tbuckley/cabot-search huggingface dataset:
Timing of androgen deprivation therapy for prostate cancer patients after radiation: Planned combined analysis of two randomized phase 3 trials.
Authors: Andrew Loblaw, Julie Bassett, Catherine D'Este, Gregory Russell Pond, Patrick Cheung, Jeremy Laurence Millar, Mark Frydenberg, Madeleine Trudy King, Himu Lukka, Shawn Malone, Roger L Milne, Tom Pickles, Rosemary Smith, Martin R. Stockler, Sandra Turner, Keen Hun Tai, Henry Woo, Gillian M. Duchesne
Journal: Journal of Clinical Oncology (2018)

5018 Background: The TOAD (TROG 03.06; NCT00110162) phase 3 randomized trial showed that immediate androgen deprivation therapy (IADT) improved overall survival (OS) and time to clinical progression compared with delayed ADT (DADT) in progressive or relapsed prostate cancer patients after radical radiotherapy (RT) or prostatectomy + RT. ELAAT (NCT00439751) was a similarly designed trial but failed to reach its accrual goal. The two investigative teams planned a combined analysis before ELAAT was activated. Methods: The PSA failures from TOAD and 78/79 patients accrued to ELAAT were combined (1 patient was excluded due to castrate resistant prostate cancer (CRPC)). Participants for both trials were randomized 1:1 to IADT or DADT. The primary endpoint was all-cause mortality by intention-to-treat. Secondary endpoints were cancer-specific mortality (CSM), local progression, distant progression, CRPC, and prostate cancer complications (PCC). Results: 261 patients from TOAD and 78 patients from ELAAT were followed a median of 5.0y. TOAD patients were younger (mean age 70.5 vs 73.8y) and more had a relapse-free interval < 2y from RT (30% vs 10%). In the DADT arms, 63% received ADT a median of 1.58y for TOAD; 38% received ADT a median 1.65y for ELAAT. For patients receiving ADT, the mean pre-ADT PSAs were 3.52 and 30.2 ng/ml in the IADT and DADT arms of TOAD and 3.98 and 18.1 ng/ml in ELAAT. There were 60 deaths, 40 and 20 respectively. Overall, for IADT and DADT arms the proportions of deaths in each trial were 15%, 11%, 19% and 26%, 27% and 24%. All-cause mortality (HR 0.75, 95% CI 0.40, 1.41; p = 0.37) and CSM (HR 0.57, 95% CI 0.22, 1.49) were not statistically different between IADT and DADT. Time to local progression (survival time ratio 1.97, 95% CI 1.28, 3.04; p = 0.002) and distant progression (survival time ratio 1.28, 95% CI 1.04, 1.58; p = 0.02) was higher while PCC (3.7 v 7.5%, p = 0.06) was lower with IADT. CRPC outcomes will be presented at conference. Conclusions: No difference in OS was detected between IADT and DADT in the combined analysis. A possible explanation is that ELAAT accrued older patients with lower risk of CSM and had a smaller difference in PSA between the IADT and DADT arms.
Subcutaneous daratumumab (DARA) in patients (Pts) with relapsed or refractory multiple myeloma (RRMM): Part 2 update of the open-label, multicenter, dose escalation phase 1b study (PAVO).
