tbuckley/cabot-search huggingface dataset:
Baseline tumor size as an independent prognostic factor for overall survival in patients with metastatic melanoma treated with the anti-PD-1 monoclonal antibody MK-3475.
Authors: Richard Wayne Joseph, Jeroen Elassaiss-Schaap, Jedd D. Wolchok, Anthony M. Joshua, Antoni Ribas, F. Stephen Hodi, Omid Hamid, Caroline Robert, Adil Daud, Wen-Jen Hwu, Richard Kefford, Peter Hersey, Jeffrey S. Weber, Amita Patnaik, Dinesh Prasad De Alwis, Andrea Marie Perrone, Soonmo Peter Kang, Scot Ebbinghaus, Keaven M. Anderson, Tara C. Gangadhar
Journal: Journal of Clinical Oncology (2014)

3015 Background: We explored baseline tumor size (BTS) as a prognostic factor in addition to standard prognostic variables for overall survival (OS) in pts with metastatic melanoma treated with MK-3475. Methods: In a phase I clinical trial, 411 pts received MK-3475 2 mg/kg Q3W, 10 mg/kg Q3W, or 10 mg/kg Q2W. Response was assessed every 12 wk by RECIST 1.1 by independent central review. BTS was quantified as the sum of the longest dimensions of all RECIST target lesions. Log-rank, Kaplan-Meier (KM), and Cox proportional hazards regressions were used to identify independent prognostic factors for OS. Cutpoints and combinations of prognostic factors were determined by binary tree analysis. Results: Of the 411 melanoma pts studied, 365 had measurable tumors at baseline and a median follow-up duration of 10 mo as of the 10/18/2013 cutoff date. Median OS was not reached, and 1-y OS was 71% in all 411 pts and 69% in the 365 pts included in this analysis. By univariate analysis, the following traditional factors were associated with OS: elevated LDH, ECOG performance status of 1, and M-stage 1c (Table). BTS (median 97.8 mm, range 10.4-895 mm) was significantly and strongly associated with OS using log-rank tests, Cox models, KM methods, and binary tree analysis. Binary tree analysis provided a cutpoint of 90 mm BTS as an independent factor. While tumor size >90 mm was associated with a worse prognosis, these pts did have a median OS of 14 mo in the combined data set, suggesting they derive benefit from MK-3475. Conclusions: Baseline tumor size is the strongest independent prognostic factor in pts with metastatic melanoma treated with MK3475. If further validated, baseline tumor size could serve as an additional factor when randomizing pts for future clinical trials using anti-PD1 therapies. Clinical trial information: NCT01295827. N = 363 n % Alive at 1 Year [95% CI] HR P value LDH Elevated 135 54.8 [37.8-71.9] 2.33 <0.001 Normal 225 77.2 [69.6-84.9] M-Stage M1c 213 64.9 [54.2-75.6] 1.56 <0.05 Not M1c 152 75.4 [65.5-85.4] ECOG performance status 0 261 74.6 [66.8-82.3] 2.23 <0.001 1 104 55.5 [36.5-74.4] Baseline tumor size >90 194 54.8 [40.4-69.2] 3.51 <0.001 ≤90 171 84.3 [77.4-91.3]
Tacrolimus/Sirolimus Vs. Tacrolimus/Methotrexate for Graft-Vs.-Host Disease Prophylaxis After HLA-Matched, Related Donor Hematopoietic Stem Cell Transplantation: Results of Blood and Marrow Transplant Clinical Trials Network Trial 0402
Authors: Corey Cutler, Brent R. Logan, Ryotaro Nakamura, Laura Johnston, Sung W. Choi, David L Porter, William J Hogan, Marcelo C Pasquini, Margaret L. MacMillan, John R. Wingard, Edmund K. Waller, Stephan A. Grupp, Philip L. McCarthy, Juan Wu, Zhenhuan Hu, Shelly L Carter, Mary M. Horowitz, Joseph H. Antin
Journal: Blood (2012)
Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer
Authors: Sampurna Chatterjee, Lukas C. Heukamp, Maike Siobal, Jakob Schöttle, Caroline Wieczorek, Martin Peifer, Davide Frasca, Mirjam Koker, Katharina König, Lydia Meder, Daniel Rauh, Reinhard Buettner, Jürgen Wolf, Rolf A. Brekken, Bernd Neumaier, Gerhard Christofori, Roman K. Thomas, Roland T. Ullrich
Journal: Journal of Clinical Investigation (2013)
The relationship between the degree of aberrant methylation in colorectal cancer tissue and appearance of tumor-derived DNA in blood.
Authors: Erin L Symonds, Susanne Kartin Pedersen, Rohan Baker, Scott Mansfield, Dawn Bastin, Graeme P Young
Journal: Journal of Clinical Oncology (2017)

