tbuckley/cabot-search huggingface dataset:
TheraP: A randomized phase II trial of [<sup>177</sup>Lu]-PSMA-617 theranostic versus cabazitaxel in progressive metastatic castration-resistant prostate cancer.
Authors: Michael Hofman, Louise Emmett, John A Violet, Nicola Jane Lawrence, Scott Williams, Martin R. Stockler, Roslyn J Francis, Amir Iravani, Alison Yan Zhang, Andrew James Martin, Arun Azad, Sonia Yip, Ailsa Langford, Margaret Mary McJannett, Ian D. Davis
Journal: Journal of Clinical Oncology (2019)

TPS332 Background: Lutetium-177 [ 177 Lu]-PSMA-617 is a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), which is commonly overexpressed in prostate cancer. This treatment has demonstrated promising activity and tolerability in men progressing after multiple lines of chemotherapy and endocrine therapy. This trial will determine the activity and safety of 177 Lu-PSMA-617 compared to cabazitaxel chemotherapy in men with progressive metastatic castrate resistant prostate cancer. Methods: TheraP is an open-label, randomised, two-arm, multi-centre, phase 2 trial comparing the activity and safety of experimental treatment with [ 177 Lu]-PSMA-617 versus standard 2 nd line chemotherapy with cabazitaxel. Key eligibility criteria include prior chemotherapy with docetaxel; rising serum PSA; sufficient PSMA avidity according to central reviewed of imaging with PSMA PET/CT and FDG PET/CT; no discordance between FDG PET and PSMA PET. The trial will include 200 participants randomised in a 1:1 ratio to either [ 177 Lu]-PSMA-617 intravenously every 6 weeks, 8.5 GBq for cycle 1, decreasing by 0.5 GBq with each subsequent cycle, up to maximum 6 cycles (experimental group); or, chemotherapy with cabazitaxel (20 mg/m 2 ) intravenously every 3 weeks, for 10 cycles (standard group). In the event of an exceptional response to [ 177 Lu]-PSMA-617, according to centrally-reviewed, post-therapy SPECT imaging, treatment is suspended but can recommence subsequently on progression. The primary endpoint is a 50% or greater reduction from baseline in serum PSA. Secondary endpoints include overall survival, progression-free survival (PFS), PSA-PFS, pain-PFS, radiographic-PFS, health-related quality of life, pain response, and adverse events. The outcomes of patients excluded because of discordant disease on FDG PET and PSMA PET will be reported as a tertiary objective. The study has accrued 79 of 200 planned participants from 29 January 2018 to 23 October 2018. Clinical trial information: NCT03392428.
Correlation of expression Ki-67 and ERCC-1 with survival and treatment strategy in head and neck squamous cell cancer.
Authors: Georgy M. Manikhas, Svetlana I. Kutukova, Andrey I. Yaremenko, Natalia P. Belyak
Journal: Journal of Clinical Oncology (2015)