Authors: Ajai Chari, Saad Zafar Usmani, Maria-Victoria Mateos, Niels Van De Donk, Jonathan L. Kaufman, Philippe Moreau, Albert Oriol Rocafiguera, Torben Plesner, Lotfi Benboubker, Kevin Liu, Peter Hellemans, Tara J. Masterson, Pamela L. Clemens, Andrew Farnsworth, Hareth Nahi, Jesus San-Miguel
Journal: Journal of Clinical Oncology (2018)

8013 Background: Intravenous (IV) administration of DARA 16 mg/kg is approved as monotherapy and in combination with standard of care regimens for RRMM. The phase 1b PAVO study (NCT02519452) demonstrated that delivery of DARA with recombinant human hyaluronidase enzyme (rHuPH20) by subcutaneous (SC) infusion through a syringe pump (Part 1) or by manual SC injection (Part 2) was well tolerated with an efficacy profile consistent with IV DARA (Chari A, et al. ASH 2017; abstract 838). We present updated data from Part 2. Methods: Eligible pts received ≥2 prior lines of therapy (LOTs) including a proteasome inhibitor and an immunomodulatory drug. In Part 2, pts received a concentrated co-formulation of DARA (DARA SC; 1,800 mg in 15 mL) and rHuPH20 (30,000 U) dose in a single, pre-mixed vial, which was administered in 3 to 5 minutes by manual SC injection. Primary endpoints were Ctrough of DARA at the end of weekly dosing on Cycle 3 Day 1 (C3D1) and safety. Secondary endpoints included overall response rate (ORR), rate of complete response, time to response, and duration of response. Results: Pts in Part 2 (n = 25) had a median age of 68 years and received a median of 3 prior LOTs. At a median follow-up of 4.6 months, none discontinued due to treatment-emergent adverse events (TEAEs). Pharmacokinetic analyses indicated that DARA SC had a Tmax of approximately 72 h and achieved similar or greater Ctrough on C3D1 compared to what has been observed with DARA IV. Most common Grade 3/4 TEAEs ( > 1 pt) were lymphopenia (16%), thrombocytopenia (8%), and neutropenia (8%). IRRs were reported in 3 (12%) pts, all occurring ≤6 h of the first injection. No grade 4 IRRs or discontinuations due to IRRs occurred. DARA SC injections in the periumbilical area were well tolerated with reversible erythema observed in 20% of pts. DARA SC achieved an ORR of 44%, including 28% ≥very good partial response. Conclusions: DARA SC, which enables dosing in 3-5 minutes, was well tolerated with low IRR rates, had an acceptable PK profile, and demonstrated clinical response rates similar to DARA-IV. Updated data based on longer follow-up will be presented at the meeting. Clinical trial information: NCT02519452.
Outcomes by CD30 expression in patients with CTCL receiving brentuximab vedotin (BV) vs physician's choice (PC) in the Phase 3 ALCANZA study.
Authors: Youn H. Kim, H. Miles Prince, Sean Whittaker, Steven M. Horwitz, Madeleine Duvic, Julia Scarisbrick, Pietro Quaglino, Pier Luigi Zinzani, Pascal Wolter, Oliver Bechter, Yinghui Wang, Maria Corinna Palanca Wessels, Kenneth W. Wood, Martha Li, Yi Liu, Hui-Min Lin, Meredith Little, Hadi Danaee, William L. Trepicchio, Reinhard Dummer
Journal: Journal of Clinical Oncology (2017)

7517 Background: The Phase 3 ALCANZA study showed significant, durable responses with CD30-directed antibody-drug conjugate BV vs PC of methotrexate (MTX) or bexarotene (Bex) for CD30-positive (CD30+) cutaneous T cell lymphoma (CTCL). Uniform CD30 expression is characteristic of primary cutaneous anaplastic large cell lymphoma (pcALCL), but is variable among other subtypes including mycosis fungoides (MF). We examined activity of BV and MTX / Bex by CD30 expression in pts treated on the ALCANZA study. Methods: Adults with previously treated CD30+ MF or pcALCL were enrolled. MF pts had ≥2 skin biopsies from separate lesions, pcALCL had ≥1. Patients were scored CD30+ if ≥1 biopsy had ≥10% CD30+ lymphoid cells using an investigational Ventana diagnostic test, centrally assessed by one pathologist. We compared the proportion of MF subgroup pts (n=50 per treatment arm) with objective response lasting ≥4 months (ORR4; ALCANZA primary endpoint) and PFS in pts with all biopsies ≥10% CD30+ (CD30 min ≥10%) vs ≥1 biopsy &lt;10% CD30+ (CD30 min &lt;10%). Pts were randomized 1:1 to BV 1.8 mg/kg IV, Q3W, or PC for up to 16 three-week cycles. Results: 125/184 (68%) MF and 44/47 (94%) pcALCL pts were screened and scored CD30+. High inter-lesional variability in CD30 expression was seen in MF pts; 55/125 CD30+ MF pts (44%) had ≥1 biopsy with low (&lt;10%) or undetectable CD30. 100/125 CD30+ MF pts were eligible and enrolled. In the BV arm, ORR4 was higher in MF pts with CD30 min ≥10% vs &lt;10%; median PFS with BV was higher in the CD30 min &lt;10% group (Table). ORR4 with BV was greater than PC over all CD30 expression ranges (CD30 min &lt;5%, 38% vs 13%; CD30 ≥5–≤20%, 35% vs 10%; CD30 &gt;20%, 76% vs 7%, respectively). Conclusions: Notable inter-patient or inter-lesional variability in CD30 expression was seen in MF pts. Highly superior ORR4 and PFS endpoints were seen with BV over PC regardless of CD30 min expression level. Clinical trial information: NCT01578499. [Table: see text]
PD-1/PD-L1 interaction and CD25/FOXP3+ t cells to predict survival benefit from adjuvant chemotherapy in early stage non–small-cell lung cancer (ES-NSCLC).
