III or IV cHL. Part C will evaluate the efficacy and tolerability of AN+AD in patients with Stage I or II cHL without bulky disease. The primary objective of Parts B and C is to estimate the CR rate at EOT in patients with treatment-naïve cHL. Approximately 240 patients will be enrolled in this study: 40 in Part A, 50 in Part B, and 150 in Part C. Parts A and B have completed enrollment. Patients in Part C must have histologically confirmed cHL and have an ECOG performance status of ≤2. Patients with nodular lymphocyte-predominant HL or prior treatment with immune checkpoint inhibitors will be ineligible for enrollment. Patients in Part C will be treated with BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m 2, and dacarbazine 375 mg/m 2, administered separately by intravenous infusion on Days 1 and 15 of each 28-day cycle. Patients in Part C will receive 4 cycles of treatment. The primary efficacy endpoint is the CR rate at EOT with AN+AD in patients with previously untreated cHL. Duration of response, duration of complete response, event-free survival, PFS, ORR, and safety and tolerability of AN+AD will be evaluated as secondary endpoints. Efficacy will be assessed by PET/CT scans at Cycle 2 and EOT; disease response and progression for Part C will be assessed using the LYRIC modification of the Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2014). Patients will be followed for disease progression and OS for 5 years. Safety and efficacy endpoints will be summarized with descriptive statistics. The CR rate at EOT and its two-sided 95% confidence interval will be presented (Clopper 1934). Time-to-event endpoints will be analyzed using Kaplan-Meier methodology. Enrollment for Part C is ongoing in the US, with plans for global expansion. Disclosures Flinn: MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Friedman: Seagen Inc.: Research Funding. Ho: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company.

Introduction Brentuximab vedotin (BV) and nivolumab are both active and well tolerated in patients (pts) with classical Hodgkin lymphoma (cHL) and were previously studied in first salvage (overall response rate [ORR] 85%; complete response [CR] 67%) (Advani 2021) and as firstline therapy in older adults (ORR 95%; CR 79%) (Yasenchak 2019). BV is approved for the treatment of adults with treatment-naïve Stage III or IV cHL in combination with doxorubicin, vinblastine, and dacarbazine (AVD) (Connors 2017) and targets CD30, a receptor expressed on the Reed-Sternberg cells. Nivolumab is approved for treatment of adults with relapsed/refractory cHL and restores antitumor immunity by blocking the PD-1 receptor on activated T-cells. The combination of BV plus nivolumab demonstrated promising activity that supports this combination when evaluated as a frontline treatment option for pts over 60 years of age with cHL (Friedberg 2018). Additionally, in pts with non-bulky Stage I or II cHL, treatment with BV plus doxorubicin and dacarbazine (AD) resulted in a CR rate of 97% at end of treatment (EOT), as well as a promising 4-year progression-free survival (PFS) estimate of 91%. Importantly, there were no cases of ≥Grade 3 peripheral neuropathy and only 9% were Grade 2 (Abramson 2021). Herein, we present preliminary safety results from Part B of this phase 2 study, where combination treatment with AN+AD (BV, nivolumab, doxorubicin, and dacarbazine) was well tolerated without excessive dose modifications or discontinuations and is consistent with the known safety profiles of the individual components of this treatment regimen. Methods SGN35-027 (NCT03646123) is an open-label, multiple part, multicenter, phase 2 clinical trial. Part B of this study enrolled pts with Ann Arbor Stage I or II cHL with bulky mediastinal disease (defined as ≥ 10 cm) or Stage III or IV cHL. Pts received up to 6 cycles of AN+AD (consisting of BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m 2, and dacarbazine 375 mg/m 2). All study drugs were administered by IV infusion on Days 1 and 15 of each 28-day cycle. The primary endpoint was CR rate at EOT. Secondary endpoints included safety, tolerability, overall response rate, and PFS. Disease response and progression was assessed by investigators using the Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin Lymphomas (Cheson 2014) and Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) (Cheson 2016) at Cycle 2 and EOT. Results In Part B, the majority of the 58 pts enrolled were white (86%), not of Hispanic or Latino/a or Spanish origins (79%), and less than 65 years old (95%). Median age was 35 years (range: 19-78 years). Twenty-nine percent of pts had Stage II cHL with bulky mediastinal disease, while the remainder had Stage III (17%) or Stage IV (50%) cHL. Of the 58 pts enrolled, 57 received at least one dose of study treatment. Of the 57 pts who received at least one dose of study treatment, 1 pt discontinued treatment (all study drugs) by the end of Cycle 2 due to treatment-emergent adverse events (TEAEs). By end of Cycle 2, the majority of TEAEs were Grades 1 and 2; 16% of pts experienced ≥Grade 3 TEAEs. Nausea, fatigue, and alopecia were the most frequently reported treatment-related TEAEs (51%, 33%, and 26% of pts, respectively). No febrile neutropenia was observed, and there were no Grade 5 adverse events. Two pts (4%) experienced treatment-related treatment-emergent serious adverse events; 1 pt (2%) experienced hypophysitis and aseptic meningitis, and discontinued treatment, and 1 pt (2%) experienced pneumonitis. Preliminary efficacy results are anticipated for presentation. Conclusions Preliminary results demonstrate that AN+AD is well-tolerated, and no new safety signals were observed. The omission of bleomycin and vinblastine may have contributed to the absence of certain AEs, such as febrile neutropenia. This study of AN+AD is ongoing, and updated safety and efficacy results will be presented at the meeting. Disclosures Lee: BMS: Honoraria, Research Funding; Aptitude Health: Honoraria; Century Therapeutics: Consultancy; Pharmacyclics: Research Funding; Guidepoint: Honoraria; Oncternal: Research Funding; Seagen: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Honoraria. Flinn: Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Melear: Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau; Janssen: Speakers Bureau. Ramchandren: curis: Research Funding; MERCK: Consultancy, Research Funding; pharmacyclics: Consultancy, Research Funding; seattle genetics: Consultancy, Research Funding; BMS: Consultancy; Trillium: Research Funding. Friedman: Seagen Inc.: Research Funding. Burke: MorphoSys: Consultancy; Beigene: Consultancy, Speakers Bureau; AbbVie: Consultancy; Epizyme: Consultancy; Adaptive Biotechnologies: Consultancy; Bristol Myers Squibb: Consultancy; Kymera: Consultancy; AstraZeneca: Consultancy; Verastem: Consultancy; Kura: Consultancy; X4 Pharmaceuticals: Consultancy; SeaGen: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy. Linhares: Seagen Inc.: Research Funding. Peterson: Seagen Inc.: Research Funding. Raval: Abbvie Pharmaceuticals: Speakers Bureau; Adaptive Biotechnologies: Consultancy; ADCT Therapeutics: Consultancy, Speakers Bureau; Alexion Pharmaceuticals: Speakers Bureau; Amgen Biotechnology Company: Research Funding; Astellas Pharmaceuticals: Speakers Bureau; Astrazeneca Pharmaceuticals: Consultancy, Speakers Bureau; Beigene Pharmaceuticals: Speakers Bureau; Bristol Meyers Squibb Pharmaceuticals: Consultancy; Epizyme Pharmaceuticals: Consultancy, Speakers Bureau; Genetech Biotechnology Company: Research Funding; GlaxoSmithKline Pharmaceuticals: Consultancy; Incyte Pharmaceuticals Corporation: Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Morphosys Biotech Company: Speakers Bureau; Sanofi Genzyme: Consultancy; Seagen Biotechnology Company: Research Funding; Takeda Pharmaceuticals: Consultancy, Speakers Bureau. Chintapatla: Seagen Inc.: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Yimer: Janssen: Speakers Bureau; Beigene: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Islas-Ohlmayer: Seagen Inc.: Research Funding. Dean: Seagen Inc.: Research Funding. Rana: Seagen Inc.: Research Funding. Gandhi: GlaxoSmithKline: Honoraria; Karyopharm Therapeutics: Honoraria; TG Therapeutics: Honoraria. Renshaw: Amgen: Speakers Bureau; SeaGen: Consultancy; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Texas Oncology: Current Employment. Gillespie-Twardy: Seagen Inc.: Research Funding. Ho: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Fanale: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Guo: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Yasenchak: Seagen Inc.: Research Funding.

