tbuckley/cabot-search huggingface dataset:
A phase II study of mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in combination with 5-azacitidine in patients with myelodysplastic syndrome (MDS).
Authors: Selina M. Luger, Casey Lee O'Connell, Virginia Klimek, Maureen A. Cooper, Emmanuel C. Besa, James M. Rossetti, Gregory K. Reid, Rachel Humphrey, Robert E. Martell, Guillermo Garcia-Manero
Journal: Journal of Clinical Oncology (2013)

7116 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single agent activity in AML and both Hodgkin’s and non-Hodgkin’s lymphomas. Preclinical evaluation demonstrating in vitro and in vivo synergy and antileukemic activity with demethylating agents, including 5-azacitidine (AZA), prompted clinical evaluation of mocetinostat + AZA in MDS and AML. Methods: This open-label, Phase II trial enrolled patients with MDS or AML. Patients received AZA (75 mg/m 2 SC; days 1-7 every 28 days) and mocetinostat (90-110 mg 3x/wk starting on AZA day 5). Anticancer activity, safety and pharmacokinetics and pharmacodynamics were evaluated. We report here on the MDS cohort. Results: Twenty patients with MDS were enrolled. Eight patients had received prior therapy for MDS including decitabine (n=1), lenalidomide (n=3), tipifarnib (n=2) and cytarabine (n=2). Median age was 70.5 yrs (range 41-81). Disease control rate (defined as CR + marrow-CR + PR + SD) was 80% (16/20). Ten patients (50%) had baseline marrow blast counts ≥10% (protocol-defined high risk). Responses in high-risk patients included 5 (50%) with CR + marrow-CR and 2 (20%) with SD. Six patients (30%) had an on-treatment marrow blast count of 0. These included 3 patients in the high-risk category, with baseline blast counts of 11%-15%. CR was observed in one patient, a 74-yr-old male with previously untreated RAEB. In this patient, marrow blasts fell from a baseline of 11% to 0% following 1 cycle of treatment; CR with normalization of all cell lines was achieved by late Cycle 3. He remained on study for 1 yr. Most drug-related AEs in the study were grade 1 or 2. The most common drug-related grade 3/4 events were nausea (15%), vomiting, fatigue, anemia, thrombocytopenia and febrile neutropenia (10% each). There was one death (5%), due to pneumonia that was not felt by the investigator to be drug related. Conclusions: The combination of mocetinostat and 5-azacitidine in patients with MDS demonstrated an acceptable safety profile and encouraging evidence of clinical benefit. Further clinical studies are warranted. Clinical trial information: NCT00324220.
Efficacy of 12-weeks of neoadjuvant TDM1 with or without endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer: WSG-ADAPT HER2+/HR+ phase II trial.
Authors: Nadia Harbeck, Oleg Gluz, Matthias Christgen, Michael Wilhelm Braun, Sherko Kummel, Jochem Potenberg, Bahriye Aktas, Claudia Schumacher, Helmut Forstbauer, Doris Augustin, Stefan Kraemer, Marianne Just, Joke Tio, Anke Kleine-Tebbe, Cornelia Liedtke, Ronald E. Kates, Daniel Hofmann, Rachel Wuerstlein, Hans Heinrich Kreipe, Ulrike Nitz
Journal: Journal of Clinical Oncology (2015)

506 Background: Evidence suggests differential efficacy of standard neoadjuvant chemo- + targeted therapy in HER2+ early breast cancer (eBC) according to hormone-receptor (HR) status. ADAPT HER2+/H...
Lenalidomide and rituximab for untreated indolent non-Hodgkin's lymphoma
Authors: N. H. Fowler, P. McLaughlin, L. Kwak, F. Hagemeister, M. Fanale, L. Fayad, B. Pro, F. Samaniego
Journal: Journal of Clinical Oncology (2009)