Authors: Jennifer Bordeaux, Naveen Dakappagari, Nathan A. Pennell, James Stevenson, Monica Khunger, Christine Vaupel, Kurt A. Schalper, David L. Rimm, Vamsidhar Velcheti
Journal: Journal of Clinical Oncology (2018)

12059 Background: Adjuvant chemotherapy (ACT) for ES-NSCLC provides only a modest improvement in survival and is associated with serious adverse effects. Thus, identifying subgroups of ES-NSCLC patients who will benefit from ACT is of high clinical relevance. Utilizing novel digital pathology algorithms, we evaluated relationship between pre-treatment tumor immune microenvironment and survival benefit from ACT in ES-NSCLC patients. Methods: 451 tissue sections of formalin-fixed, paraffin embedded surgical resection specimens from ES-NSCLC patients with/without ACT were tested with multiplexed fluorescence immunohistochemistry assays designed to detect key immune cell markers such as PD-1, PD-L1, CD4, CD8, CD25, FOXP3 and Ki67. Fluorescence Images were acquired on the Vectra platform (Perkin Elmer) and analyzed with novel AQUA algorithms designed to accurately measure the co-localization of PD-1 and PD-L1 (the Interaction Score), regulatory (CD25+/FOXP3+) and activated (Ki67+) T cell subsets. Results: High PD-1/PD-L1 Interaction Scores (≥ 643) and regulatory T cell burden (≥ 1%) in pre-treatment tumors exhibited significant correlations with improved recurrence free (p = 0.003) and overall survival (p = 0.004) in patients receiving ACT after surgery, whereas no difference in survival was observed for patients who received surgery alone (p > 0.5). Median RFS was not reached in signature positive patients vs 93.2 months in signature negative patients. Interestingly, the levels of PD-1 or PD-L1 alone did not predict survival for surgery + ACT or surgery alone patient populations. Conclusions: PD-1/PD-L1 Interaction Score and CD25/FOXP3 positive T cells are predictive of benefit from ACT in patients with ES-NSCLC. Future studies will determine if these biomarker signatures can be used to select patients that may be spared chemotherapy without compromising outcome.
The FOXC1/FBP1 signaling axispromotes tumorigenicity by enhancing the Warburg effect in colorectal cancer.
Authors: Dawei Li, Qingguo Li, Sanjun Cai, Keping Xie
Journal: Journal of Clinical Oncology (2017)

e15123 Background: Aberrant expression of Forkhead Box transcription factors plays vital roles in the oncogenesis and metastasis of many types of cancer. The purpose of this study is to elucidate the function of Forkhead Box C1(FOXC1) in colorectal cancer (CRC)malignancy maintenance. Methods: FOXC1 expression in CRC specimens was analyzed in the TCGA database and validated by immunohistochemistry using a tissue microarray (TMA). The effect of FOXC1 expression on cancer proliferation and glycolysis was assessed in cells by altering the expression of FOXC1 in vitro and in vivo. Mechanistic investigation was carried out by using cell and molecular biology approaches. Results: FOXC1 was found to be overexpressed in CRC specimens compared with that in the adjacent benign tissues. Univariate survival analyses of the TCGA and validated cohorts showed that high expression of FOXC1 was significantly correlated with shortened patient survival ( P&lt; 0.05). Attenuation of FOXC1 expression inhibited proliferation, clone formation and decreased glucose consumption and lactate production. By contrast, overexpression of FOXC1 had the opposite effect. Furthermore, increased FOXC1 expression downregulated the expression of a key glycolytic enzyme,fructose-1, 6-Bisphosphatase 1 (FBP1). Mechanistically, FOXC1 bound directly to the promoter regions of the FBP1 gene and negatively regulated its transcriptional activity. Aberrant FBP1 expression contributes to CRC tumorigenicity, and decreased FBP1 coupled with increased FOXC1 provided better prognostic information than FOXC1 did alone. Conclusions: The FOXC1/FBP1 axis induces cell proliferation, reprograms the metabolic process in CRC and provides potential prognostic predictors and therapeutic targets for patients with CRC.
