tbuckley/cabot-search huggingface dataset:
Investigating the Utility of comprehensive genomic Profiling for patients with newly diagnosed breast cancer.
Authors: Casey B. Williams, Robert Goldberg, Kirstin Anne Williams, Pradip De, Jessica Klein, Nandini Dey, Brandon Michael Young, Kimberly C. Banks, Christine Elaine Lee, Richard Burnham Lanman, Siraj Mahamed Ali, Jeffrey S. Ross, Vincent A. Miller, Benjamin Maurice Solomon, Amy K. Krie, Brian Leyland-Jones
Journal: Journal of Clinical Oncology (2016)

TPS11617 Background: Studies of neoadjuvant chemotherapy in Stage II and III breast cancer patients suggest that some have significant benefit from chemotherapy while others appear to derive much less value. Since breast cancer is a genetically and clinically heterogeneous disease, the ability to identify markers that predict early responders to standard chemotherapy and long-term survival would markedly improve the breast cancer treatment paradigm. Rational matching of approved and investigational drugs with cohorts of patients whose disease characteristics suggest they might benefit from this “personalized” therapy requires an understanding of the fundamental regulatory pathways that control breast cancer biology as well as development of validated assay methods to reproducibly identify tissue or serum markers that predict response. We will report the early results of a study to evaluate the utility of comprehensive genomic profiling (including cell-free circulating DNA (cfDNA) next generation sequencing (NGS)) to target agents to the biology of specific signatures and to rapidly assess response to neoadjuvant chemotherapy, with confirmation of response at the time of surgical excision. We hypothesize that genomic and proteomic profiling of tumor samples will identify aberrations that are linked to targeted therapies and that can be combined in treating patients. We also believe that such personalized treatment will be of significantly higher value to the patient compared to a standard of care or population based pathways. Methods: All newly diagnosed breast cancer patients enrolled to the protocol NCT02470715 from June 2014 to April 2016 and eligible for neoadjuvant therapy will be evaluated for two primary outcomes: 1) Aggregate results of the multiplatform comprehensive genomic profiling utilized in the trial and any subsequent therapy recommendations if applicable 2) Compare the outcomes and cost of the therapy for patients that received all of the recommended treatment, at least one, but not all of the recommended drugs, or only standard of care. Clinical trial information: NCT02470715.
Vinorelbine-based chemotherapy in metastatic epithelioid sarcoma.
Authors: Camille Tlemsani, Sarah Dumont, Stanislas Ropert, Françoise Rimareix, Julien Adam, Philippe Terrier, Julien Domont, Arslane Skander Rahal, Andrea Cavalcanti, Isabelle Sourrouille, Nicolas Leymarie, Gilles Missenard, Leila Haddag-Miliani, Charles Honoré, Axel Le Cesne, Olivier Mir
Journal: Journal of Clinical Oncology (2016)

e22549 Background: Epithelioid sarcoma (ES) is a rare soft tissue sarcoma subtype, with poor and short-term responses to conventional, doxorubicin-based chemotherapy (Jones et al, Am J Clin Oncol 2011). We hypothesized that chemotherapy targeting the epithelioid component of the disease (i.e. a vinorelbine-base regimen) could display clinical activity in this setting, as suggested by Anderson et al (Sarcoma, 2006). Methods: Retrospective, electronic records review of adult patients (pts) with metastatic ES treated with vinorelbine (90 mg orally, once weekly) or IV vinorelbine-cisplatin regimen, in Gustave Roussy Cancer Campus from January 1st, 2008 to December 31st, 2015. Results: With a median follow-up of 9.3 months, 15 pts were eligible for this analysis [median age 36 (range : 24-66), 2 with axial ES, 14 being pre-treated with doxorubicin-based chemotherapy]. All pts had documented progressive disease according to RECIST v1.1 before treatment initiation. Median number of previous treatment lines in the metastatic setting was 2 (range: 0-5). Vinorelbine was given alone in 7 pts, or in combination with CDDP in 8 pts. Toxicity profile was excellent, except for 1 patient in whom CDDP-induced grade 3 nephrotoxicity led to replace CDDP by oxaliplatin. Pts received a median number of 6 cycles (range: 1-8). Best response (RECIST v1.1) was: 26.6% PR, 53.4% SD, 20% PD. Median PFS was 4.2 months, and median OS was 9.3 months. No baseline parameter significantly influenced treatment efficacy. Conclusions: Vinorelbine-based chemotherapy is an effective and well tolerated regimen in pts with metastatic ES. A prospective evaluation of vinorelbine-based regimens in this setting is warranted.
RbBP6 gene expression in cancers
Authors: Zodwa Dlamini, Zukile Mbita, Charleen Rupnarain, Thoko Ledwaba, Raymond Motadi
Journal: Cancer Research (2005)