579 Background: We have developed a blood test for colorectal cancer (CRC) detecting circulating tumor DNA (ctDNA) by measuring the presence of methylated BCAT1 and IKZF1. This study aimed to compare the levels of methylated BCAT1/IKZF1 in tissue from patients with colorectal cancer to those in blood before and after tumor resection. Methods: 80 people with invasive CRC had blood collected prior to resection. Tumor and adjacent non-tumor colorectal tissue was collected at surgery. Five patients had tissue collected from secondary cancers in the liver. Additional blood samples were collected within a year of surgery from 45 of these patients. DNA was extracted from all samples and assayed for methylated BCAT1 and IKZF1 DNA. Results: The median % BCAT1 and IKZF1 methylation in colorectal tissues were 45.7% and 59.9% (tumor), and 4.8% and 0% (non-tumor), p &lt; 0.001. Median methylation levels in secondary tumors of the liver were 4.9% for BCAT1 and 29.5% for IKZF1, compared to 0% for both biomarkers in non-tumor liver tissue (p &lt; 0.01). The methylation levels did not differ across CRC stages (p &gt; 0.05), whereas the detection of ctDNA in the blood was significantly associated with tumor staging (p &lt; 0.01). Of the 21 ctDNA positive CRC patients, 18 (86%) tested negative post resection. Of the 3 that remained blood positive post resection, further cancers were confirmed in two (one with recurrence in the lung, one with thyroid cancer). Conclusions: Aberrant BCAT1 and IKZF1 methylation is an early event in CRC development and is localised to the tumor tissue. Methylated BCAT1 and IKZF1 in blood are dependent on tumor stage and measuring minimal residual disease by detecting ctDNA based on methylated BCAT1 and IKZF1 may inform completeness of tumor resection.
Association of serum levels of the growth factor GP88 with disease progression in breast cancer patients
Authors: G. Serrero, K. Tkaczuk, M. Zhan, N. Tait, C. Ilan, D. Eklund, B. Yue
Journal: Journal of Clinical Oncology (2009)

e22021 Background: The autocrine growth factor GP88 is an important player in breast cancer. GP88 is expressed in human BC tumors in correlation with their tumorigenicity. Increased GP88 expression was associated with anti-estrogen therapy resistance in ER+ cells and Herceptin resistance in Her-2 overexpressing breast tumors. Inhibition of GP88 expression inhibited tumor incidence and growth in nude mice. Immunohistochemical studies have shown that GP88 is expressed in invasive ductal carcinomas (IDC) and that high GP88 expression correlated with increased recurrence and mortality. Since GP88 is found in serum, we hypothesized that GP88 was elevated in the sera of breast cancer patients compared to healthy individuals and that GP88 serum level increases with disease progression. Methods: An IRB approved prospective study was established at the University of Maryland Breast Clinic to determine the serum level of GP88 in breast cancer patients (BC pts). Approximately 5 ml of blood was drawn every three months. GP88 serum concentration was determined in triplicate by human GP88 enzyme immunoassay. 190 BC pts were accrued. Sera from healthy volunteers (HV) were obtained to establish GP88 baseline. BC patient characteristics: Caucasian- 91, African American-92, Asian-6; median age, 51 (range 29- 86), stage I - 48, II - 52, III - 26, IV - 63. Results: Median serum GP88 level was 28.7 ng/ml (range 16.6–38.2) in HV, 40.7 ng/ml (range 6.4–100) in early stage (stage 1 -3) BC pts (p- value = 0.007) and 45.3 ng/ml (range 9.8 to 158.4) in stage 4 BC patients (p- value= 0.0007). Statistically significant increase in serum GP88 level was found in early stages as well as in metastatic disease when compared to HV. In addition, patients that were initially diagnosed with early stage disease but recurred showed a 5 to 10 fold increase in their GP88 serum levels. Conclusions: GP88 serum level is significantly higher in the sera of BC than HV subjects. Moreover, GP88 serum level increased in association with disease recurrence and progression. This study identifies GP88 as a measurable biomarker for disease progression not only at the tissue but also at the serum level. These results are also interesting since GP88 is also a therapeutic target of malignant progression of breast carcinoma. No significant financial relationships to disclose.
New safeguards are urgently needed for people with reduced capacity, report says
Authors: Clare Dyer
Journal: BMJ (2017)

A new system of safeguards for people with dementia and severe learning disabilities is urgently needed at a time when tens of thousands are being unlawfully deprived of their liberty, the official law reform body for England and Wales has said.