e17075 Background: Taking decision about treatments tactics is a main strategic aim for patient with HNSCC. The purpose of our study was investigate some correlation between level of predictive markers, treatment options and PFS for this patient’s cohort. Methods: In the retrospective study were 39 patient with HNSCC (I-III stage). All patient were under complex protocol (induction chemotherapy (DCF, PF), resection of primary tumor and regional dissection, and postoperative RT). All patients were under our supervision from 2009 to 2014. We studied clinical stage, level of expression Ki-67, ERCC-1, their correlation with PFT and treatment protocol. Results: The average PFS by 22 patient was 4.45 months, OS - 47.97 month (group A). 17 patient (groupB) hadn’t evidence of progression (OS 54.4 month at jan-2015). In groupA we registered next levels of Ki-67 expression: 77.27% patients - medium-low (20-50%), 18.18% - low ( < 20%), 4.55 - high ( > 70%); ERCC-1 expression: 81.82% - high (0-33%), 18.18% - medium (34-66%) and 0% - low. In groupB: 82.35% - medium-high (50-70%) Ki-67, 11.76% - low and 5.88% - high level; ERCC-1 expression was: 70.59% - medium, 23.53% - high and 5.88% - low expression of ERCC-1. Examination of correlation let us identified next relations: 64.71% patients in groupB had medium-low Ki-67 expression + medium ERCC-1 expression, 11.76% - medium-low Ki-67 + high ERCC-1, 1 by1 patient (5.88%) had: low Ki-67 + high ERCC-1, medium-low Ki-67 + low ERCC-1 and high Ki-67 + high ERCC-1. In groupA (with recurrence) 59.9% patients had medium-high expression Ki-67 + high ERCC-1, 18.18% - low Ki-67 + high ERCC-1, 13.64% - medium-high Ki-67 + medium ERCC-1, 1 by 1 (4.55%) - high Ki-67 + medium and high expression ERCC-1. Conclusions: Patients with I-III stage HNSCC with medium-high (50-70%) expression of Ki-67 combined with high level of ERCC-1 had high risk of recurrence and induction chemotherapy can be excluded from treatment options for this cohort. Combination of medium-low (20-50%) expression Ki-67 + medium ERCC-1, low Ki-67 + any ERCC-1, medium Ki-67 + low ERCC-1 had correlation with good prognosis for OS and in this cohort we can use platinum-based induction chemotherapy (even ERCC-1 level of expression is medium).
Sites of metastases (mets) and their association with clinical outcomes (CO) in urothelial cancer patients (pts) treated with immunotherapy (IO).
Authors: Julie M. Shabto, Dylan J Martini, Yuan Liu, Deepak Ravindranathan, Meredith R Kline, Elise Hitron, Greta Russler, Sarah Caulfield, Haydn Kissick, Mehrdad Alemozaffar, Kenneth Ogan, Wayne Harris, Viraj A. Master, Omer Kucuk, Bradley Curtis Carthon, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2019)

473 Background: Several IO agents have been approved for treatment of advanced urothelial cancer pts. We investigated the association between sites of mets and CO in urothelial cancer pts treated with IO in the real world setting. Methods: We performed a retrospective review of 67 urothelial cancer pts treated with PD-1 or PD-L1 inhibitors at Winship Cancer Institute from 2015-2018. Overall survival (OS) and progression free survival (PFS) were measured from first dose of IO to date of death or hospice referral and radiographic or clinical progression, respectively. Sites of mets were collected from radiology and clinic notes at baseline. Univariate analysis (UVA) and multivariable analysis (MVA) used Cox proportional hazard. Results: The median age was 70 and most (79.1%) were men. Pts had mets to sites such as lymph node (73.1%), bone (29.9%), liver (20.9%), lung (31.3%), and brain (1.5%). Pts with bone or liver mets had significantly shorter OS and PFS in UVA. Pts with bone mets also had significantly shorter OS and PFS in MVA (Table). The median OS of pts with bone mets was 2.2 months (12-month survival=28.0%), while those without bone mets had a median OS of 21.9 months (12-month survival=52.5%) per Kaplan-Meier estimation. The median OS of pts with liver mets was 2.2 months (12-month survival=28.6%), while those without liver mets had a median OS of 12.8 months (12-month survival=50.1%) per Kaplan-Meier estimation. Conclusions: Bone and liver mets are poor prognostic factors in urothelial cancer pts receiving IO in the real world setting. These findings should be validated in a larger study. [Table: see text]
Abstract MP56: Length of Stay and Allostatic Load in Immigrants to the United States-Evidence From the 2011 - 2016 National Health and Nutrition Examination Surveys
Authors: Ruth-Alma N Turkson-Ocran, Nwakaego A Nmezi, Nancy Perrin, Yvonne Y Commodore-Mensah, Sarah L Szanton
Journal: Circulation (2019)