5464  RbBP6 deficient cells have been found to be resistant to apoptosis induced by chemical inducers and this directly links RbBP6 to apoptosis. The RbBP6 gene is 36 kb long and contains 18 exons. It is transcribed to two mRNA transcripts, 1.1 kb and 6.1 kb and the latter is alternatively spliced in exon 16. The two mRNAs are transcribed to a 13 kD and a 200 kD proteins respectively. The 13 kD protein contains the DWNN domain only whereas the 200 kD proteins have the RING Finger, Rb and p53 binding domains linked to the DWNN domain. The aim of the study was to determine the expression pattern and tissue distribution of RbBP6 gene products in normal and diseased human tissues. We have studied several cancers compared the expression pattern and levels of expression to normal tissues. We have also compared the levels of expression and apoptosis in these tissues. Using both in situ hybridization and immunocytochemistry, we have found that in most if not all cancers, RbBP6, is found upregulated and in some cancers we found that it accumulates in the cytoplasm like the mutated p53. The nuclei in some instances did show some localization in some cancers as well. In normal tissues RbBP6 was found to be localizing mostly in nuclei and rarely in the cytoplasm. We have found that RbBP6 is upregulated around islands of tumors in well differentiated squamous tumors where the apoptosis is high and very much involved in fighting the invading tumors and there was none or little RbBP6 localization in the islands of tumors where apoptosis had completely halted. The RbBP6 expression level correlated with apoptosis and was found to be inversely proportional to proliferation as it was shown by TUNEL and Ki67 respectively. We have also used real time quantitative RT-PCR using Roche Light Cycler and have confirmed that the RbBP6 expression levels are increased in tumors as compared to normal respective tissues. The RbBP6 200 cDNA variant had previously been cloned by detecting its interaction with tumor suppressor proteins p53 and Rb, which have a major role in apoptosis and cancer development. Accumulation of these proteins, p53 and RbBP6, suggests that RbBP6 may be involved in a p53 dependant apoptotic pathway.
Cost effectiveness of G-CSF after allogeneic peripheral blood stem cell transplant.
Authors: Vijendra Singh, Seongho Kim, Hyejeong Jang, Asif Alavi, Divaya Bhutani, Lois Jeanne Ayash, Voravit Ratanatharathorn, Joseph P. Uberti, Abhinav Deol
Journal: Journal of Clinical Oncology (2017)

e18540 Background: In spite of the fact G-CSF has been used post stem cell transplant (SCT) to accelerate neutrophil engraftment its use post allogeneic SCT remains controversial. ASCO does not recommend its use after allogeneic SCT. To further evaluate the effectiveness of its use, we compared outcomes in pts who underwent related and unrelated peripheral blood SCT(PBSCT) either with or without the use of G-CSF post SCT. Methods: This is a retrospective study comparing early outcomes in pts who received G-CSF starting on day + 6 post SCT until engraftment with pts who did not receive a planned course of G-CSF. Pts who underwent Allogeneic PBSCT between 2012-2014 at our institution were included. Pts who received marrow, haploidentical or cord blood transplants were excluded. Associations with survival outcomes were assessed by univariable and multivariable Cox proportional regression models. Results: A total of 162 patients were evaluated. Sixty-five pts received G-CSF post SCT and 97 did not. The only difference between the two groups was that more pts in the G-CSF group received myeloablative-conditioning (MAC) regimen (78% vs. 55%, p = 0.008). Other pt characteristics were not significantly different. Length of hospital stay was significantly lower in the G-CSF group (24 vs. 27 days P = 0.002). Pts who received G-CSF had earlier neutrophil engraftment (median, days 11 vs. 14 p = &lt; 0.001). The median day of platelet engraftment was 15 days in both groups. There was no significant difference between the 2 groups in re-admissions in the first 100 days, and the incidence of acute or chronic GVHD. In multivariate analysis use of G-CSF did not significantly impact non- relapse mortality, relapse free survival and overall survival. However, relapse rate was significantly lower in G-CSF group in multivariable analysis (hazards ratio = 0.44, p = 0.03). Conclusions: Use of G-CSF post allogeneic PBSCT is associated with earlier neutrophil engraftment, shorter hospital stay and a suggestion of a reduced relapse rate after PBSCT. Our experience suggests that use of G-CSF (on average for approximately 5 days) in this setting is cost effective as it reduces hospitalization duration without adversely impacting post-transplant outcomes.
Dynamics of tumor response in advanced melanoma patients treated with Coxsackievirus A21.
Authors: Robert Hans Ingemar Andtbacka, Brendan D. Curti, Howard Kaufman, John J. Nemunaitis, Gregory A. Daniels, Sigrun Hallmeyer, Eric D. Whitman, Jose Lutzky, Stephen Michael Schultz, Lynn E. Spitler, Zipei Feng, Christopher Paustian, Bernard A. Fox, Carlo Bruno Bifulco, Karl Zhou, Mark Grose, Darren Shafren
Journal: Journal of Clinical Oncology (2016)