Background: Human papillomavirus (HPV) testing from clinician-collected cervical and self-collected cervico-vaginal samples is more sensitive for detecting CIN2+/CIN3+ than cytology-based screening, stimulating interest in HPV testing from urine. The objective was to determine the performance of the Trovagene HPV test for the detection of CIN2+ from urine and PreservCyt cervical samples. Methods: Women referred for colposcopy at St Mary's Hospital (London, United Kingdom), following abnormal cytology, were recruited to this diagnostic accuracy study by convenience sampling (September 2011 to April 2013). A total of 501 paired urine and cervical samples were collected. Primary outcomes were sensitivity for CIN2+/CIN3+ and specificity for Results: Trovagene HPV test sensitivity and specificity from PreservCyt were similar to well-established tests [sensitivity for CIN3+ (n = 145) 96.3% (95% confidence interval (CI), 89.6–99.2); CIN2+ (n = 81) 94.5% (95% CI, 89.4–97.6); specificity for Conclusions: Trovagene HPV test's performance on PreservCyt cervical samples was comparable with established HPV tests. Sensitivity in urine, although slightly lower, may nevertheless be adequate for self-sampling. This referral population's higher HPV positivity rate affects specificity, warranting further studies in a screening population. Impact: This may prove useful for women not attending for cervical screening. Cancer Epidemiol Biomarkers Prev; 26(7); 1053–9. ©2017 AACR.

TPS8068 Background: Brentuximab vedotin (BV, ADCETRIS) is approved for the treatment of adults with treatment-naïve Stage III or IV cHL in combination with AVD (Connors 2017). Nivolumab is approved for treatment of adults with relapsed/refractory cHL. Both agents have been well tolerated with promising activity when combined with multi-agent chemotherapy. The combination of BV plus nivolumab was evaluated as a frontline treatment option for patients (pts) with cHL who are over 60 years and ineligible for or declined conventional combination chemotherapy (Friedberg, 2018). The ongoing study reported an ORR of 82% in 11 pts and appears well tolerated in this population. In another trial in 93 patients in the first salvage setting, the combination produced a 67% CR rate (Herrera 2018, Moskowitz 2019) and the majority of patients were able to undergo subsequent stem cell transplant. It is reasonable to expect that the combination of BV, nivolumab, A, and D (AN + AD) will result in high response rates and be well tolerated, with potentially less toxicity. Methods: SGN35-027 (NCT03646123) is a phase 2 study designed to evaluate the efficacy and safety of A+AVD when administered with growth factor prophylaxis in pts with stage III/IV cHL (Part A). Part B will evaluate the combination of AN + AD in a similar patient population. The primary objective of Part B is to estimate the CR rate at EOT in pts with treatment-naïve advanced cHL. Patients in Part B will have Ann Arbor Stage IIB/III/IV cHL or Stage IIA cHL with bulky mediastinal disease. Enrollment is ongoing in both parts of the study. Approximately 50 pts will be enrolled in Part B. All pts will be treated with BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m2, and dacarbazine 375 mg/m2, administered separately by IV infusion on Days 1 and 15 of each 28-day cycle for up to 6 cycles. Efficacy will be assessed by PET/CT scans at C2 and EOT. Disease assessments will be performed periodically during follow up. Disease response and progression will be assessed using Lugano with the incorporation of LYRIC (Cheson 2016). Clinical trial information: NCT03646123 .