Effectiveness of self-help workbook intervention on quality of life in cancer patients receiving chemotherapy: Results of a randomized controlled trial.
Authors: Toshimi Takano, Ayako Matsuda, Noriko Ishizuka, Yukinori Ozaki, Koichi Suyama, Yuko Tanabe, Yuji Miura, Eisuke Matsushima
Journal: Journal of Clinical Oncology (2016)

10070 Background: Cancer patients receiving chemotherapy experience physical and psychosocial distress that negatively influences quality of life (QOL). Self-help workbook is expected to support them to cope with the distress, to facilitate communication with medical staff, and to improve QOL. We conducted a randomized controlled trial to evaluate the effectiveness of self-help workbook intervention on QOL. Methods: Japanese patients with breast, colorectal, gastric, and lung cancer receiving chemotherapy on an outpatient basis were randomized to the intervention arm or the control arm. In the intervention arm, patients received workbooks originally made for this study, read advice on how to cope with problems related to disease or treatment, and filled out questionnaires on the workbooks periodically. In the control arm, patients were treated with standard care without the workbooks. EORTC QLQ-C30, cancer site-specific modules (EORTC QLQ-BR23, CR29, STO22, or LC13), and HADS were evaluated at baseline, after 12 weeks, and after 24 weeks. The primary outcome measure was global QOL (GQOL). Two-way repeated-measures analysis of variance was used to investigate the intervention effect. Results: From June 2014 to March 2015, 200 patients were enrolled to this study. Median age was 58 years (range 28-83), 81% of patients were female, 65% metastatic disease, 68% breast, 23% colorectal, 5.5% gastric, and 3.5% lung cancer. 90% of 100 patients in the intervention arm and 91% of 100 patients in the control arm completed questionnaires at all the time points. At baseline, after 12 weeks, and after 24 weeks, mean scores of GQOL were 68, 64, and 64 in the intervention arm and 63, 61, and 61 in the control arm, respectively. GQOL did not significantly improve in the intervention arm as compared with in the control arm. Among patients with non-metastatic disease, emotional functioning scores of EORTC QLQ-C30 tended to improve in the intervention arm. Conclusions: Although self-help workbook intervention was feasible in cancer patients receiving chemotherapy on an outpatient basis, the effect of the intervention on QOL was limited in this study. Clinical trial information: UMIN000012842.
Draft genome sequence of wild Prunus yedoensis reveals massive inter-specific hybridization between sympatric flowering cherries
Authors: Seunghoon Baek, Kyung Choi, Goon-Bo Kim, Hee-Ju Yu, Ara Cho, Hoyeol Jang, Changkyun Kim, Hyuk-Jin Kim, Kae Sun Chang, Joo-Hwan Kim, Jeong-Hwan Mun
Journal: Genome biology (2018)

Hybridization is an important evolutionary process that results in increased plant diversity. Flowering Prunus includes popular cherry species that are appreciated worldwide for their flowers. The ornamental characteristics were acquired both naturally and through artificially hybridizing species with heterozygous genomes. Therefore, the genome of hybrid flowering Prunus presents important challenges both in plant genomics and evolutionary biology.We use long reads to sequence and analyze the highly heterozygous genome of wild Prunus yedoensis. The genome assembly covers > 93% of the gene space; annotation identified 41,294 protein-coding genes. Comparative analysis of the genome with 16 accessions of six related taxa shows that 41% of the genes were assigned into the maternal or paternal state. This indicates that wild P. yedoensis is an F1 hybrid originating from a cross between maternal P. pendula f. ascendens and paternal P. jamasakura, and it can be clearly distinguished from its confusing taxon, Yoshino cherry. A focused analysis of the S-locus haplotypes of closely related taxa distributed in a sympatric natural habitat suggests that reduced restriction of inter-specific hybridization due to strong gametophytic self-incompatibility is likely to promote complex hybridization of wild Prunus species and the development of a hybrid swarm.We report the draft genome assembly of a natural hybrid Prunus species using long-read sequencing and sequence phasing. Based on a comprehensive comparative genome analysis with related taxa, it appears that cross-species hybridization in sympatric habitats is an ongoing process that facilitates the diversification of flowering Prunus.
