tbuckley/cabot-search huggingface dataset:
Safety, efficacy, and health-related quality of life (HRQoL) of the investigational single agent orteronel (ortl) in nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Maha Hussain, Paul Gettys Corn, M Dror Michaelson, Hans J. Hammers, Joshi J. Alumkal, Charles J. Ryan, Justine Yang Bruce, Susan Moran, David MacLean, Shih-Yuan Lee, H. Mark Lin, Yanyan Zhu, Hongliang Shi, Peter Mortimer, Daniel J. George
Journal: Journal of Clinical Oncology (2013)

5076 Background: Ortl is a selective, non-steroidal, oral 17,20-lyase inhibitor. Due to its lower inhibition of 17α-hydroxylase vs 17,20-lyase, ortl may allow steroid-free dosing. Ortl 300 mg BID was studied in nmCRPC patients (pts). Methods: Pts with nmCRPC, PSA ≥2 ng/mL (PSA ≥8 ng/mL if doubling time &gt;8 mo), and testosterone (T) &lt;50 ng/dL received ortl 300 mg BID until PSA progression, development of metastases (mets), or unacceptable toxicity. Primary endpoint: the percentage of pts with PSA ≤0.2 ng/mL at 3 mo. Secondary endpoints included safety, PSA kinetics, time to mets, and PFS (PSA progression, mets, or death), endocrine and bone markers, bone mineral density (BMD), HRQoL, cardiac and lipid assessments. Results: 38 pts enrolled: median PSA 11.7 ng/mL (range 2.6–67.8), T 8.5 ng/dL (1.4–17.3), and ACTH 20 ng/L (n=32; 0–47). Median therapy duration was 12.4 mo (0.7–27.8); 55% of pts were treated &gt;12 mo. 6 had dose reduction, 12 discontinued due to adverse events (AEs), including 2 for possible adrenal insufficiency. Gr 3 hypertension occurred in 7 pts (18%); various ≥Gr 3 AEs occurred in another 14 pts; 10 pts (26%) had serious AEs. At 3 mo, median T declined 89% to 0.78 ng/dL; median ACTH increased 171%; median cortisol declined 21%, but remained within normal range. 97% of pts had PSA declines; median PSA declined 83%. 18% had PSA ≤0.2ng/mL at 3 mo; 32% achieved PSA ≤0.2ng/mL as best response. Median time to PSA progression was 13.8 mo. Median PFS was 13.8 mo. Kaplan-Meier estimates of 1 and 2 y mets-free rates were 94% and 69%, respectively; 8 pts developed mets on study. The patient-reported Aging Male Symptoms Scale showed no decrease in overall scores, psychological, somatic, or sexual domains in 37, 34, 25, and 19 pts assessed at visits 2, 4, 7, and 13, respectively. Serum lipids, cardiac assessments, HbA 1C , or bone-specific enzymes (N-telopeptide, or BMD) were not adversely affected. Conclusions: In pts with nmCRPC, long-term steroid-free ortl was feasible, with clinical activity as reflected by sustained marked declines in PSA and T, and had manageable toxicities, with no adverse effects on HRQoL, cardiac, bone or lipid profiles. Clinical trial information: NCT01046916.
Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF-Mutant Metastatic Colorectal Cancer (SWOG S1406)
Authors: Scott Kopetz, Katherine A. Guthrie, Van K. Morris, Heinz-Josef Lenz, Anthony M. Magliocco, Dipen Maru, Yibing Yan, Richard Lanman, Ganiraju Manyam, David S. Hong, Alexey Sorokin, Chloe E. Atreya, Luis A. Diaz, Carmen Allegra, Kanwal P. Raghav, Stephen E. Wang, Christopher H. Lieu, Shannon L. McDonough, Philip A. Philip, Howard S. Hochster
Journal: Journal of Clinical Oncology (2020)

mutations are rarely associated with objective responses to the BRAF inhibitor vemurafenib in patients with metastatic colorectal cancer (CRC). Blockade of
Laparoscopic versus laparotomic cytoreduction in patients with advanced ovarian cancer submitted to NACT: Evaluation of oncologic safety.
Authors: Giovanni Favero, Nathalia Macerox, Tatiana Pfiffer, Altamiro Ribeiro, Vanessa Costa Miranda, Maria Del Pillar Estevez Diz, Edmund Chada Baracat, Jesus Paula Carvalho
Journal: Journal of Clinical Oncology (2014)