Introduction: Stress alters the cardiometabolic and inflammatory systems. Allostatic load, a measure of chronic and cumulative stress is associated with cardiovascular events and mortality. Immigration is known to be a stressful experience; however, it is unclear how length of stay, a proxy for acculturation, is associated with allostatic load in US immigrants. Hypothesis: We hypothesized that greater length of stay will be associated with higher allostatic load among US immigrants. Methods: We used a cross-sectional design to examine the 2011-2016 National Health and Nutrition Examination Surveys. Allostatic load was defined by a count of the number of high-risk classifications for 10 cardiovascular, metabolic, and immune system biomarkers: systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, glycated hemoglobin, albumin, creatinine clearance, body mass index, waist circumference, and white blood cells. Logistic regression was used to examine the odds of a high allostatic load score (≥ 4) as in previous literature, adjusting for survey weights. Results: We included 7318 immigrants with mean age (±se) 44(±0.52); 49% were male. Half of the sample was of Mexican/Hispanic origin, 26% were Asian and 7% were Black. The median allostatic load score was 2.2. The odds of high allostatic load decreased with longer stay in the US. After adjusting for age, race, education, income, insurance status, and routine place for healthcare, those who had resided in the US for 10 to 20 years were 45% (95% CI: 1.1-1.9) more likely to have a high allostatic load than those who had been in the US &lt;10 years. The unadjusted and adjusted results are presented in the Table. Conclusion: Length of stay in immigrants is associated with having a high allostatic load. The odds of increased allostatic load declines with longer length of US residence. Additional research is needed to further understand the process and impact of cumulative stress among immigrants to reduce racial/ethnic health disparities.
Multidimensional flow characterization of circulating immune cells in cisplatin-resistant metastatic urothelial cancer (mUC) patients (pts) treated with pembrolizumab (P) with or without acalabrutinib (acala).
Authors: Tian Zhang, Janet S. Staats, Cliburn Chan, Ajjai Shivaram Alva, Peter H. O'Donnell, Michael Roger Harrison, Kristen A Batich, Veerendra Munugalavadla, Daniel J. George, Kent J. Weinhold
Journal: Journal of Clinical Oncology (2019)

357 Background: Immunotherapy checkpoint inhibitors (ICIs) are now standard treatments (txs) in mUC, with response rates ranging 15-25%. A phase 2 randomized study (NCT02351739) treated 75 pts with mUC with either P or PA. We profiled peripheral blood mononuclear cells (PBMCs) to understand changes on tx. Methods: Comprehensive immune profiling of PBMCs was performed at baseline, weeks (wk) 4, 7, and 10. The Wilcoxon rank sum (WRS) test was used to compare tx arms, as well as pts with complete and partial response (CR/PR) vs disease progression (PD). Using the Benjamini-Hochberg (BH) method, results were deemed significant if they had false discovery rate (FDR) of 0.1 or less. Results: Clinical responses did not differ between tx arms (Zhang T et al, ESMO, 2017). The majority of patients showed largest immune changes from baseline at wk7. Comparing P vs PA pts, the PA group had statistically significant increases in PD-L1+ monocytes; CD8 T cells expressing: CD39, CTLA-4, ICOS, PD-1, TIM3, HLA-DR, Ki67, CD39/HLA-DR, CD39/Ki67, and PD-1/TIM-3; and exhausted (CD28-) CD8 T cells expressing ICOS and PD-L1 (Table). Comparing CR/PR vs PD pts, Treg subsets expressing CCR4/HLA-DR and CD39/HLA-DR were significant by WRS but not FDR criteria. Conclusions: From this extensive, exploratory, non-functional flow analysis of PBMCs, PA may potentiate immune changes of PD-L1+ monocytes and CD8+ T cell subsets. Increasing activated peripheral Tregs in CR/PR pts in either arm may indicate marginalization of Tregs from the tumor microenvironment. [Table: see text]
Male breast cancer as a second primary cancer (SPC): Increased risk following hematologic malignancies.
Authors: Deborah Elaine Farr, Alexandra Thomas, Sonia L Sugg, William John Gradishar, Seema Ahsan Khan, Mary Chen Schroeder
Journal: Journal of Clinical Oncology (2015)