8548 Background: Despite advances in therapy and a better understanding of the natural history of indolent non-Hodgkins lymphomas (NHL), the optimal treatment for newly diagnosed patients (pts) has not been determined. While several combination chemotherapy regimens have response rates approaching 90%, toxicity is common with genotoxic drugs and secondary malignancies is a concern. Lenalidomide has been shown to have single agent activity in indolent NHL, and is approved for the treatment of multiple myeloma and myelodysplastic syndrome. Rituximab is effective as a single agent and in combination with chemotherapy for indolent NHL. The aim of this phase II, single arm study is to evaluate the efficacy and safety of lenalidomide and rituximab in pts with untreated, stage III, or IV indolent NHL. Methods: Pts with indolent NHL who were previously untreated, with measurable disease (&gt;1.5 cm), were eligible for enrollment. Pts received 20mg of lenalidomide orally once daily on days 1–21 and rituximab 375mg/m 2 intravenously on day 1 of each 28 day cycle. Pts could receive up to 6 cycles of therapy. Response was assessed after 3 cycles and at the end of therapy using the International Working Group Response Criteria. Results: At time of this report 17 pts have been enrolled and 14 are eligible for safety evaluation. The median age was 55 (33–77) years and 53% were male. Therapy was well tolerated with the following grade 3 adverse events (AE) reported; myalgia (1 pt), rash (1 pt), peripheral neuropathy (1pt). There were no grade 4 AEs. There have been no reported grade 3/4 hematologic AEs. There has been no tumor flare observed. In the 5 pts eligible for response assessment, 4 pts (80%) attained a complete response (CR), 1 patient (20%) had stable disease (SD). After 3 cycles, one patient had unconfirmed stable disease who also was previously treated with combination chemotherapy for Hodgkin's lymphoma. Updates for response will be presented. Conclusions: The combination of lenalidomide and rituximab has activity and is well tolerated with minimal toxicity in patients with newly diagnosed indolent lymphoma. [Table: see text]
Is there a role for multi-gene screening panels in patients who previously underwent noninformative genetic testing?
Authors: Melissa K Frey, Sarah H Kim, Jessica Martineau, Rebecca Yee Bassett, Stephanie V. Blank
Journal: Journal of Clinical Oncology (2015)

1536 Background: The availability of next-generation sequencing coupled with the recent discovery of multiple cancer-related genes has caused a shift away from single gene testing towards multi-gene panel testing for familial cancer syndromes. However, the utility of multi-gene panels in individuals who previously underwent noninformative genetic screening has yet to be evaluated. We aim to evaluate the use of rescreening and results of multi-gene panels in this rescreened population. Methods: We reviewed all patients who had previously undergone genetic testing for familial cancer syndromes and then underwent multi-gene panel testing at a single institution between 9/2013-11/2014. Results: One hundred and twenty-four patients with prior non multi-gene panel testing underwent multi-gene panels. One hundred patients (81%) had a history of cancer and 115 patients (93%) had at least one family member with cancer. On primary testing, no deleterious mutations were identified and 11 variants of uncertain significance (VUS) were found in 10 patients (8%). On repeat multi-gene panel testing, 5 patients (4%) had a deleterious mutation, 54 (44%) had VUS and 4 (3%) had a mutation and VUS. Among patients with a VUS on rescreening, 14 (24%) had more than one VUS identified (range 2-4). Rescreening found a total of 9 deleterious mutations and 80 VUS and resulted in a change in mutation characterization for 9 patients and VUS characterization for 48 patients. Conclusions: Among patients with negative primary testing there was a 47% rate of change in result characterization with multi-gene panels. Our data suggest that patients with noninformative prior screening may benefit from rescreening with multi-gene panels. As more about mutations now classified as VUS is learned, the additional information offered by multi-gene panel testing may prove to be increasingly relevant. Gene Primary testing - VUS Repeat multi-gene panel - VUS Repeat multi-gene panel - Mutation MUTYH 0 3 3 BRIP1 0 2 2 BRCA2 5 10 1 ATM 0 9 1 APC 0 3 1 RAD51D 1 1 1 MLH1 2 7 0 CHEK2 0 5 0 MSH6 0 5 0 RAD50 0 4 0 PALB2 0 4 0 BARD1 0 4 0 CDH1 1 3 0 PMS2 1 3 0 TP53 1 2 0 AXIN2 0 2 0 BRCA1 0 1 0 NF1 0 1 0 MSH2 0 1 0 CDKN2A 0 1 0 NBN 0 1 0 XRCC2 0 1 0 BMPR1A 0 1 0 SMAD4 0 1 0 BLM 0 1 0 EPCAM 0 1 0 MET 0 1 0 MRE11A 0 1 0 RAD51 0 1 0
Long-term incidence of venous thromboembolic events following cystectomy: A population-based analysis.
Authors: Christopher J.D. Wallis, Diana Magee, Raj Satkunasivam, Robert Nam
Journal: Journal of Clinical Oncology (2017)