5589 Background: Surgery represents the cornerstone in the treatment of advanced ovarian cancer (AOC). In contrast to other gynecological cancers, the use of laparoscopy in AOC is presently considered the ultimate frontier for the method. However, modern technology couple with skilled laparoscopic surgeons afforded performance of diverse oncologic procedures. In parallel, neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (DS) is an alternative for patients with AOC unresectable disease. In selected cases, complete endoscopic DS may be technically possible and considered an alternative to laparotomy. The current paucity of prospective trials addressing the use of laparoscopy in AOC after NACT motived us to investigate the oncologic safety of the method. Methods: Prospective pilot study with patients with initially unresectable advanced high-grade serous ovarian carcinoma (Stages IIIc or IVa) treated with six cycles of Carboplatin and Paclitaxel followed by DS between 2011 and 2014. Major inclusion criteria were: clinical complete response, normalization of the CA-125, absence of disease in critical areas according to radiology after NACT and optimal debulking surgery. Patients were randomized into laparoscopic versus laparotomic cytoreduction. Results: Twenty-one patients were included in the study; 10 patients in the laparoscopic group and 11 in the laparotomic group. The epidemiologic and oncologic features of the groups were not different. Median age was 58 years (45–78) and BMI was 29 Kg/m2 (21 – 40). Complete resection of all macroscopic and microscopic disease (R0) in both groups was achieved in 100%. Surgical morbidity were equally uncommon; 2 patients needed a second procedure due to complications. Over a median follow-up period of 24.2 (15 – 36) months, 80% of the patients in the laparoscopic group and 88% in the open surgery group recurred (CI not reached). Nevertheless, the mean chemotherapy- free interval was significantly inferior in the laparoscopic group; 8,3 versus 15,3 months, respectively (p – 0,02). Conclusions: Laparoscopic cytoreduction seems to be not oncologically safe in patients with AOC submitted to NACT.
Enriched expression of PD-L1 and other immune targets after epithelial-mesenchymal transition (EMT) in squamous head and neck and lung cancers.
Authors: Milena Perez Mak, Lixia Diao, Pan Tong, Jing Wang, Patrick Kwok Shing Ng, Robert Cardnell, David N. Hayes, Gordon Robertson, Jeffrey Myers, Adel K. El-Naggar, William Nassib William, Kevin R Coombes, John N. Weinstein, Gordon B. Mills, John Heymach, Don Lynn Gibbons, Lauren Averett Byers
Journal: Journal of Clinical Oncology (2015)