Background Despite the advances in therapy of classical Hodgkin lymphoma (cHL) and CD30-expressing peripheral T-cell lymphoma (PTCL) over the years, the outcomes seen in younger patients with the disease have not been attained in patients ≥60 years of age. Studies cite 5-year progression-free survival (PFS) and freedom from treatment failure rates of 30%-45% in older patients with HL, as compared to rates of 75%-80% expected in younger patients (Evens 2008; Proctor 2009). In a recent retrospective study of patients >60 years of age diagnosed with PTCL between 2008-2014, a multivariate analysis demonstrated that a Charlson Comorbidity Index (CCI) ≥2 and high IPI score (3-5) were independent risk factors for worse overall survival (OS) and PFS (Zhao 2016). Similarly, multivariate analysis of registry data from Sweden shows that a CCI ≥2, when adjusted for age, is independently associated with worse OS and PFS outcomes (Ellin 2018). There is no standard treatment regimen for elderly patients with cHL and PTCL, and co-morbidities including depressed cardiac and renal function limit the ability to use combination chemotherapy, and represent a high unmet need. Brentuximab vedotin (BV, ADCETRIS®) is a CD30-directed antibody-drug conjugate (ADC) consisting of the chimeric IgG1 antibody cAC10, specific for human CD30; the microtubule-disrupting agent monomethyl auristatin E (MMAE); and a protease-cleavable linker that covalently attaches MMAE to cAC10. Following the binding of BV to CD30-expressing cells, the ADC-CD30 complex is internalized, and MMAE released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptosis. Single-agent BV has demonstrated robust activity in patients with HL refractory to several lines of chemotherapy and the ECHELON-1 study (Connors 2017) established its efficacy in combination with chemotherapy for the front line treatment of HL. In a phase 2 study of single-agent BV in 27 patients aged ≥ 60 years with HL, there was an objective response rate of 92%, with 73% achieving complete remission (Forero-Torres, 2015). For CD30-expressing PTCL, single-agent BV is an active and well-tolerated treatment for patients with relapsed or refractory disease (Horwitz 2014) and the ECHELON-2 study showed that the addition of BV to combination chemotherapy in the frontline treatment improves both PFS and OS (Horwitz 2018). In the elderly patient populations who are not candidates for multi-agent chemotherapy, frontline treatment with single-agent BV may have the potential to be an active and well-tolerated treatment. Study Design Two additional cohorts have been added to the SGN35-015 phase 2 open-label study (NCT01716806) to evaluate the efficacy and tolerability of BV as monotherapy in treatment-naive patients with cHL, which excludes nodular lymphocyte-predominant HL (Part E) or treatment-naive patients with CD30-expressing PTCL (Part F). The primary objective of these cohorts is to assess objective response rates of single-agent BV as frontline therapy in patients ≥60 years of age and ineligible for conventional chemotherapy for HL (Part E) or CD30-expressing PTCL (Part F). Eligible patients in Parts E and F must be ≥75 years or ≥60 years of age and have one of the following: confirmed ejection fraction Approximately 30 evaluable patients will be enrolled in Parts E and F of the study and administered BV 1.8 mg/kg as a single intravenous infusion on Day 1 of each 21-day cycle. Patients achieving a complete remission, partial remission, or stable disease will receive up to 16 cycles of treatment. Treatment response will be assessed by spiral CT scans of the chest, abdomen, and pelvis and PET scans at Cycles 2, 6, and 11. Response assessment will be determined by blinded independent central review. Disclosures Yasenchak: BMS: Consultancy; Seattle Genetics: Consultancy. Bordoni:Phillips & Gilmore: Honoraria; Genentech: Speakers Bureau; Merck: Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Practice Point Communication: Honoraria; Deciphera: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yazbeck:Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Larson:Seattle Genetics, Inc.: Research Funding. Newhook:Seattle Genetics, Inc.: Employment. Ho:Seattle Genetics, Inc.: Employment, Equity Ownership. Mei:Seattle Genetics, Inc.: Research Funding.

Background. In patients with Hodgkin lymphoma (HL) aged ≥60 years, comorbidities and treatment-related toxicities often prevent delivery of optimal intensity and/or duration of standard frontline chemotherapy. Brentuximab vedotin (BV) and nivolumab (Nivo) have two distinct mechanisms of action, tolerability of the combination has been observed in relapsed/refractory HL in a phase 1/2 study (85% objective response rate [ORR]; 62% complete remission [CR] rate) (Herrera 2017); thus, our phase 2 study was amended to evaluate this combination in a cohort of newly diagnosed HL patients aged ≥60 years (NCT01716806). Methods. Eligible subjects have treatment-naive classical HL and are ineligible for or declined initial conventional combination chemotherapy (planned N = 20). Subjects received BV 1.8 mg/kg + Nivo 3 mg/kg as well as prophylactic premedication for infusion-related reactions on Day 1 of each 3-week cycle for ≤16 cycles. CT/PET scans were performed at Cycles 2 (CT only), 4, 8, 12, and 16 (assessed per Lugano Classification Revised Staging System [Cheson 2014] and Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) [Cheson 2016]). The primary objective is ORR. Results. Twenty-one subjects received BV + Nivo (median age, 72 years [range, 60-88]). The majority had an ECOG performance status of 0/1 (95%), Stage III/IV disease (77%), and presented with B symptoms at baseline (57%). In this elderly population, 48% had bulky disease and 38% had extranodal disease at the initial diagnosis. Of the 21 subjects treated, 7 remain on treatment, 2 discontinued treatment due to progressive disease, 6 completed treatment, 4 withdrew due to subject decision, 1 withdrew due to pneumocystis jiroveci pneumonia, and 1 had an unrelated Grade 3 serious adverse event of acute renal failure and sepsis, resulting in death. The most common treatment-related adverse events (TRAE) of any grade were fatigue (48%), peripheral sensory neuropathy (38%), diarrhea, infusion-related reactions, and pyrexia (24% each). No infusion-related reactions required steroid intervention. Among TRAE ≥Grade 3, the most common were elevated lipase (19%) and peripheral motor neuropathy (14%). Three subjects had immune-related AEs with a maximum severity of Grade 3. Three of the 21 subjects treated were not evaluable for efficacy, defined in the protocol as subjects who had both a baseline and at least one post-baseline disease assessment or who had documented progression of disease any time after receiving any amount of BV. Non-evaluable subjects included 1 who died from renal failure prior to assessment, 1 who withdrew consent prior to assessment, and 1 who had not been assessed at the time of the data cutoff. Based on the 18 evaluable subjects, the ORR was 100%, with a 72% CR rate and a 28% PR rate. Conclusions. Elderly HL remains an unmet clinical need. These data suggest that BV + Nivo is an active treatment with an encouraging CR rate (72%) and appears well tolerated in these patients. These results also suggest that with further follow-up and validation, treatment with BV + Nivo may improve patient outcomes. Enrollment in this cohort is complete (21 subjects), with 7 subjects continuing to receive treatment. Disclosures Yasenchak: BMS: Consultancy; Seattle Genetics: Consultancy. Bordoni:Seattle Genetics, Inc.: Research Funding; Practice Point Communication: Honoraria; Phillips & Gilmore: Honoraria; Merck: Speakers Bureau; Genentech: Speakers Bureau; Deciphera: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yazbeck:Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Anderson:Seattle Genetics, Inc.: Research Funding. Larson:Seattle Genetics, Inc.: Research Funding. Newhook:Seattle Genetics, Inc.: Employment. Mei:Seattle Genetics, Inc.: Research Funding. Ho:Seattle Genetics, Inc.: Employment, Equity Ownership. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee.