288 Background: Cancer and immobility both contribute to the development of venous thromboembolic events (VTE), including pulmonary embolism and deep vein thrombosis. As such, patients undergoing radical cystectomy for bladder cancer are at elevated risk. We sought to assess the long-term incidence of VTE among all patients undergoing radical cystectomy in the province of Ontario. Methods: We conducted a population-based cohort study to examine the incidence of VTE, a composite of pulmonary embolism and deep vein thrombosis, among all patients treated with radical cystectomy for bladder cancer between 2002 and 2014 in Ontario, Canada. We estimated the cumulative incidence of VTE and used Fine and Grey competing risk survival analysis to assess risk factors for VTE while accounting for the risk of any cause mortality. Results: Among 3623 eligible patients, the 10 year cumulative incidence of VTE was 6.68% (Table 1). Among those who experienced VTE, the median time from surgery was 216 days (interquartile range 52-677 days; mean 527 days). However, VTE rates peaked much earlier with a mode of 20 days. Neither preoperative (HR 0.68, 95% CI 0.39-1.18) nor postoperative chemotherapy (HR 1.32, 95% CI 0.95-1.84) were significantly associated with VTE incidence. While patients with a prior history of VTE had increased risk of VTE after cystectomy (HR 5.1, 95% CI 2.2-12.0), age, gender, comorbidity score, rurality, diversion type (continent vs ileal conduit), treatment at an academic institution, or year of treatment were not significantly associated with the risk of VTE. Conclusions: Among patients undergoing cystectomy for bladder cancer, the cumulative incidence of VTE continues to rise long after the date of surgery indicating that previous studies may have underestimated these rates, but the highest rates occur at 20 days after surgery. Chemotherapy does not appear to increase the risk of VTE. [Table: see text]
Canada announces plans to legalise recreational marijuana
Authors: Owen Dyer
Journal: BMJ (2017)

Canada’s government will introduce legislation in two weeks to legalise recreational marijuana for anyone over 18 and expects to see a regulated legal marijuana market up and running by 1 July 2018—Canada Day.

The policy change will make Canada the biggest jurisdiction in the world to freely allow consumption of marijuana.

Prime minister Justin Trudeau told television network CBC that legalisation and regulation would keep marijuana out of the hands of the young.

“It’s easier for a teenager to buy a joint right now than a bottle of beer, and it’s not right,” he said. “We know that by controlling and regulating it, we are going to make it more difficult …
Interim performance of a non-DRE urine exosome gene signature to predict Gleason ≥7 prostate cancer on initial prostate needle biopsy from patients enrolled in a prospective observational trial.
Authors: Michael J. Donovan, Mikkel Noerholm, Stefan Bentink, Susan Belzer, Johan Skog, Gordon Andrew Brown, James S. Cochran, Vince O'Neill
Journal: Journal of Clinical Oncology (2015)

5064 Background: PSA and DRE are used for biopsy decisions; however, limited sensitivity and specificity have resulted in the over-diagnosis and treatment of low risk prostate cancer (PCa). Non-invasive screening tools that add predictive value for identifying high-grade, Gleason score (GS) ≥ 7, should impact the current paradigm. We sought to evaluate performance of a gene signature that differentiated GS7+ from GS6 + benign disease by evaluating patients with first-time biopsy results and gray zone PSA (4-10ng/mL) from an ongoing prospective clinical trial. Methods: 499 sequentially obtained first-catch non-DRE urine specimens (standard cups) from 15 urology practices were collected from patients presenting for biopsy. Exosomes were isolated and RNA extraction performed. RT-qPCR RNA copy numbers of ERG and PCA3, normalized to SPDEF, were measured to generate a three-gene signature, defined to yield a score discriminating GS7+ vs. GS6 and benign lesions, evaluating NPV, Sensitivity and Specificity relative to standard of care. Results: Urine samples from 205 men of 499 total (PSA 4-10 ng/mL, first biopsy, < 50 mL donation volume; median age 64 years, median PSA 5.46 ng/mL, 80% negative DRE, 74% no family history, 68% Caucasian), were evaluated. With 50% and 33% prevalence of positive biopsy for any cancer or GS7+ disease, respectively, a dichotomous gene signature + standard of care demonstrated good clinical performance in predicting biopsy result. For GS7+, with a 90% fixed sensitivity, the NPV and PPV were 92% and 48%, respectively compared to 79% and 35% for the prostate cancer prevention trial risk calculator (PCPTRC). A continuous score alone had an AUC of 0.74 for discriminating GS7+ from GS6 and benign disease and the results were significantly better than PCPTRC, AUC 0.64(p = 0.026). Conclusions: We confirmed a novel, non-invasive urine exosome gene signature demonstrated independent, negative predictive value for the diagnosis of GS7+ from first biopsy patients with 'gray zone' PSA. Its use in the biopsy decision process should result in fewer prostate biopsies pending completion of the prospective trial.
Systematic assessment of potential cardiac effects of the novel histone deacetylase (HDAC) inhibitor romidepsin
Authors: C. Cabell, S. Bates, R. Piekarz, S. Whittaker, Y. Kim, C. Godfrey, C. Schoonmaker, W. McCulloch, J. Nichols, H. A. Burris
Journal: Journal of Clinical Oncology (2009)