6016 Background: Epithelial-to-mesenchymal transition (EMT) is associated with poor prognosis and resistance to EGFR inhibitors. To determine molecular alterations and novel targets associated with EMT in head and neck squamous cell cancers (HNSCC), we conducted a comprehensive analysis of molecular alterations associated with EMT, using our previously established EMT gene signature. Methods: 504 HNSCCs from two independent patient cohorts and 178 lung squamous (LUSC) tumors were scored using the EMT gene signature. EMT score was correlated with mRNA, miRNA, and protein (reverse phase protein array, RPPA) levels (Spearman correlation) and with mutations and HPV status (t-test). Ingenuity Pathway Analysis (PA) software was used for PA. Results: Mesenchymal (M) HNSCCs had higher expression of known EMT markers, such as vimentin and fibronectin, lower levels of E-cadherin and miR-200 family members (p < 0.001 for all), and a higher frequency of TP53 mutations (p = 0.016). In contrast, epithelial (E) tumors were more commonly HPV positive (p = 0.019) and were associated with better survival (p = 0.054). At the protein level, the receptor tyrosine kinase (RTK) Axl was overexpressed in M tumors (p < 0.001), whereas other RTKs, such as pHer2 (p = 0.005) and pEGFR (p = 0.02) were higher in E tumors. PA revealed a striking enrichment in genes involved with immune trafficking and inflammatory response in M tumors from HNSCC and LUSC. In a supervised analysis, of 20 targetable immune checkpoints, 18 were overexpressed in M tumors, including PD-L1, ADORA2, CCL2, CD276 (r > 0.44, p < 0.001 for all). PD-L1 overexpression was confirmed by RPPA (p < 0.001). Consistent with these results, EMT was positively correlated with scores from ESTIMATE, which assesses stromal and immune infiltrates in tumor samples (r = 0.63, p < 0.001). Conclusions: Among several molecular alterations associated with EMT, we found a strong enrichment in targetable immune checkpoints (mRNA and protein) and immune cell infiltrates in HNSCC and LUSC cohorts. Given our recent findings that EMT promotes immune escape in lung cancer, our data suggests that EMT status could improve patient selection for immune targeting.
Compliance with ASCO 2006 recommendations for the use of "white blood cell growth factors" in advanced lung cancer (LC) or breast cancer (BC) or non-Hodgkin lymphoma (NHL): An interim analysis of French National Observational Study—The ZOHé study.
Authors: Hubert Orfeuvre, Jean-Loup Mouysset, Omar Benbrahim, Kunlun Liu, Jean-Christophe Eymard, Domitille Fernet, Camille Aubron-Olivier, Henri Hubert Roche, Philippe Solal-Celigny, Toledano Alain, Corinne Haioun
Journal: Journal of Clinical Oncology (2014)

e20663 Background: ZOHé is a French prospective, non-interventional, longitudinal, observational study describing biosimilar GCSF (Zarzio) use in routine practice, in patients receiving chemotherapy (CT) treatment for solid tumor or lymphoid malignancies. Methods: This interim analysis reports the impact in real life of ASCO guidelines on GCSF primary prophylaxis (PP) for the chemotherapy-induced febrile neutropenia (FN) prevention. Baseline characteristics, previous FN, comorbidities were collected in patients with LC, BC or NHL. Patients’ data were evaluated with ASCO guidelines algorithm in term of GCSF PP initiation. Results: 549 patients were recruited between June and December 2013, 141 had LC, 179 BC, and 229 NHL. A total of 140 patients (25.5%) received a CT regimen associated with a FN risk ≥ 20% justifying by itself the GCSF PP initiation. However, for patients receiving a CT regimen with a FN risk < 20% or unknown, the vast majority (342 patients i.e. 62.3 % of total evaluated population) had at least one risk factor for increased incidence of FN: 100% in LC, 72.8% in BC, and 95.7% in NHL (Table). According to ASCO criteria, GCSF PP was recommended in 100%, 67% and 96.5% of the cases of LC, BC and NHL respectively in this study. Conclusions: These data report routine practice FN prevention in patients suffering from LC or BC or NHL. The intrinsic CT FN risk accounted for 25% of patients. Almost all other patients prescription was justify by patient related risk factors. Of note, GCSF prescription was not supported by ASCO guidelines in 24% of the patients with BC. Risk factors in patients receiving a CT regimen with a FN risk < 20% or unknown. Patients (N=409) Lung (n=116) Breast (n=174) NHL (n=119) Risk factors, n (%) Age> 65 yo 53 (45.7%) 42 (24.1%) 79 (66.4%) Advanced cancer 114 (98.3%) 91 (52.3%) 93 (81.6%) Performance status: ECOG≥2 or Karnofsky≤70% 30 (28%) 12 (8.1%) 28 (24.6%) Prior FN 5 (4.3%) 4 (2.4%) 5 (4.7%) Comorbidities 46 (39.7%) 22 (12.6%) 26 (21.8%) Missing data 0 16 (9.2%) 3 (2.5%) Presence of at least one patient-related risk factor 116 (100%) 115 (72.8%) 111 (95.7%)
Results of a cluster randomized trial to evaluate a nursing lead supportive care intervention in newly diagnosed breast and colorectal cancer patients.
Authors: Jonathan Sussman, Doris Howell, Daryl Bainbridge, Kevin Brazil, Susan Schiff, Timothy Joseph Whelan, Jennifer Wiernekowski
Journal: Journal of Clinical Oncology (2012)