Background For patients with advanced classical Hodgkin lymphoma (cHL), the most common frontline regimen has historically consisted of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which originated in 1975 (Connors 2018). However, up to 30% of patients treated with ABVD as frontline therapy will relapse or are refractory to treatment (Canellos 1992; Carde 2016; Gordon 2013). Additionally, bleomycin is associated with potentially fatal pulmonary toxicity (Canellos 2004; Martin 2004), and vinblastine is associated with neutropenia and peripheral neuropathy. Brentuximab vedotin (BV, ADCETRIS®) has been approved for the treatment of adult patients with previously untreated Stage III or IV cHL in combination with doxorubicin, vinblastine, and dacarbazine based on the results of the ECHELON-1 study (Connors 2017). Data reported from ECHELON-1 showed patients randomized to the BV + doxorubicin, vinblastine, and dacarbazine (A + AVD) treatment arm had a statistically significant 23% risk reduction in modified PFS events vs patients randomized to the ABVD arm of the study. The combination of BV plus nivolumab was reported as showing potential for the treatment of cHL. The combination was evaluated as a potential frontline treatment option for patients with cHL who are over 60 years of age and ineligible for or declining conventional combination chemotherapy (Friedberg, 2018). The ongoing study reported an ORR of 82% in 11 patients and the regimen appears well tolerated in this population. In another trial in 62 patients in the first salvage setting, the combination produced a 61% CR rate (Herrera 2018) and the patients were able to undergo subsequent stem cell transplant. BV and nivolumab have been combined separately with doxorubicin, vinblastine, and dacarbazine and shown to be active and well tolerated. Furthermore, BV has been evaluated in combination with just doxorubicin and dacarbazine, omitting vinblastine, in 34 patients with previously untreated non-bulky stage I/II cHL and showed 100% complete response rate at end of treatment (EOT) and PFS and OS rates of 100% at last follow up (median=15 months; Abramson 2018). This combination resulted in a low incidence of neutropenia and alopecia, and moderate (Grade 1 or 2) peripheral neuropathy. It is therefore reasonable to expect that the combination of BV, nivolumab, doxorubicin, and dacarbazine (AN + AD) will result in high response rates and be well tolerated, with potentially less toxicity. Study Design SGN35-027 (NCT03646123) is a phase 2 study designed to evaluate growth factor prophylaxis plus BV in combination with AVD in patients with stage III and IV cHL (Part A). A second cohort has been added to the study (Part B), which will evaluate the combination of AN + AD in this patient population. The primary objective of Part B is to estimate the CR rate at EOT with AN + AD in patients with previously untreated advanced cHL. All enrolled patients will be 12 years or older, with an ECOG performance status of ≤2. Patients in Part B will be treatment-naïve with Ann Arbor Stage IIB/III/IV cHL or Stage IIA cHL with bulky disease. Patients must have bidimensional measurable disease, as documented by radiographic technique, and qualifying baseline laboratory data. Patients will be excluded if they have nodular lymphocyte predominant HL or have symptomatic neurologic disease that compromises normal activities of daily living or requires medication. Patients with known cerebral or meningeal disease, including signs or symptoms of progressive multifocal leukoencephalopathy, will also be excluded. Approximately 50 patients will be enrolled in Part B. All patients will be treated with BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m2, and dacarbazine 375 mg/m2. All study drugs will each be administered separately by IV infusion on Days 1 and 15 of each 28-day cycle for up to 6 cycles of treatment. Efficacy will be assessed by PET and CT scans at Cycle 2 and EOT. Disease assessments will be performed during follow-up every 3 months for the first year, every 6 months for 2 additional years, and then per institutional standard of care. Disease response and progression will be assessed by investigators using the Lymphoma Response to Immunomodulatory Therapy Criteria modification of Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2016). Disclosures Friedman: Amgen: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics, Inc.: Research Funding. Lee:Seattle Genetics, Inc.: Research Funding. Ho:Seattle Genetics, Inc.: Employment, Equity Ownership. Flinn:AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding.

Neuropilin-1 (NRP-1)/CD304 is a marker for plasmacytoid dendritic cells. We determined the distribution of NRP-1/CD304 expression on normal hematopoietic cells and in 167 acute leukemias by flow cytometry. NRP-1/CD304 surface expression was frequent in precursor B-cell acute lymphoblastic leukemia (36/51 [71%]) and uncommon in acute myeloid leukemia (22.9%). In acute myeloid leukemia, expression was noted in all (4/4) acute myeloid leukemias with the M4eo subtype and in 50% of specimens (6/12) with complex cytogenetics. On hematopoietic cells, NRP-1/CD304 was expressed on normal erythroid progenitors, plasma cells, and B-cell progenitors, as well as plasmacytoid dendritic cells. Expression was not consistently detected on other hematopoietic cell types. Owing to this distribution of expression, the detection of NRP-1/CD304 alone on a hematopoietic cell cannot be used to determine plasmacytoid dendritic cell differentiation. Finally, we show that NRP-1/CD304 is overexpressed in 30% of precursor B-cell acute lymphoblastic leukemia samples compared with normal B-cell progenitors, allowing for its potential use as a marker for the detection of minimal residual disease.

We prove that any collection which tiles the positive integers must contain one of two types of sub-collections. We then use this result to prove a variation of the Ratio Test for convergence of series. This version of the Ratio Test shows the convergence of certain series for which the Root Test (which is known to be more powerful than the conventional Ratio Test) fails. This version of the Ratio Test is also used to prove a version of the Banach Contraction Principle for self-maps of a complete metric space.