Smoking cessation after a cancer diagnosis and survival in cancer patients.
Authors: Graham W. Warren, Anthony Alberg
Journal: Journal of Clinical Oncology (2018)

1561 Background: Extensive literature confirms that continued smoking by cancer patients and survivors increases overall mortality, but the benefits of smoking cessation specifically after a cancer diagnosis has not been well described. Methods: Comprehensive evaluation of all Pubmed studies identified using “smoking” and “cancer” published since 2000 was performed to identify all studies with at least 100 patients reporting on the effects of smoking cessation after a cancer diagnosis on overall mortality. Studies that evaluated the exclusive or combined effects of smoking cessation before a cancer diagnosis were not included. Results: Ten (10) studies were identified that met all inclusion criteria including 7 prospective and 3 retrospective studies. The effects of smoking cessation were evaluated for lung cancer patients in 4 studies, head/neck cancer patients in 3 studies, breast cancer patients in 1 study, and multiple cancers in 2 studies. In 3 prospective studies, continued smoking increased risk of overall mortality as compared with never smoking and quitting smoking had an intermediate risk between continued smoking and never smoking. In 7 studies comparing smoking cessation with continued smoking, the median risk of overall mortality in patients who quit smoking was 0.55 (range 0.19-0.92) as compared with continued smoking including 6 of 7 studies with statistically significant reductions in overall mortality risk. Only 1 study reported on overall mortality in cancer patients who were actively enrolled in a smoking cessation program after a cancer diagnosis, and quitting smoking was observed to reduce overall mortality by 44% (HR 0.56, 95% CI 0.36-0.89). Conclusions: Of larger contemporary studies evaluating the effects of smoking cessation after a cancer diagnosis on overall mortality, most demonstrate a significant benefit of quitting smoking.
Cisplatin Every 3 Weeks Versus Weekly With Definitive Concurrent Radiotherapy for Squamous Cell Carcinoma of the Head and Neck
Authors: Joshua M Bauml, Ravi Vinnakota, Yeun-Hee Anna Park, Susan E Bates, Tito Fojo, Charu Aggarwal, Sewanti Limaye, Nevena Damjanov, Jessica Di Stefano, Christine Ciunci, Eric M Genden, Juan P Wisnivesky, Rocco Ferrandino, Ronac Mamtani, Corey J Langer, Roger B Cohen, Keith Sigel
Journal: JNCI Journal of the National Cancer Institute (2018)

Concurrent chemoradiotherapy is an established component of the nonoperative management of locally advanced head and neck squamous cell carcinoma (HNSCC), but the standard dose of 100 mg/m2 cisplatin every 3 weeks is associated with clinically significant toxicity. Interest in a more tolerable regimen has led to the widespread use of weekly lower dose cisplatin, but few randomized trials have compared these approaches. We examined outcomes of patients with stage III–IVb HNSCC treated with definitive intent chemoradiotherapy using either high-dose cisplatin (HDC) or low-dose cisplatin (LDC), using population-based Veterans Affairs data. In an intent-to-treat analysis, patients were assigned to the HDC vs LDC group according to the dose of their first cycle. Variables potentially influencing treatment decisions including cancer site, stage, smoking/alcohol use, and comorbidities were used to generate propensity scores (PS) for the use of HDC. We compared overall survival (OS) by treatment group using Cox regression, adjusting for PS. We then determined the risk of toxicities using PS-adjusted logistic regression. A total of 2901 patients were included in the analysis; 2200 received HDC (mean initial dose 100 mg/m2). The mean initial dose of LDC was 40 mg/m2. After PS adjustment, HDC was not associated with improved OS over LDC (hazard ratio = 0.94, 95% confidence interval = 0.80 to 1.04). Adjusting for PS, HDC was associated with an increased risk of acute kidney injury, neutropenia, dehydration/electrolyte disturbance, and hearing loss. In this large, population-based study of US military veterans, LDC was associated with similar survival to HDC in the nonoperative definitive management of locally advanced HNSCC of the oral cavity, oropharynx, and hypopharynx/larynx. HDC was associated with statistically significantly more toxicity than LDC. Adoption of LDC may reduce toxicity burden while maintaining OS.