e19533 Background: Romidepsin is a novel pan-HDAC inhibitor with single-agent activity in T-cell lymphoma. HDAC inhibitors reportedly have cardiovascular effects, in particular, QTc prolongation. To systematically and rigorously evaluate the potential cardiac effects of romidepsin, a cardiac safety monitoring plan was developed after discussions with the FDA. Methods: The effect of romidepsin on the change from baseline QTcF (Fridericia's correction) at key pharmacokinetic and pharmacodynamic (PD) time points was investigated. ECGs from 110 pts with advanced malignancies in 3 open-label, clinical studies of romidepsin 14 mg/m 2 administered on days 1, 8 and 15 of a 28 day cycle were evaluated by blinded, independent assessors. Results: A mean 2.7 msec increase (90% confidence interval [CI]: 0.2, 5.3) in QTcF interval from a baseline post-antiemetic administration to after infusion of romidepsin was measured. A subanalysis of 74 patients (pts) evaluated QTcF from pre-antiemetic to post-romidepsin showed a mean change in QTcF of 5.0 msec (90% CI: 2.3, 7.7). Thus, antiemetic comedications likely accounts for a portion of the clinically apparent QTc effect. The QTc returned to baseline within 48 hrs. No absolute QTc values &gt;480 msec and no QTc changes &gt;60 msec were observed. No relationship was observed in an analysis of romidepsin plasma concentration versus QT changes. Mean heart rate (HR) increased 10.1±9.0 bpm after romidepsin administration, with a return to baseline by 24 hrs. Several treatment-emergent morphological changes in ECGs (including T wave and ST-segment) were reported. Many of the ECG morphologic abnormalities (determined by automated machine reading) were also observed at baseline. These ECG changes were transient and were not associated with functional cardiovascular changes or with symptoms. Conclusions: Romidepsin has a slight effect on the QT interval but rigorous ECG evaluation found this effect to be mild, below the threshold of regulatory and clinical concern, and not associated with any observed clinical cardiovascular events. Concentration response modeling found no PD relationship between romidepsin concentration and changes in QTcF, but did suggest a relationship between romidepsin concentration and HR. [Table: see text]
Improved disease-free survival with intraportal chemotherapy plus adjuvant chemotherapy (mFOLFOX6) as adjuvant treatment in colon cancer.
Authors: Wenju Chang, Jianmin Xu, Ye Wei, Li Ren, Tianshu Liu, Jingwen Chen, Dexiang Zhu, Qi Lin, Xinyu Qin
Journal: Journal of Clinical Oncology (2014)