6035 Background: Patient transitions during the early phases of cancer care from initial diagnosis through oncology consultation are often poorly coordinated resulting in unmet need, poor continuity, and resultant distress. It has been proposed that better coordination of care during this period would improve the care experience from the patient’s perspective. We designed a randomized trial to test a community based nursing lead coordination of care intervention in newly diagnosed breast and colorectal cancer patients. Methods: Cluster randomized control trial in 193 newly diagnosed breast and colorectal cancer patients enrolled through surgical practices within 7 days of cancer surgery in Toronto, Canada. Surgical practices were randomized between a standardized nursing intervention and a control group involving usual care practices. The intervention consisted of a standardized in person supportive care assessment with ongoing supportive care by telephone or in person that included linkage to community services using protocol specified guidelines according to identified needs. The primary outcomes measured at 8 weeks were validated patient reported outcomes (PROs) of 1) unmet need (SCNS) and 2) continuity of care (CCCQI). Secondary outcomes included 1) quality of life (EORTC QLQ-C30), 2) health resource utilization, and 3) level of uncertainty with care trajectory (MUIS) at 8 weeks. Results: 121 breast and 72 colorectal patients were randomized through 28 surgical practices. The intervention group had a median of 6 nursing contacts over the study period. There were no differences between groups on PROs of unmet need, continuity of care, quality of life, or uncertainty. Health service utilization did not differ between groups. Conclusions: A specialized oncology nursing intervention early in the care trajectory did not result in improved supportive care outcomes for patients. [Table: see text]
Evaluating results from the multiple myeloma subset of patients treated with denosumab or zoledronic acid (ZA) in a randomized phase III study.
Authors: Noopur S. Raje, Wolfgang Willenbacher, Vania Hungria, Andrew Spencer, Yulia Alexeeva, Thierry Facon, A. Keith Stewart, David Roodman, Evangelos Terpos, Amy Feng, Ada Braun, Arun Balakumaran
Journal: Journal of Clinical Oncology (2013)

8589 Background: Denosumab (dmab) is a fully human monoclonal antibody against RANKL and is superior to ZA in preventing skeletal-related events (SREs) as shown in 3 identically designed phase 3 trials (N=5723). Overall survival (OS) was balanced between treatment groups in the overall study populations of these trials. In the trial of patients (pts) with solid tumors (excluding breast and prostate) and multiple myeloma (MM), OS was longer for dmab pts with lung cancer, shorter for pts with MM, and balanced for pts with other solid tumors. This analysis further characterizes the results from the MM subset of this trial. Methods: Pts with solid tumors or MM were randomized (1:1) to receive 120 mg of SC dmab or 4 mg of IV ZA Q4W. Daily calcium and vit D supplements were strongly recommended. The primary endpoint was the time to first on-study SRE; results from the primary endpoint and lung cancer subset were previously reported. Results: Of 1776 randomized pts, 10% had MM (93 ZA, 87 dmab). OS favored ZA (hazard ratio: 2.26; 10 subject difference in deaths). 1-year OS was 83% dmab, 97% ZA. Imbalances in baseline prognostic characteristics were observed. More pts in the dmab arm had low baseline renal function (CrCl &lt; 40 mL/min) (ZA 2 [2%], dmab 9 [10%]) and more ZA pts underwent stem cell transplant (ZA 23 [25%], dmab 15 [17%]). Additionally, more ZA pts had stage I tumors at diagnosis (ZA 13 [14%], dmab 9 [10%]) and better performance status (ECOG = 0; ZA 30 [32%], dmab 21 [24%]). Study discontinuations due to consent withdrawal or lost to follow-up were also higher in the ZA group (ZA 17 [18%], dmab 11 [13%]) and occurred earlier in the ZA arm (ZA 59%, dmab 45% within 9 months of randomization). Conclusions: In this SRE study of dmab vs ZA, pts were stratified by baseline characteristics known to affect SRE outcomes, but not by prognostic factors or concurrent anticancer therapy that may impact survival in MM. OS results in the MM cohort are difficult to interpret due to small sample size and imbalances in baseline disease characteristics, stem cell transplant therapy, and consent withdrawal or loss of follow-up that favored ZA. A phase 3 trial is currently underway, which controls for these factors in pts with MM. Clinical trial information: NCT00330759.
Use of Mechanical Circulatory Support in Patients Undergoing Percutaneous Coronary Intervention
Authors: Amneet Sandhu, Lisa A. McCoy, Smita I. Negi, Irfan Hameed, Prashant Atri, Subhi J. Al’Aref, Jeptha Curtis, Ed McNulty, H. Vernon Anderson, Adhir Shroff, Mark Menegus, Rajesh V. Swaminathan, Hitinder Gurm, John Messenger, Tracy Wang, Steven M. Bradley
Journal: Circulation (2015)