A Nomogram to Predict Significant Estimated Glomerular Filtration Rate Reduction After Robotic Partial Nephrectomy
Authors: Alberto Martini, Shivaram Cumarasamy, Alp Tuna Beksac, Ronney Abaza, Daniel D. Eun, Akshay Bhandari, Ashok K. Hemal, James R. Porter, Ketan K. Badani
Journal: European Urology (2018)
OrienX010 oncolytic viral therapy in phase Ic trial of intralesional injection in liver metastases among patients with stage IV melanoma after standard treatment.
Authors: Chuanliang Cui, Bin Lian, Zhihong Chi, Lu Si, Xinan Sheng, Dan Li, Si Ming Li, Bixia Tang, Li Li Mao, Xuan Wang, Li Zhou, Xieqiao Yan, Xue Bai, Jun Guo
Journal: Journal of Clinical Oncology (2017)

e21013 Background: The liver is one of the most common metastases in melanoma pts and associated with extremely poor prognosis. However, effective treatment has not been found. The safety and efficacy of OrienX010, a herpes simplex virus type 1-derived oncolytic immunotherapy with expression of gene encoding human GM-CSF, was tested in phaseⅠc trial of intralesional injection in liver metastases among patients with stage IV melanoma after standard treatment. Methods: We studied safety and efficacy of OrienX010 (8×10 7 pfu/ml, 10ml per injection) q2w by ultrasound guided puncture. Efficacy was evaluated q8w by CT scan. The primary endpoint was toxicity. Secondary endpoints included Objective Response Rate (ORR), Disease Control Rate (DCR) as well as PFS time. Treatment continued until intolerance, or disease progression per Immune Related Response Criteria. Results: From May 2016, 15 pts received OrienX010 intralesional therapy. The median age was 47 y (32, 61), and 53.3% were female. The primary anatomic sites were: 40.0% (6 pts) from ocular, 33.3% (5 pts) from acral, 26.7% (4 pts) from mucosal. Only 1 patient with c-Kit mutation, 14 pts were wide-type in genotype. All pts had received at least one prior therapy, 53.3% (8 pts) had received transcatheter hepatic arterial chemoembolization. 73.3% (11 pts) had multiple liver metastases, 60.0% (9 pts) had extrahepatic metastases such as lung, bone, abdominal, distant lymph node. 60.0% (9 pts) had an elevation of serum LDH. Mean injection times were 6 (4-18). Mean size of all injectable lesions was 30.4mm (10.0-59.0). AEs were all grade 1/2, pyrexia 80.0%, fatigue 33.3%, injection site pain 26.7%, nausea/vomiting 20.0%, hepatotoxicity 20.0%, leucopenia 6.7%. 12 pts were eligible for evaluation till Jan 2017, and the median follow-up time was 6.0 months. ORR was 8.3% (1 PR), DCR was 41.7% (1 PR, 4 SD). Time to response was 8-16 wks, median PFS was 13.3 wks (95%CI 8.3-18.4), OS was not reached. Conclusions: This is the first trial for evaluating OrienX010 of intralesional injection in liver metastases among melanomas. It appears to be tolerable and with a potentially beneficial effect. Phase 2 and combination trial are pending.