9553 Background: CAVATAK, an oncolytic immunotherapy, is a bio-selected oncolytic strain of Coxsackievirus A21 (CVA21). Intratumoral (IT) injection of CVA21 induces lytic tumor cell infection, up-regulation of immune checkpoint molecules and increased immune-cell infiltration. The Phase II CALM study investigated the efficacy and safety of IT CVA21 in 57 pts with advanced melanoma resulting in a confirmed ORR of 28.1% and DRR (continuously > 6 mths) of 21.1%. The CALM extension study (13 pts) investigated CVA21 induced changes in immune cell infiltrates within the tumor-microenvironment (TME). We describe factors regarding the nature of clinical responses in 70 pts with stage IIIC-IV melanoma given IT CVA21. Methods: The association of prior lines of therapy, tumor pseudo-progression, baseline tumor burden (BTB) and levels of immune cell infiltrates in the TME were examined with regard to clinical response. Results: Responders on the CALM study (16/57 pts, 28.1%) displayed reductions in both injected and non-injected lesions, suggesting the generation of significant host anti-tumor responses. A comparable ORR was observed in pts administered prior immunotherapy, 29.0% (9/31) vs other tx 27.0% (7/26). Interestingly, 26.7% (4/15) and 40% (2/5) of pts previously treated with ipilimumab and talimogene laherparepvec, respectively, developed confirmed responses. Three pts (18.8%) exhibited pseudo-progression (irRECIST criteria) prior to response. BTB of the 57 pts in the CALM study was 3.9 cm (95% CI 4.3, 6.5). A BTB less than median was associated with: superior ORR (39.3 vs 17.2 %), superior DRR (35.7 vs 6.9 %), and greater OS (p = 0.003). In the CALM extension study, CVA21 tx induced increases in immune cell infiltrates within the TME. In patients with responses, increases in CD8+ T-cells and PD-L1+ expression were observed in injected lesions. Reconstitution of immune cell infiltrates was observed in a number of CVA21 treated lesions from pts failing prior tx with immune-checkpoint blockade. Conclusions: IT administration of CVA21 can notably influence the dynamics of the TME and generate systemic anti-tumor immune responses as evidenced by increases in immune cell infiltrates and widespread non-injected lesion responses. Clinical trial information: NCT01227551.
A phase 1a / 1b first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-0903, a potent inhibitor of AXL kinase, administered daily for 21 days to patients with advanced solid tumors.
Authors: John Sarantopoulos, Muhammad Shaalan Beg, Georgios Fotopoulos, Josephine Amalia Taverna, Stephen P. Anthony, Steven D. Weitman, Steven L Warner, Lars Mouritsen, David Bearss, Susan Smith, Holly Beever, Vivek Khemka
Journal: Journal of Clinical Oncology (2018)