Purpose – This paper seeks to identify collaboration elements and evaluate their intensity in the Brazilian supermarket retail chain, especially the manufacturer‐retailer channel.Design/methodology/approach – A structured questionnaire was elaborated and applied to 125 representatives from suppliers of large supermarket chains. Statistical methods including multivariate analysis were employed. Variables were grouped and composed into five indicators (joint actions, information sharing, interpersonal integration, gains and cost sharing, and strategic integration) to assess the degree of collaboration.Findings – The analyses showed that the interviewees considered interpersonal integration to be of greater importance to collaboration intensity than the other integration factors, such as gain or cost sharing or even strategic integration.Research limitations/implications – The research was conducted solely from the point of view of the industries that supply the large retail networks. The interviews were not...

A putative juvenile hormone esterase (JHE) binding protein, P29, was isolated from the tobacco hornworm Manduca sexta [J. Biol. Chem. 275(3), 1802–1806]. A homolog of P29 was identified in Drosophila melanogaster by sequence alignment. This gene, CG3776 was cloned, recombinant DmP29 expressed in Escheriscia coli and two anti-DmP29 antisera raised. In vitro binding of the P29 homolog to Drosophila JHE was confirmed. P29 mRNA and an immunoreactive protein of 25 kDa were detected in Drosophila larvae, pupae and adults. The predicted size of the protein is 30 kDa. Drosophila P29 is predicted to localize to mitochondria (MitoProt; 93% probability) and has a 6 kDa N-terminal targeting sequence. Subcellular organelle fractionation and confocal microscopy of Drosophila S2 cells confirmed that the immunoreactive 25 kDa protein is present in mitochondria but not in the cytosol. Expression of P29 without the predicted N-terminal targeting sequence in High Five TM cells showed that the N-terminal targeting sequence is shorter than predicted, and that a second, internal mitochondrial targeting signal is also present. An immunoreactive protein of 50 kDa in the hemolymph does not result from alternative splicing of CG3776 but may result from dimerization of P29. The function of P29 in mitochondria and the possible interaction with JHE are discussed.

A hybrid capture test that can be used to detect at least 13 high-risk HPV types (referred to collectively as HPV-HR) in cervical scrapes (Hybrid Capture 2 probe set B, HC2-B) was evaluated. The HC2-B test is accurate and highly reproducible and the results obtained show excellent agreement with those obtained by a multiplexed type-specific polymerase chain reaction (mts-PCR). An additional assay to identify a subset of HPV-HR types may improve specificity without compromising sensitivity in HC2-B positive specimens with a test result close to the cut-off value given by 1 pg/ml HPV DNA.

Lorenzato F, Ho L, Terry G, Singer A, Santos LC, de Lucena Batista R, Lubambo T. The use of human papillomavirus in detection of cervical neoplasia in Recife (Brazil). High risk types of human papillomavirus (HR-HPV) play a major role in cervical cancer oncogenesis. This study aims to evaluate the efficacy of HPV detection and typing as a means of identifying cervical neoplasia in a high risk population. A management algorithm for implementation of HPV detection in clinical practice is also proposed. A nested case-control within a cohort study was undertaken in Recife (Brazil). All 479 participants had cervical scrapes collected for HPV detection followed by colposcopy. Samples were blindly analyzed by polymerase chain reaction (PCR) and typed by restriction fragment length polymorphism (RFLP). HPV detection by PCR and typing with RFLP cost US$ 4.92 per woman screened in this study and is significantly better than cytology in identifying women at risk of developing cervical cancer (P = 0.0001). Women who tested positive for HR-HPV had over 35-fold increased risk of having high grade squamous intraepithelial lesion (HSIL) or cervical cancer, although this does not necessarily translate into the same risk rate for women with latent HPV infection developing major cervical neoplasia. HPV typing offers 90% sensitivity and 85% specificity for cervical cancer detection. In combination with cytology it provides a negative predictive value of 99.4% and a sensitivity of over 96% for detection of HSIL and cervical cancer. We conclude that HPV typing is an inexpensive and effective method for identification of cervical neoplasia and women at risk of developing it. It improves quality control for both false negative and false positive cytology results. Routine screening intervals could safely be increased to 3–5 years, decreasing anxiety and socio-economic inconveniences.

Background HR HPV genotypes when assayed collectively, achieve high sensitivity but low specificity for the prediction of CIN2+. Knowledge of the specific genotypes in an infection may facilitate the use of HR HPV detection in routine clinical practice. Objectives To compare the rate of HR HPV detection and the accuracy of CIN2+ prediction between PapType test (Genera Biosystems) and other commercially available HR HPV assays, and to examine the value of full HPV genotyping. Study design PreservCyt samples from 1099 women referred for abnormal cervical cytology were used. CIN2+ was chosen as the primary end-point but CIN3+ was also evaluated. A hierarchy of HR HPV genotypes was created using PPV and this was used to create 3 groups of genotypes with potentially different management. Results The PapType assay has a specificity of 22.4% and a sensitivity of 94.6% for CIN2+ prediction. Classification into Groups A (HPV33 and HPV16, very highly predictive), B (HPV31, 18, 52, 35, 58, 51 highly predictive) and C (HPV68, 45, 39, 66, 56, 59, intermediate predictive) could double the specificity (44.5%) but only slightly reduce the sensitivity for CIN2+ (91.5%) and CIN3+ (94.0%). Conclusions The PapType assay is a simple, reproducible and effective test for HR HPV detection and genotyping. HPV 33 was found to have a very high PPV and should therefore be managed as for HPV16.

Background: Several new assays have been developed for high-risk HPV testing of cervical samples; we compare six HPV tests in a screening population. Methods: Residual material from liquid-based PreservCyt samples was assayed. Four tests (Hybrid Capture 2, Cobas, Abbott and Becton-Dickinson (BD)) measured HPV DNA while two used RNA (APTIMA and NorChip). Results: Positivity rates ranged from 13.4 to 16.3% for the DNA-based tests with a significantly lower positivity rate for the Abbott assay. The Gen-Probe APTIMA assay was positive in 10.3% of women, which was significantly lower than all the DNA tests; the NorChip PreTect HPV-Proofer test was much lower at 5.2%. 40 CIN2+ cases were identified, of which 19 were CIN3+. All CIN3+ cases were HPV positive by all tests except for one, which was negative by the Abbott assay and five which were negative by the NorChip test. Conclusion: All HPV tests except NorChip showed high sensitivity for high-grade lesions positive by cytology, suggesting co-testing is unnecessary when using HPV tests. Positivity rates in cytology-negative specimens were similar for the DNA-based tests, but lower for the APTIMA test suggesting this maintains the high sensitivity of DNA tests, but with better specificity.