Many people are not benefiting from the rights that parliament intended them to have because current safeguards are unworkable, the Law Commission said in a report commissioned by the government.1

Deprivation of liberty safeguards were introduced in 2007, requiring local authorities to carry out …
CheckMate 214: A phase III, randomized, open-label study of nivolumab combined with ipilimumab versus sunitinib monotherapy in patients with previously untreated metastatic renal cell carcinoma.
Authors: Hans J. Hammers, Elizabeth R. Plimack, Cora Sternberg, David F. McDermott, James M. G. Larkin, Alain Ravaud, Brian I. Rini, Padmanee Sharma, Prabhu Bhagavatheeswaran, Paul Gagnier, Robert Motzer
Journal: Journal of Clinical Oncology (2015)

TPS4578 Background: Therapeutic options have improved outcomes for patients (pts) with metastatic renal cell carcinoma (mRCC). Nivolumab, a fully human IgG4 programmed cell death-1 immune checkpoint inhibitor antibody, has shown clinical activity in RCC and in other tumor types. In CheckMate 016, a phase I study, nivolumab + ipilimumab demonstrated acceptable safety and encouraging antitumor activity in patients with mRCC (Hammers HJ, et al. J Clin Oncol. 2014;3215 suppl]:4504). This phase III study evaluates nivolumab + ipilimumab compared with sunitinib monotherapy for previously untreated mRCC (NCT02231749). Methods: Adults with advanced or metastatic clear-cell RCC with no prior systemic therapy are eligible. Pts with one prior adjuvant/neoadjuvant therapy (excluding VEGF targeted therapies) following RCC resection are eligible if recurrence occurred ≥ 6 months after the last dose. Other key inclusion criteria include: Karnofsky Performance Status ≥ 70%, measurable disease per RECIST v1.1, and available tumor tissue. Pts with a history of, or current, central nervous system metastases are ineligible. Prior treatment with systemic corticosteroids/immunosuppressants within 14 days before first dose of study drug, or with any agent targeting T cell co-stimulation or checkpoint pathways is not permitted. The study is expected to randomize ~1,070 pts stratified by International mRCC Database Consortium prognostic score (0 vs 1–2 vs 3–6) and region (US vs Canada/Europe vs rest of world). Pts will be randomized to either: i) nivolumab 3 mg/kg intravenously (IV) + ipilimumab 1 mg/kg IV every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg IV every 2 weeks or ii) sunitinib 50 mg orally once daily for 4 weeks followed by 2 weeks off. Treatment will be discontinued for unacceptable toxicity or withdrawal of consent. Pts may continue treatment beyond progression (RECIST v1.1) if investigator-assessed clinical benefit is achieved and treatment is well tolerated. The co-primary endpoints are progression-free survival and overall survival. Secondary endpoints include objective response rate and safety. Clinical trial information: NCT02231749.
A phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone (QUAD) in relapsed and/or refractory multiple myeloma (MM).
Authors: David H. Vesole, David Samuel DiCapua Siegel, Joshua Ryan Richter, Ann McNeill, Palka Anand, Urszula Bednarz, Kristin Ivanovski, Laura McBride, Laura Raucci, Veena Batra, Adolfo Aleman, Taliah Sims, Laura Guerrero, Judith Smith, Anthony R. Mato, Elizabeth Bilotti
Journal: Journal of Clinical Oncology (2014)