Background— Little is known about the contemporary use of intra-aortic balloon pump (IABP) and other mechanical circulatory support (O-MCS) devices in patients undergoing percutaneous coronary intervention (PCI) in the setting of cardiogenic shock. Methods and Results— We identified 76 474 patients who underwent PCI in the setting of cardiogenic shock at one of 1429 National Cardiovascular Data Registry CathPCI participating hospitals from 2009 to 2013. Temporal trends and hospital-level variation in the use of IABP and O-MCS were evaluated. No mechanical circulatory support was used in 41 286 (54%) patients, 29 730 (39%) received IABP only, 2711 (3.5%) received O-MCS only, and 2747 (3.6%) received both IABP and O-MCS. At the start of the study period, 45% of patients undergoing PCI in the setting of cardiogenic shock received an IABP and 6.7% received O-MCS. The proportion of patients receiving IABP declined at an average rate of 0.3% per quarter, whereas the rate of O-MCS use was unchanged over the study period. The predicted probability of IABP use varied significantly by site (hospital median 42%, interquartile range 33% to 51%, range 8% to 85%). The probability of O-MCS use was &lt;5% for half of hospitals and &gt;20% in less than one-tenth of hospitals. Conclusions— In this large national registry, the use of IABP in the setting of PCI for cardiogenic shock decreased over time without a concurrent increase in O-MCS use. The probability of IABP and O-MCS use varied across hospitals, and the use of O-MCS was clustered at a small number of hospitals.
Vasculogenic mimicry signaling revisited: focus on non-vascular VE-cadherin
Authors: Daniel Delgado-Bellido, Santiago Serrano-Saenz, Mónica Fernández-Cortés, F. Javier Oliver
Journal: Molecular Cancer (2017)

Vasculogenic mimicry (VM) is a blood supply system independent of endothelial vessels in tumor cells from different origins. It reflects the plasticity of aggressive tumor cells that express vascular cell markers and line tumor vasculature. The presence of VM is associated with a high tumor grade, short survival, invasion and metastasis. Endothelial cells (ECs) express various members of the cadherin superfamily, in particular vascular endothelial (VE-) cadherin, which is the main adhesion receptor of endothelial adherent junctions. Aberrant extra-vascular expression of VE-cadherin has been observed in certain cancer types associated with VM. In this review we focus on non-endothelial VE-cadherin as a prominent factor involved in the acquisition of tubules-like structures by aggressive tumor cells and we summarize the specific signaling pathways, the association with trans-differentiation and stem-like phenotype and the therapeutic opportunities derived from the in-depth knowledge of the peculiarities of the biology of VE-cadherin and other key components of VM.
Predictors of circulating tumor-derived methylated <i>BCAT1</i> and <i>IKZF1</i> DNA in colorectal cancer patients.
Authors: Erin L Symonds, Susanne Kartin Pedersen, David Murray, Rohan Baker, Graeme P Young
Journal: Journal of Clinical Oncology (2017)