Women referred for colposcopy with mild and moderate dyskaryosis and found to have only minor cervical abnormalities were screened for oncogenic human papilloma virus (HPV) types. The natural development of these abnormalities in 42 HPV-positive women was assessed by cytology and colposcopy at 6-month intervals for up to 2 years. As is the case with cancers and high-grade cervical intra-epithelial neoplasia (CIN), minor cervical abnormalities were frequently found to be associated with HPV16, -18, -31 and -33. Viral persistence and the development of high-grade lesions were found to be closely associated with HPV16; 56% of HPV16 isolates were persistent compared to 7% of other HPV types, and all 4 subsequent CIN 3 lesions were in women with persistent infection. A striking association of persistence with a variant of HPV16 having a base change at nucleotide 350 was observed. Ten of 12 women with this variant had persistent infection compared to only 1 of 16 women infected with the HPV16 prototype. © 1996 Wiley-Liss, Inc.

Human papillomaviruses (HPV) play a causative role in the aetiology of cervical intra-epithelial neoplasia (CIN) and cervical cancer. Human leukocyte antigens (HLA) are important in the regulation of immune response to foreign antigens. The role of genetic variation at the HLA class II loci (DR and DQ) in CIN (HPV 16, 18, 31 and 33 typed) was investigated by PCR DNA amplification and oligonucleotide probe typing of cervical smears from British Caucasian patients (n = 176) and controls (n = 416). The alleles of the DQB1*03, DRB1*04 and DRB1*11 loci were strongly associated with susceptibility to CIN. Specifically, the haplotypes DRB1*0401-DQB1*0301 and DRB1*1101-DQB1*0301 were significant and indicated susceptibility. The DQB1*03 locus was more contributory to this association than the DRB1 loci. A weak protective effect was shown for the haplotype DRB1*0101-DQB1*0501. Positive correlation was also observed for HPV-positive CIN, suggesting that specific HLA class II alleles may be important in determining the immune response to HPV antigens and the risk for CIN after HPV infection. Our results should help in the rational design of vaccines against HPV.

Cervical intraepithelial neoplasia (CIN) and cervical cancer have been shown to be strongly associated with infection by human papillomavirus (HPV). However, other factors may be contributory in the progression from normal epithelium to CIN and cervical cancer, since not all women with HPV infection develop disease. Recently, it was demonstrated that there is a high risk for cervical cancer and CIN in women with HLA DQB1 * 03 (RR = 7.1, p < 0.0009) (1). Subsequent reports have been conflicting, due to sample size, genetic heterogeneity and differences in the techniques employed for the detection of HLA DQB1 * 03. DNA from cervical smears of 178 women with CIN and 420 controls with normal cervical cytology was analyzed by polymerase chain reaction (PCR) with type-specific primers for HPV 16, 18, 31, and 33. The DNA from test and control samples were also analyzed by a novel PCR technique, which mutates the first base of codon 40 (DQ alleles) from T to G to create an artificial restriction site for an enzyme Mlu I that distinguish DQB1 * 03 from other alleles and are confirmed by digestion of amplified DNA with Mlu I. Further analysis of individual DQB1 * 03 alleles was performed using PCR and allele-specific primers. One hundred forty-four (34%) out of 420 controls (all HPV 16, 18, 31, or 33 negative and normal cytology), 37/66 (56%) of CIN I and 72/112 (64%) of CIN III were positive for DQB1 * 03 (trend test, p < 0.001, χ2 = 37.3). A significant association was observed between DQB1 * 03 and CIN (odds ratio 3.03; 95% CI 2.11–3.45). Of women with CIN, 131/ 178 (73.5%) had HPV (types 16, 18, 31, or 33) infection. There was a significant association between DQB1 * 03 and presence of HPV (odds ratio 3.43; 95% CI 2.25–5.10). Homozygosity for DQB1 * 03 was more strongly associated with CIN than heterozygosity (odds ratios 4.0 and 2.63, respectively); and for the presence of HPV (odds ratio 4.47; 95% CI 2.58–7.77). HLA DQB1 * 0301 was the most strongly associated allele with CIN and HPV (odds ratios 2.53 and 2.63, respectively). HLA DQB1 * 03 is associated significantly with CIN and may be permissive for HPV infection. Further analysis of class II HLA typing in CIN is necessary to evaluate this association.

High-risk human papillomavirus (HPV) DNA/RNA testing provides higher sensitivity but lower specificity than cytology for the identification of high-grade cervical intraepithelial neoplasia (CIN). Several new HPV tests are now available for this purpose, and a direct comparison of their properties is needed. Seven tests were evaluated with samples in liquid PreservCyt transport medium from 1,099 women referred for colposcopy: the Hybrid Capture 2 (Qiagen), Cobas (Roche), PreTect HPV-Proofer (NorChip), Aptima HPV (Gen-Probe), and Abbott RealTi m e assays, the BD HPV test, and CINtec p16 INK4a cytology (mtm laboratories) immunocytochemistry. Sensitivity, specificity, and positive predictive value (PPV) were based on the worst histology found on either the biopsy or the treatment specimen after central review. Three hundred fifty-nine women (32.7%) had CIN grade 2+ (CIN2+), with 224 (20.4%) having CIN3+. For detection of CIN2+, Hybrid Capture 2 had 96.3% sensitivity, 19.5% specificity, and 37.4% PPV. Cobas had 95.2% sensitivity, 24.0% specificity, and 37.6% PPV. The BD HPV test had 95.0% sensitivity, 24.2% specificity, and 37.8% PPV. Abbott RealTi m e had 93.3% sensitivity, 27.3% specificity, and 38.2% PPV. Aptima had 95.3% sensitivity, 28.8% specificity, and 39.3% PPV. PreTect HPV-Proofer had 74.1% sensitivity, 70.8% specificity, and 55.4% PPV. CINtec p16 INK4a cytology had 85.7% sensitivity, 54.7% specificity, and 49.1% PPV. Cytology of a specimen taken at colposcopy (mild dyskaryosis or worse) had 88.9% sensitivity, 58.1% specificity, and 50.7% PPV. Our study confirms that, in a referral setting, HPV testing by a number of different tests provides high sensitivity for high-grade disease. Further work is needed to confirm these findings in a routine screening setting.