1583 Background: Male breast cancer accounts for approximately 1% of all breast cancer. The association of male breast cancer with other malignancies has been described; however the risk of males developing breast cancer as an SPC, after specific types of index primary malignancies, relative to population risk, has not been reported. Methods: SEER 9 data was used to identify male breast cancer patients with a prior index malignancy. In the period 1973-2011, the five most common index primary sites included breast, prostate, colorectal, ureter and urinary bladder, and hematologic malignancies (leukemia, lymphoma and myeloma). Standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) of male breast cancer as an SPC were calculated (observed/expected rates) for each of these five most common index malignancies. Excess risk was expressed per 100,000. All analyses were conducted using SEER*Stat software, version 8.1.5. Results: Over a 38-year period, 512 male breast cancers were identified as second primary malignancies. The most common index malignancies were breast (SIR 28.44, 95% CI 20.32-38.73) hematologic (SIR 1.55, 95% CI 1.11-2.10), ureter/urinary bladder (SIR 1.10, 95% CI 0.80-1.46), prostate (SIR 0.97, 95% CI 0.84-1.11), and colorectal (SIR 0.94, 95% CI 0.72-1.21). Apart from the known association with prior breast cancer, the only significant association was with a prior hematologic malignancy (p-value 0.007). 42.6% of SPC breast malignancies occurred within 5 years of the index malignancy. When incidence rates were compared from 1973-1974 to 2010-2011, the rate of primary breast cancer remained stable at 1.15 and 1.11 respectively, while the incidence rate of breast cancer as SPC increased from 0.12 to 0.39, a 225% increase (p-value < 0.001). Conclusions: Compared with the general population, the risk of developing male breast cancer was significantly elevated after initial hematologic malignancies. The risk of developing breast cancer as SPC increased markedly from 1973 to 2011. These observations have implications for clinical surveillance in this population, and point to potential etiologic connections with prior therapy, or with genetics.
Socioeconomic Differences in Referral to Phase I Cancer Clinical Trials: A Danish Matched Cancer Case-Control Study
Authors: Katrine Toubro Gad, Christoffer Johansen, Anne Katrine Duun-Henriksen, Anja Krøyer, Maja Halgren Olsen, Ulrik Lassen, Morten Mau-Sørensen, Susanne Oksberg Dalton
Journal: Journal of Clinical Oncology (2019)

In this nationwide registry study, we investigated socioeconomic and structural patterns in referral to phase I cancer trials in a case-control study design.Personal identification numbers on all Danish patients referred to the Danish Phase I Unit at Rigshospitalet from 2005 to 2016, and a control group matched on age, sex, type of cancer, year of diagnosis, and time from diagnosis to referral ensured individual-level linkage between several registries. We examined the association between nonclinical factors-indicators of socioeconomic position and distance to the Phase I Unit-and referral using a conditional logistic regression analysis adjusted for several clinical factors. Association between nonclinical factors and enrollment once referred was examined with a Cox proportional hazards regression analysis in an historical cohort study design.Complete data were available for 1,026 (84%) of 1,220 referred patients. Significantly decreased odds for referral were identified for patients with long distance to the Phase I Unit compared with short distance (adjusted odds ratio [OR], 0.35; 95% CI, 0.30 to 0.41), for less education (less than 9 years) compared with more (more than 12 years; OR, 0.69; 95% CI, 0.56 to 0.91), and for belonging to the lowest income quintile compared with the highest (OR, 0.78; 95% CI, 0.62 to 0.97). Medium education (9 to 12 years) compared with more, being outside the workforce compared with being within, and living alone compared with living with a partner were also negatively associated with referral. Among patients referred, 252 enrolled in a trial. Nonclinical factors were not associated with enrollment.On the basis of individual long-term registry data from an unselected cohort, novel anticancer therapies seem to be tested on a socially selected group of patients with cancer.
A Nearly Stressful Situation—A Case of Wellens Syndrome
Authors: Daniel Yazdi, Justin Sharim
Journal: JAMA Internal Medicine (2019)

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Overall responses with coordinated pembrolizumab and high dose IL-2 (5-in-a-row schedule) for therapy of metastatic clear cell renal cancer: A single center, single arm trial.
Authors: Jonathan Alexander Chatzkel, Jennifer Swank, Steven Ludlow, Kristina Lombardi, Cortlin Croft, Yesenia Artigas, Yazmin Rodriguez, Tina Terraciano, Sarah Hart, Jennifer Rembisz, Elaine Johnson, Michael J. Schell, Jiqiang Yao, Jingsong Zhang, Mayer N. Fishman
Journal: Journal of Clinical Oncology (2019)