TPS2612 Background: AXL kinase has emerged as a key regulator of the epithelial to mesenchymal transition (EMT), a process that enables cancer cells to develop migratory and invasive properties and acquire resistance to chemotherapeutics and targeted agents. AXL kinase is also known to serve to dampen the immune response to dying tumor cells. By activating EMT, AXL signaling allows cancer cells to engulf neighboring cancer cells undergoing apoptosis, reducing presentation of pro-inflammatory stimuli to the immune system. Consequently, the inhibition of AXL by TP-0903 may potentially reduce cancer cell metastasis, target cancer cells that demonstrate immunity to chemotherapeutics and activate the anti-cancer immune response. Methods: Patients with advanced solid tumors that are refractory or intolerant to established therapy have been enrolled in a standard 3+3 dose escalation trial of TP-0903 given orally once daily for 21 days of a 28-day cycle. Cohort dose levels 1 through 5 have been completed without DLT, enrollment into cohort 6 began January 2018. The primary objective is to determine the MTD and DLTs; secondary objectives are PK, radiographic response, PD activity (e.g. GAS6/AXL and other EMT markers), biological activity and RP2D. Key eligibility criteria include age ≥ 18 years, ECOG ≤1, adequate organ function, life expectancy of > 3 mos. Once the MTD has been reached, the study will be expanded into 5 cohorts of 20 patients each: 1) Patients on immunotherapy who demonstrate progression but are clinically stable, 2) EGFR + NSCLC having progressed on ≤ 2 lines of TKIs, 3) BRAF, KRAS or NRAS mutated CRC with no standard therapy remaining, 4) Platinum refractory/resistant ovarian, 5) BRAF mutated melanoma that hasn't responded to immunotherapy or combination BFAF/MEK inhibitor. Patients will be biopsied in each cohort to explore changes to the EMT phenotype. Clinical trial information: NCT02729298.
The safety of four cycles of CAPEOX combined with radiotherapy vs. capecitabine combine with radiotherapy for locally advanced rectal cancer: Mid-term analysis of NCT02031939.
Authors: Rong-xin Zhang, Zhen-hai LU, Fu-long WANG, Desen Wan, Yuan-Hong Gao, Zhi-Fan Zeng, Pei-Rong Ding, Xiao Jun Wu, Li-ren LI, Jun-Zhong Lin
Journal: Journal of Clinical Oncology (2016)

e14040 Background: Although neoadjuvant chemoradiotherapy has significantly reduced the risk of local recurrence in locally advanced rectal cancer, systemic failure remains a predominant issue probably due to the insufficient control of systemic micro-metastasis in the neoadjuvant treatment. Methods: We designed a single center perspective clinical trial to detect whether locally advanced rectal caner patients can benefit more from four cycles of CapeOX combining with standard radiotherapy than standard chemoradiotherapy (Capecitabine combine with radiotherapy). The primary endpoint of NCT02031939 is the overall survival. This clinical trial started from January 2014, and 194 patients were enrolled up to now. Results: 179 patients finished the randomization and received treatment. 131 patients finished their treatment and follow-up has been conducted. One patient in CapeOX group and one patient in control group received emergency operation because of perforation. Five patients refused to receive radical surgery because of good respond to neoadjuvant therapy and the possibility of permanent colostomy (3 patient in CapOX group and 2 patients in control group). 91 patients received AR (20 patients had prophylactic ileostomy), 36 patients received APR, and four patients received palliative rectum resection and sigmoid stoma. Three patients in CapeOX group underwent palliative resection because of local disease progression, and one patients in control group progressed. Two patients in control group experienced distance metastasis after neoadjuvant treatment. Two patients in CapeOX group and one patient in control group experienced grade 3 Leucopenia. Two patients in CapeOX group had grade 3 Thrombocytopenia, and one patient in control group had grade 4 Thrombocytopenia. One patient in CapeOX group experienced grade 3 renal disorder. No severe neuropathy were observed in CapeOX group. Conclusions: CapeOX can be used safely to combine with radiotherapy. Further investigation is required to determine whether this this new kind of treatment wouldbring better response rate and low distance metastasis. Clinical trial information: NCT02031939.
Outpatient management of pulmonary embolism in cancer patients: A matched-cohort analysis.
Authors: Adi Joseph Klil-Drori, Janie Coulombe, Samy Suissa, Andrew Hirsch, Vicky Tagalakis
Journal: Journal of Clinical Oncology (2016)