HPV DNA testing is known to be much more sensitive than cytology, but less specific. A range of HPV and related tests in 858 women referred for colposcopy because of an abnormal smear were evaluated to compare the performances of these tests. This article compared the Abbott test to other tests which had been previously evaluated. This test was a real true test for 14 high-risk HPV types. The Abbott test was found to be highly sensitive for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) (98.9%) with a specificity of 31.5%. These numbers were comparable with the Qiagen HC2 test, the Roche Linear Array and Amplicor tests, and the Gen-Probe APTIMA test. Differences between these tests appeared to be related mostly to the choice of cutoff level. An added feature of the Abbott test was the provision of type specific results for HPV 16 and 18. J. Med. Virol. 82: 1186–1191, 2010. © 2010 Wiley-Liss, Inc.

Background: The detection of high-risk human papillomavirus (HPV) DNA provides higher sensitivity but lower specificity than cytology for the identification of high-grade cervical intraepithelial neoplasia (CIN). This study compared the sensitivity and specificity of several adjunctive tests for the detection of high-grade CIN in a population referred to colposcopy because of abnormal cytology. Methods: 953 women participated in the study. Up to seven tests were carried out on a liquid PreservCyt sample: Hybrid Capture II (Digene), Amplicor (Roche), PreTect HPV-Proofer (NorChip), APTIMA HPV assay (Gen-Probe), Linear Array (Roche), Clinical-Arrays (Genomica), and CINtec p16INK4a Cytology (mtm Laboratories) immunocytochemistry. Sensitivity, specificity, and positive predictive value (PPV) were based on the worst histology seen on either the biopsy or the treatment specimen after central review. Results: 273 (28.6%) women had high-grade disease (CIN2+) on worst histology, with 193 (20.2%) having CIN3+. For the detection of CIN2+, Hybrid Capture II had a sensitivity of 99.6%, specificity of 28.4%, and PPV of 36.1%. Amplicor had a sensitivity of 98.9%, specificity of 21.7%, and PPV of 33.5%. PreTect HPV-Proofer had a sensitivity of 73.6%, specificity of 73.1%, and PPV of 52.0%. APTIMA had a sensitivity of 95.2%, specificity of 42.2%, and PPV of 39.9%. CINtec p16INK4a Cytology had a sensitivity of 83.0%, specificity of 68.7%, and PPV of 52.3%. Linear Array had a sensitivity of 98.2%, specificity of 32.8%, and PPV of 37.7%. Clinical-Arrays had a sensitivity of 80.9%, specificity of 37.1%, and PPV of 33.0%. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3033–42)

Several studies have shown that HPV testing is substantially more sensitive than cytology for primary cervical screening. However, less data exist concerning the duration of protection afforded by a negative HPV test compared to a normal cytological outcome. Here we report the long-term findings from the Hammersmith study in women aged 35 or more. HPV testing by Hybrid Capture II was performed on all available samples from the baseline screening visit. Passive surveillance of subsequent cytology screening results for the 2,982 women in the study was undertaken using a national registry. Histological outcomes were sought for all women with abnormal smears. The primary outcome was duration of protection against histologically confirmed CIN2+ afforded by a negative HPV test compared to normal cytology. 2,516 women had at least one further smear at least 1 year after entry and 20 new cases of CIN2+ were identified during a median follow-up of 6.4 years. Including disease identified at baseline, the risk of developing CIN2+ at 1, 5 and 9 years after a normal cytology was 0.33%, 0.83% and 2.20% respectively whereas it was 0.19%, 0.42% and 1.88% after a negative HPV test. HPV testing offered excellent protection from CIN2+ for at least 6 years after a negative test, whereas the protection from cytology began to wane after about 3 years. Substantially more CIN2+ lesions were found in the follow-up period in those initially HPV positive compared to those HPV negative (HR = 6.52, p = 0.001), whereas there was little difference according to initial cytology (HR = 1.64, p = 0.51).

We studied the usefulness of self-sampling in cervical cancer prevention.A cross-sectional study was undertaken at screening services in Recife (Brazil); 253 women aged 16 to 88 years were included. Participants were randomly selected from a high-risk population for cervical neoplasia. All participants collected a self-sample with a cotton-tipped swab by rotating it against the vaginal epithelium and, possibly, the cervix. Physician-collected samples from the ectocervix and endocervix, respectively, with an Ayre's spatula and a Cytobrush endocervical brush (Medscand) were followed by thorough colposcopy. Human papillomaviruses were detected by consensus polymerase chain reaction and typed by restriction fragment length polymorphism.The difference among human papillomavirus results in samples that were self-collected versus physician collected was significant (P.03). The agreements were poor among patients with cervical intraepithelial neoplasia (CIN) grade 3 (kappa0.29) and cervical cancer (kappa0.10). Self-sampling missed 50% more cancers than did physician sampling (P =.04).Self-sampling with a cotton-tipped swab for human papillomavirus detection is not a safe method for the collection of samples that are aimed at primary cervical cancer screening.

Human papillomavirus (HPV) 16 and HPV 18 E2 amino acid variants and host HLA DR/DQ haplotypes have been identified by direct nucleic acid sequencing from cervical scrapes. HPV16 E2 variants co-segregate with a nucleotide variant at nt350 (in E6), which previously has been associated with persistent infections. Both HPV16 and HPV18 E2 variants occur relatively more frequently in individuals with HLA DR/DQ haplotypes 0401/0301 and 1101/0301 but are not related to lesion grade.

First trimester rubella carries a high risk of congenital abnormalities in the fetus. Evidence of an intrauterine infection is therefore of value for prenatal counselling. We present data to show that the polymerase chain reaction has advantages over other conventional techniques in confirming such a diagnosis, but problems remain in its application, and these are also discussed.

The present study investigated the effects of an orienting task on both the immediate and delayed recall of a linear arm movement. All 60 college and graduate students were given the instructions to learn an experimenter-defined target position; however, some subjects were presented additional non-target positions interpolated between presentations of the target position. One group made verbal estimates of the distance between the target and non-target positions, another group made no estimates concerning target and non-target positions, while a third group was presented only the target positions. The group making the verbal estimates was most accurate after an immediate and a 10-min. filled retention interval.