657 Background: Ligation of IL-2 receptor or blockade of PD-1 receptor may change lymphocytes to induce regression of cancers with diverse histology or site of origin. Single agent objective response rates of 14-25% have been reported for IL-2 therapy of metastatic clear cell RCC (ccRCC). A response rate of 33% was observed in pembrolizumab treated ccRCC patients. Nivolumab treated ccRCC patients were observed to have early intratumoral migration of lymphocytes. A case report of IL-2 induced major regression right after no change on nivolumab therapy suggested that combining the two means of lymphocyte stimulation could be effective. Other trials combining IL-2 receptor agonists (NKTR-214) and PD-1 blockade have also reported regression of ccRCC. Distinctive attributes of high dose IL-2 therapy are the required inpatient stay and the durability of the complete responses. Methods: This single-institution, single arm study addresses the safety and feasibility of the combination of IL-2 and pembrolizumab in the treatment of metastatic ccRCC. Subjects are treated on four nine-week blocks, as follows: Pembrolizumab is given on weeks 1, 4, and 7 of each block. Patients are admitted for 5 doses of high dose IL-2 (given over ~ 33 hours/3 days) on weeks 2, 3, 5, and 6 of blocks 2 and 3. Safety is monitored by a Pocock boundary of .05 likelihood of 0.15 dose limiting toxicity rate. The Simon 2-stage alternative hypothesis for the sample size was a 45+% major response rate vs null hypothesis &lt; 20%, at alpha = 0.10, 90% power. Results: No accrual stop for safety was triggered. Thirteen of the first 18 patients responded, substantially exceeding the requirement of 8+/24 combination-treated patients to reject the null. Seven patients responded after receiving pembrolizumab alone, six after starting combination therapy in block 2. Accrual is completed; at 27. Kaplan-Meier analysis projects ORR of 69%, with ORR 90%-lower confidence bound of 55%. Conclusions: The combination of high dose IL-2 and pembrolizumab is feasible, with a high response rate, justifying further exploration of this dual immune treatment of metastatic ccRCC. Clinical trial information: NCT02964078.
Safety and immunogenicity of the optimized cryptic peptide TERT572Y in patients with advanced cancer : a phase I clinical study
Authors: K. Kosmatopoulos, E. Bolonaki, S. Cornet, E. Nikoloudi, P. Kanellou, G. Millaki, J. Menez-Jamet, Ch Christophylakis, M. Spiropoulou, P. Kordopatis, D. Mavroudis, V. Georgoulias
Journal: Cancer Research (2006)

1418  TERT572Y is an optimized cryptic peptide that induces efficient antitumoral T cell cytotoxic immunity but not autoreactivity in vivo in HLA-A*0201 transgenic mice and in vitro in healthy blood donors and prostate cancer patients (J. Clin. Invest., 2004, 113,425). A phase I trial evaluating the safety and immunogenicity of the cryptic TERT572Y peptide was conducted in HLA-A*0201 cancer patients. Forty nine patients with chemotherapy refractory and progressing malignant tumors were enrolled. The vaccination protocol consisted of two subcutaneous injections of optimized TERT572Y peptide in Montanide ISA51 followed by four injections of native TERT572 peptide. Thirty one patients completed the entire vaccination program. The median follow up was 6 months (range 1.4-29.9). Only grade I/II toxicity was observed. TERT572Y-specific cytotoxic T cells were detected. Ex vivo specific tetramer572Y stained CD8+ cells varied from 0.26% to 1.85% (mean: 0.82±0.50%) and ELISPot-detected TERT572 specific CD8+ cells were 0.074+0.033. CTLs were still detectable one year after the sixth vaccination. They were fully functional, recognizing the native TERT572 peptide and killing TERT-overexpressing tumor cells. Fourteen patients (28.6%) experienced stable disease for a median of 10 months (range 5-24). Sixteen (33%) patients died and the median overall survival was 18.7 months (range 1.7-29.9), the 1-year survival rate 74%. In conclusion, TERT572Y peptide vaccine is well tolerated and effective in eliciting a specific T cell immunity. This is the first clinical trial demonstrating that cryptic peptides are promising candidates for cancer immunotherapy.