8535^ Background: Carfilzomib in combination with an immunomodulatory agent has proven efficacy in NDMM and RRMM. There is also synergistic activity of the combination of a proteasome inhibitor and a histone-deacetylase inhibitor Methods: To determine the toxicity and activity of the quadruplet using carfilzomib with lenalidomide, vorinostat and dexamethasone. The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of QUAD. Secondary objectives included ORR, DOR, TTP and TTNT. All patients had relapsed or RRMM after at least one line of Tx. Tx consisted of 28-d cycles of lenalidomide d 1-21, vorinostat d 1-7 and 15-21, IV carfilzomib d 1, 2, 8, 9, 15 and 16 and IV/po dexamethasone 40 mg q wk. A standard 3+3 dose escalation schema to determine DLTs occurring in Cycle 1. AEs were graded using the NCI-CTCAE v3. Response was assessed by the modified IMWG criteria. Results: As of January 20, 2014, 21 pts have been enrolled: 1 patient was replaced due to inability to complete Cycle 1 due to AE. Pt characteristics included: median age 61 yrs (range 48-71), 57% male, median # of prior regimens: 3 (range 1-9), median time from Dx: 4 years. All pts had prior autotransplant, 20 bortezomib, 20 lenalidomide and 4 vorinostat. AEs were experienced by 100% of pts including: anemia (16), fatigue (11), thrombocytopenia (14), neutropenia (12), muscle cramping (10) and diarrhea (9). 15 pts experienced ≥ grade 3 AEs: neutropenia (9), anemia (7), thrombocytopenia (9), infection (2), electrolyte imbalances (2), hyperglycemia (3), fatigue (1) constipation (1) and 1 death from progressive disease (PD). No DLTs were observed. The ORR was 53% and the CBR was 82%. 2 patients had PD as best response. 9 pts discontinued due to PD, 1 pt choice and 1 pt due to toxicity. 3 pts have completed 18 cycles. Conclusions: QUAD is well tolerated in both relapsed and RRMM pts with no DLTs identified. The safety profile is manageable. The ORR of 53% and CBR of 82% are encouraging; the PFS is 12 months and OS not reached. Clinical trial information: NCT01297764. Cohort Pts Car Len Vor Dex ORR 1 4 15 15 300 40 3 SD 1 NE 2 3 20 15 300 40 3 PR 3 3 20 25 300 40 1 VGPR 1 PR 1 SD 4 4 20/27 25 300 40 1 VGPR 2 PR 1 PD 5 3 20/27 25 400 40 1 PR 1 SD 1 PD
Predictors of mortality in metastatic papillary renal cell cancer.
Authors: Abhinav Sidana, Amit L Jain, Meet Kadakia, Spencer Krane, Julia C. Friend, Akhil Muthigi, Martha Ninos, Joanna H. Shih, Ramaprasad Srinivasan
Journal: Journal of Clinical Oncology (2017)

509 Background: While studies have established several prognostic factors determining mortality in metastatic clear cell renal cell cancer patient, similar analysis has been lacking in metastatic papillary renal cell cancer (pRCC) patients. We aim to determine the predictors of mortality in metastatic pRCC patients. Methods: Retrospective evaluation of the medical records of patients with metastatic pRCC seen at National Cancer Institute (2000-2014) was undertaken. Patient demographics, tumor characteristics, and outcomes were studied. Kaplan-Meier Survival analysis was done to estimate overall survival (OS). Cox proportional-hazards regression analysis was done to identify predictors of All cause mortality (ACM) in this population. Results: 106 consecutive patients with metastatic pRCC were identified. The median age and follow up time after the diagnosis of metastases was 50 years (11-80) and 33.8 mon (2.3-246.7) respectively. Twenty one (19.8%) and 42 (39.6%) patients had papillary type 1 and papillary type 2 renal cancers respectively; in 43 (40.5%) patients, tumors were classified as papillary, not otherwise specified. Half (53) of patients had hereditary origin of pRCC. Median estimated OS of entire cohort was 37.5 mon. There was no difference in survival between patients with hereditary or sporadic pRCC (p = 0.80) or among patients with different subtypes of pRCC (p = 0.79). On univariate analysis, elevated serum corrected calcium elevated lactate dehydrogenase, Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, and presence of malignant ascites significantly affected the patients’ prognosis. Corrected Calcium (p = 0.03) and NLR (p = 0.004) were found to be independent predictors of ACM on multivariate analysis. Conclusions: To our knowledge, this is the largest single center series evaluating survival and predictors of survival in metastatic pRCC. Metastatic pRCC patients with elevated NLR and serum corrected calcium are significantly associated with relatively poor OS when compared to patients without these findings. If validated in larger multi-institutional cohorts, it might be reasonable to incorporate corrected calcium and NLR in nomograms predicting ACM in metastatic pRCC.
Lower PSA at 7 months is prognostic for improved overall survival (OS) in metastatic hormone sensitive prostate cancer (mHSPC) treated with ADT with and without docetaxel (D).
Authors: Lauren Christine Harshman, Yu-Hui Chen, Glenn Liu, Michael Anthony Carducci, David Frazier Jarrard, Robert Dreicer, Noah M. Hahn, Jorge A. Garcia, Maha Hussain, Daniel H. Shevrin, Mario A. Eisenberger, Manish Kohli, Yu-Ning Wong, Matthew M. Cooney, Nicholas J. Vogelzang, Joel Picus, Robert S. DiPaola, Christopher Sweeney
Journal: Journal of Clinical Oncology (2017)