e21677 Background: Around 30% of cancer patients presenting to the emergency room (ER) with pulmonary embolism (PE) in the Canadian province of Quebec are managed as outpatients (OP). We investigated whether OP management of PE in cancer patients was associated with increased risk of recurrence of venous thromboembolism (VTE) and major bleeding. Methods: Using Quebec healthcare data, we identified all cancer patients with incident PE diagnosed in ER between 2000 and 2009, after excluding high or very-high risk patients, such as patients admitted to intensive care. Outpatient management was defined as the absence of a hospital admission up to 3 days following the ER visit. Outpatients were propensity-score matched 1:1 (0.01 margin) to inpatients (IP) and followed for 90 days for the recurrence of VTE or the occurrence of major bleeding. The hazard ratios (HR) and 95% confidence intervals (CI) of major bleeding and recurrence associated with OP management were assessed with all-cause mortality as a competing risk. Results: In all, 283 OP were matched to 283 IP (Table). By 90 days, 38 recurrences and 10 major bleeding events occurred. Patients with OP management had lower short-term mortality (P = 0.0002, log-rank test). In competing risk analyses, the HR for recurrence at 90 days with OP management was 1.01 (95% CI: 0.52-1.93), and for major bleeding it was 1.00 (95% CI: 0.29-3.45). Conclusions: Outpatient management of cancer patients with low- or intermediate-risk PE was not associated with a higher risk of recurrence or major bleeding, when accounting for the higher risk of death in patients who were admitted to hospital. Baseline characteristics of matched cancer patients with pulmonary embolism. Factor Inpatients, % (n = 283) Outpatients, % (n = 283) Mean age 68.5 69.1 Men 41.3 44.2 Cancer site Breast 18.0 19.1 Lung 22.3 21.6 Colorectal 12.0 13.1 Pancreas 2.1 2.1 Hematologic 8.5 8.5 Genitourinary 26.5 29.3 Other 19.4 17.3 Chemotherapy 19.1 17.3 Radiotherapy 5.7 6.0 History of major bleed 2.1 3.2 Metastases 27.9 26.5 Charlson, median (IQR) 5 (2-8) 6 (3-9) PE risk score < 2 62.5 59.0 2-4 37.5 41.0 ER diagnoses Deep vein thrombosis 14.5 13.4 Acute kidney injury 0.7 0.4 Atrial fibrillation 3.5 3.5 Pneumonia 2.1 2.1 Myocardial infarction 1.4 1.1
Efficacy and tolerability of second-line intra-arterial 5FU or mitomycine C after intra-arterial oxaliplatin failure in patients with colorectal cancer and unresectable liver metastases.
Authors: Simon Pernot, Guillaume Velut, Hampig Raphael Kourie, Gregory Amouyal, Marc Sapoval, Anne-Laure Pointet, Bruno Landi, Yosra Zaaimi, Céline Lepère, Olivier Pellerin, Julien Taieb
Journal: Journal of Clinical Oncology (2017)

e15061 Background: Hepatic arterial infusion (HAI) chemotherapy of oxaliplatin is an option in the management of metastatic colorectal cancers (mCRC) with dominant liver metastases (LM). However, despite prolonged control some patients (pts) experience disease progression or dose-limiting toxicity. In these cases, the use of a second-line HAI with an alternative drug has never been reported to date. This pilot study is evaluating treatment outcomes in pts receiving HAI of 5-FU or mitomycine C (MMC), after HAI oxaliplatin (HAI-ox) in heavily pretreated pts. Methods: 24 pts with unresectable mCRC were enrolled, metastases were exclusively or dominant in the liver (≥80% of overall total metastatic tumour burden in the liver), all pts received prior HAI-ox. They were treated with either biweekly HAI 5-FU with dose ranging from 600 to 1200mg/m 2 over 2 hours (17 patients), or monthly MMC 7mg/m 2 over 1 hour (7 patients). Results: Mean age was 62 years. 42% of pts (10/24) had extra-hepatic metastases and 75% (18/24) had 8 LM or more. Including prior HAI-ox, pts had previously received a median of 3 prior lines of treatment (range:2 to 5). Previous HAI-ox was stopped for toxicity in 17 pts (allergy, neuropathy or abdominal pain) or progression in 7 pts. At baseline, 62% of pts had progressive disease. All pts but one received concomitant systemic therapies together with HAI 5FU or MMC. The overall RECIST V1.1 objective response rate and disease control rate were respectively 42% (10/24) and 71% (17/24). Median progression free survival (PFS) and overall survival (OS) were respectively 5.6 and 25.8 months; hepatic PFS was 8.5 months. 3 pts benefited from further curative intent treatments after 2 nd line HAI (2 radiofrequency, 1 surgery). No toxic death occurred and toxicity profile was acceptable, with only 2 grade 3 events reported (diarrhea and thrombocytopenia). Conclusions: 2 nd line HAI with 5-FU or MMC seems feasible and efficient in heavily pretreated mCRC with liver dominant disease when progressing or not tolerating oxaliplatin HAI. A phase II study is going to be performed to confirm these first results.