Tween-ether treatment of rubella virus, which has no effect on the antigenic and electrophoretic properties of the two envelope glycoproteins, destroys infectivity and enhances haemagglutinating activity. Trypsin treatment alters the electrophoretic pattern of the envelope glycoproteins so that the VPI peak is no longer evident and the VPII peak is reduced. At the same time, both the properties of haemagglutination and infectivity are inactivated but the capacity to combine with neutralizing antibody is retained, which suggests that VPII may be responsible for inducing the production of neutralizing antibody.

Summary No difference between wild type and RA27/3 strains of rubella virus was revealed by sedimentation or polyacrylamide-gel electrophoresis. Antibodies in post-infection and post-vaccination sera differed in their affinity for wild-type and RA27/3 strains, suggesting an antigenic difference.

The manipulation of the retention of a linear movement by means of different orienting tasks in an incidental learning paradigm was investigated. Subjects were presented with a target position followed by a different nontarget position on each of four presentation trials. After the presentation trials subjects were required to recall the target and nontarget positions. One group made verbal estimates of the distance between the target and nontarget positions, another group discriminated between the target and nontarget positions, while no verbal responses were required for a third group. The verbal-response groups, while not differing from each other, had less error at recall than the nonverbalizing group. These findings were discussed in terms of the levels of processing framework for memory research (Craik & Lockhart, 1972).

SV40-specific polysomes are relatively larger than host polysomes. Both 16 S and 19 S virus-specific late mRNAs are found associated with these polysomes and they are present in a ratio of approximately 2 : 1. The rates at which these virus-specific mRNAs are translated are the same, so that the relative amounts of virus-specific polypeptides synthesized in the virus-infected cells is determined by the relative amounts of 16 S and 19 S mRNAs coding for them.

The present study investigated the appropriateness of the levels-of-processing framework of memory for explaining retention of information in motor short-term memory. Subjects were given labels descriptive of the positions to be remembered by the experimenter (EL), were given no labels (NL), or provided their own labels (SL). A control group (CONT) was required to count backwards during the presentation of the criterion positions. The inclusion of a 30-sec filled retention interval as well as 0-sec and 30-sec unfilled retention intervals tested a prediction by Craik and Lockhart (1972), when attention is diverted from an item, information will be lost at a rate appropriate to its level of processing - that is, slower rates for deeper levels. Groups EL and SL had greater accuracy at recall for all three retention intervals than groups CONT and NL. In addition, there was no significant increase in error between 30-sec unfilled and 30-sec filled intervals for groups EL and SL, while there was a significant increase in error for groups CONT and NL. The data were interpreted in terms of Craik and Lockhart's (1972) levels-of-processing approach to memory.

Summary. Antibody to the ribonucleoprotein component of rubella virus occurs in only a proportion of patients with clinical rubella and is rarely present in individuals after administration of RA27/3 live attenuated virus vaccine.

The effects of relative frequency of knowledge of results on the retention of a motor skill was studied. Adams' theory (1971) contends that the perceptual trace of a critetion position gains an increment of strength each time the feedback stimuli associated with the criterion position are experienced and that it is the strength of the perceptual trace that determines retention. Schmidt's theory (1975), however, suggests that the recognition schema is updated only on trials on which the feedback stimuli associated with the criterion position are experienced in conjunction with knowledge of results and that it is the precision of the recognition schema that determines retention. Two experiments were conducted. The results provided evidence contrary to Adams' theory. Schmidt's theory, however, was only partially supported.

SUMMARY. Antibodies specific for rubella virion polypeptide, VPI, secreted by clones of hybridoma cells or produced in rabbits in response to specific antigenic stimulation, located determinants for haemagglutination inhibiting (HI) and neutralising (Nt) antibodies on this envelope component.

The effects of transcutaneous electrical nerve stimulation (TENS) upon linear-positioning performance was investigated. 30 right-handed subjects were trained and tested on a linear-positioning apparatus either under constant stimulus conditions or mixed stimulus—no-stimulus conditions. The nerve stimulation, administered by a Staodyn Model 4000 stimulator, was positioned to stimulate the brachial plexus. Subjects' task was to learn a position 300 mm along a trackway while blindfolded. 20 acquisition trials with knowledge of results, which consisted of a verbal report of the magnitude of the subjects' errors, were given followed by 20 retention trials without knowledge of results. During acquisition subjects receiving nerve stimulation required a greater number of trials to achieve asymptotic error reductions than subjects who did not receive this stimulation. However, during retention, the acquisition group, no longer receiving transcutaneous electrical nerve stimulation, consistently exhibited longer responses than control subjects. Subjects receiving the electrical stimulation for the first time during retention exhibited responses which were shorter than those exhibited by controls and acquisition-stimulated groups. Findings are discussed in terms of implications for motor-control mechanisms.

Summary IgA and IgG antibodies to the ribonucleoprotein component of rubella virus have been demonstrated by radioimmune precipitation in sera from patients with recent but not remote rubella infection. This observation suggests that a test for antibodies to the ribonucleoprotein component may provide additional evidence in the diagnosis of recent rubella infection.

The stability of “early” and “late” simian virus 40 (SV40) mRNA is compared. The stability of early 19 S mRNA clearly differentiates it from late 19 S mRNA which is less stable than the late 16 S component. No evidence of a precursor-product relationship of late 19 and 16 S mRNA was obtained.

More [3H]uridine was incorporated into RNA of SV40-infected than into uninfected cells 31 h after infection. When the specific activity of the uridine triphosphate pools in infected and uninfected cells was equated by the addition of appropriate amounts of exogenous unlabelled uridine, no difference in the rate of [3H]uridine incorporation into RNA was observed. Although no difference in [3H]uridine entry or phosphorylation was demonstrable, the apparently smaller pools of endogenous RNA precursors in infected cells resulted in less isotope dilution and thus to synthesis of uridine triphosphate and RNA of higher specific activity.

SUMMARY. A sensitive and rapid method for the detection of rubella specific IgM by fast protein liquid chromatography and enzyme-linked immunosorbent assay is described.