137 Background: Prior work from SWOG 9346 revealed that PSA ≤ 0.2 ng/dL at 7 months (mo) is prognostic for longer OS with ADT alone. We sought to evaluate if this optimal decline remained predictive of better OS when D was added to ADT for initial mHSPC treatment. Methods: We performed a landmark survival analysis at 7 mo using the E3805 database (NCT00309985). Inclusion required at least 7 mo of followup and PSA levels at 7 mo from ADT initiation. Survival was defined from ADT start or randomization to death. SWOG 9346 PSA nadirs of ≤ 0.2, &gt; 0.2-4 and &gt; 4 were used as classifiers. Results: 719 patients were eligible for analysis: 358 treated with ADT plus D and 361 with ADT alone. Median follow-up was 23.1 mo. On multivariable analysis (MVA), achieving a PSA ≤ 0.2 at 7 mo was more likely if the patient received D and had lower volume disease, prior local therapy, and lower baseline PSAs (all p ≤ 0.01). Across all patients, median OS was significantly longer if PSA at 7 mo reached ≤ 0.2 compared to &gt; 4 (p &lt; 0.0001) (Table). On MVA, PSA ≤ 0.2 at 7 mo and low volume disease were prognostic of longer OS (all p &lt; 0.01). On ADT, 28.8% achieved a PSA ≤ 0.2 at 7 mo vs. 45.3% on ADT+D. Patients on ADT alone who achieved a PSA nadir ≤ 0.2 had the best survival. These patients were more likely to have low volume disease (56.7%) compared to the ADT + D pts (46.3%). Conclusions: Achieving PSA ≤ 0.2 at 7 mo remains prognostic for longer OS with ADT for mHSPC, whether administered alone or with D. Adding D to ADT increased the likelihood of a lower PSA and improved survival. Partial support and drug supply by Sanofi. Clinical trial information: NCT00309985. [Table: see text]
A phase II study of enzalutamide (Enz) with dutasteride (Dut) or finasteride (Fin) in men ≥ 65 years with hormone-naive systemic prostate cancer (HNSPCa).
Authors: Deepak Kilari, Elizabeth A. Guancial, Deepak M. Sahasrabudhe, Kathryn A. Bylow, John D. Burfeind, Kaylinn Musto, Changyong Feng, Edward M. Messing, Supriya Gupta Mohile, Chunkit Fung
Journal: Journal of Clinical Oncology (2017)

179 Background: Older men are at a high risk for adverse events (AEs) from androgen deprivation therapy (ADT). In prior studies, peripheral androgen blockade with bicalutamide and Fin was better tolerated but less efficacious than ADT in HNSPCa. The potential syngerism of Enz (a potent antiandrogen) and Dut/Fin (5-a reductase inhibitors for conversion of testosterone [T] to dihydrotestosterone [DHT]) provided the rationale for this Phase II study that examined the clinical efficacy and safety of Enz with Dut/Fin in men &gt; 65 years with HNSPCa. Methods: Eligible patients were &gt; 65 years (y) ; at a high risk of AE from ADT by comprehensive geriatric assessment or treating physicians; had metastatic (M1) or biochemical recurrent (M0) HNSPCa with a PSA doubling time &lt; 9 months; and had T &gt; 50ng/dl. They received Enz (160mg daily) and Dut (0.5mg daily) or Fin (5mg daily) until disease progression according to the Prostate Cancer Working Group 2 guidelines. The primary study endpoint is time to PSA progression. The secondary endpoints are time to PSA nadir and treatment-related AEs. Results: As of July 31, 2016, 24 patients were screened (3 ineligible) and 21 were enrolled with a median follow-up of 31 weeks (7-79). Median age at enrollment was 79.5 y (66-94) and 14 %, 72% and 14% had ECOG performance status of 0, 1, and 2, respectively. 57% (n = 12) had M0 and 43% (n = 9) had M1 HNSPCa, with 18%, 62%, 5%, and 10% having Gleason 6, 7, 8, and 9 disease, respectively (5% with unkown Gleason sum). The median PSA at enrollment was 12 ng/ml (2-102). The median time to 90% PSA decline after treatment initiation was 7 weeks (7-20) and 92% achieved 80% DHT decline in 9 months. At the time of analysis, all patients had ongoing PSA decline of &gt; 90% without radiographic evidence of disease progression. Common Grade 1 AEs included gynecomastia (28%), fatigue (28%), hot flashes (19%) and paresthesias (15%). One patient withdrew from the study due to Grade 2 paresthesia. None had Grade 3 or 4 treatment-related AEs. One patient died due to colitis unrelated to study treatments. Conclusions: Enz with Dut/Fin appears to have clinical activity for older patients with M0 and M1 HNSPCa with acceptable side effects. Clinical trial information: NCT02213107.