567 Background: Blood tests detecting circulating tumor-derived DNA (ctDNA) are being developed for colorectal cancer (CRC) screening and monitoring. However, the underlying tumor biology resulting in circulating DNA is not well understood. This study aimed to elucidate tumor features associated with methylated BCAT1 and IKZF1 DNA in blood as well as patient demographics that predict biomarker appearance. Methods: 129 people with invasive CRC had blood collected prior to surgery. Patient sociodemographic factors were recorded. Extracted circulating cell-free DNA was assayed for methylated BCAT1 and IKZF1. Patient factors and tumor features including location, size, depth of invasion (T stage), degree of differentiation, vascularity, lymphatic and perineurial invasion, lymph node involvement and presence of metastasis were compared with blood test results using multivariate logistic regression analysis. Results: The distribution of CRC stages I to IV were 34, 43, 41 and 11, respectively and 72 (56%) were blood positive for methylated BCAT1/IKZF1. Positivity was associated with distally located tumors and a higher T stage (Table). Gender, age, BMI, race, smoking and medications were not associated with blood positivity rates, but increased alcohol intake ( &gt; 7 drinks/week, n = 31) was associated (OR 5.7, 95% CI 1.1-28.7, p = 0.036). Conclusions: The strongest predictor for appearance of ctDNA was invasion depth of the tumor. Demographic features did not influence the positivity rate of the BCAT1/ IKZF1 CRC blood test, strengthening the validity of this blood test for CRC screening and monitoring in the general population. [Table: see text]
A phase 1 first-in-human study of XMT-1107, a polymer-conjugated fumagillol derivative, in patients (pts) with advanced solid tumors.
Authors: Johanna C. Bendell, Geoffrey Shapiro, Edward A. Sausville, Suzanne Fields Jones, John Frederick Hilton, Dana Shkolny, Burkhard Blank, Donald Alan Bergstrom
Journal: Journal of Clinical Oncology (2014)

2526 Background: Fumagillol derivatives are novel anti-angiogenic agents that inhibit methionine aminopeptidase 2 (MetAP2) rather than directly inhibiting VEGF signaling. Clinical development of fumagillol derivatives (e.g. TNP-470) has been limited by CNS toxicities and short-half life. XMT-1107 is a small molecule fumagillol derivative (XMT-1191) conjugated to PHF (Fleximer), a 70 kDa biodegradable, hydrophilic polymer that does not cross the blood-brain barrier. XMT-1107 is hypothesized to decrease CNS exposure to XMT-1191 and lead to prolonged pharmacokinetic (PK) and pharmacodynamic (PD) effect. Methods: This study (NCT01011972) explored the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, PK, PD and antitumor activity of XMT-1107 as a single agent in pts with advanced solid tumors. XMT-1107 was given IV every 3 weeks at escalating doses using a 3+3 design. Results: 52 pts were enrolled in 14 dose cohorts ranging from 6-770 mg XMT-1191 equivalents/m2. MTD was not reached. Infusion volume limited the maximum administered dose to 770 mg/m2. One DLT of grade 4 thrombocytopenia was seen at 245 mg/m2; Grade 3 (n=4) and Grade 4 (n=3) thrombocytopenia were seen after Cycle 1 at 105 mg/m2 and above. Grade 3 anemia was reported in 3 pts. 2 pts had Grade 3 transaminase elevation. There were 2 cases of ataxia: Grade 3 at 40 mg/m2 in a pt with multiple CNS metastases evaluated as probably not related to study drug; and Grade 2 at 580 mg/m2 evaluated as possibly related to study drug. Otherwise there were no CNS AEs. Free and conjugated XMT-1191 concentrations increased linearly with XMT-1107 dose. Evidence of MetAP2 inhibition was detectable in leukocytes at all dose levels, with complete inhibition throughout the 21 day cycle in 6/7 pts evaluated for PD at doses above 325 mg/m2. 26 pts had a best response of stable disease with 12 pts stable for at least 4 cycles. Conclusions: XMT-1107 is well tolerated without significant CNS toxicity. The PK and PD profile supports once every 3 week intravenous dosing. The safety profile and preliminary antitumor effect supports further development in combination with chemotherapy and/or other anti-angiogenic agents. Clinical trial information: NCT01011972.