3616 Background: The optimal time from surgery to the start of chemotherapy in colon cancer is unknown. We evaluated the impact on survival of intraportal chemotherapy (IPC) administrated during surgery plus adjuvant chemotherapy (AC) as treatment for stage II and III colon cancer. Methods: Patients with stage II or stage III colon cancer were randomly assigned to receive IPC plus mFOLFOX6 (OCTREE) or mFOLFOX6 alone. The primary end point was disease-free survival (DFS). Secondary endpoints included metastasis-free survival (MFS), overall survival (OS) and safety. Results: The intent-to-treat population comprised 237 patients. After a median follow-up of 44 months, The 3-year DFS rate was 85.2% (95% Cl 81.9 to 88.4) with OCTREE and 75.6% (95% Cl 71.7 to 79.4) with mFOLFOX6 alone (P = .030). The hazard ratio (OCTREE versus mFOLFOX6) was 0.66 (95% CI, 0.43 to 0.90, P = .016). The 3-year MFS rates were 87.6% versus 78.0%, when compared OCTREE with mFOLFOX6, the hazard ratio was 0.59 (95% CI, 0.38 to 0.92, P = .023). Patients in OCTREE arm had decreased distant metastases events (12.7% versus 22.7%; P= .044) compared with those in mFOLFOX6 arm. Grade 3 hepatic toxicity was observed in 1.7% of patients receiving OCTREE within two weeks after surgery, and could be cured with medicine. Only one patient died as a result of any cause within 6 months of receiving chemotherapy, with no significant difference between regimens. Conclusions: Intraoperative intraportal chemotherapy combined with mFOLFOX6, reduced the occurrence of distant metastasis, and therefore improved DFS in patients with stage II and stage III colon cancer. Clinical trial information: NCT01972503.
Use of non-anthracycline adjuvant chemotherapy in triple-negative breast cancer: Review from a prospective registry.
Authors: Priyanka Sharma, Bruce F. Kimler, Jennifer R. Klemp, Claire Ward, Manana Elia, Carol Sue Connor, Jamie Lynn Wagner, Joshua Matthew Varghise Mammen, Amanda Leigh Amin, Carol J. Fabian, Andrew K. Godwin, Qamar J. Khan
Journal: Journal of Clinical Oncology (2015)

e12071 Background: Adjuvant chemotherapy is recommended for most patients with stage I-III triple negative breast cancer (TNBC). Anthracycline (A) and Taxane (T) form the backbone of most adjuvant regimens. One randomized study has demonstrated that 4 cycles of Docetaxel/Cyclophosphamide (TC) is superior to 4 cycles of non-dose dense AC. In an unselected population of TNBC, the proportion of patients receiving A based versus other adjuvant chemotherapy regimens is not known. Utilizing a prospective registry, our aim was to study the patterns of adjuvant chemotherapy regimens prescribed for TNBC. Methods: 316 stage I-III TNBC patients enrolled in a multisite IRB approved registry between 2011 and 2014. Patients were accrued at academic and community oncology clinics. Clinical, demographic and chemotherapy information was collected. This study was restricted to analysis of 146 study participants who received adjuvant chemotherapy. Results: For the 146 subjects, median age was 55 years (range 27-84), 17%: African-American, 62%: postmenopausal, 29%: lymph node positive. 76% of patients enrolled at community sites, 24% enrolled at academic site. Chemotherapy regimens were prescribed at the discretion of treating physician; table 1 depicts the distribution pattern of various regimens. Over one-third of patients received TC. Compared to patients receiving any other chemotherapy regimen, patients receiving TC were older (median age 60.5 years v 52.5 years, p < 0.001), more likely to be Stage I (68% v 37%, p < 0.001), and less likely to be African-American (6% v 23%, p = 0.010). Conclusions: A significant proportion (34%) of patients with TNBC are receiving TC based adjuvant chemotherapy. The only randomized study that evaluated adjuvant TC included a small number of patients with TNBC; however, our study indicates that this regimen is widely used in the general TNBC patient population. Long term breast cancer outcome information for TC compared to A and T based fourth generation chemotherapy regimens in TNBC should be prospectively studied and reported. N = 146 Chemotherapy regimen A+T A TC A/T + Platinum Other - 70 (48%) 8 (6%) 50 (34%) 13 (9%) 5 (3%) Number of chemotherapy cycles < 4 4 > 4 - 6 (4%) 47 (32%) 93 (64%)
Identifying patients at high risk for neutropenic complications during chemotherapy for metastatic breast cancer (MBC) with doxorubicin or pegylated liposomal doxorubicin: Development of a prediction model
Authors: G. Reardon, D. Rayson, J. Chang, K. Gelmon, G. Dranitsaris
Journal: Journal of Clinical Oncology (2007)

6598 Background: Despite the effectiveness of anthracycline (ACH) therapy in the adjuvant and MBC settings, neutropenic complications (NC) remain a common and often unpredictable problem. Consequences may include dose reductions or delays in chemotherapy, or hospitalization for fever or infection. This study describes the development of a cycle-based risk prediction model for NC during chemotherapy with traditional doxorubicin (DOX) or a pegylated liposomal formulation (PLD) for MBC. Methods: Data analyzed was from a randomized clinical trial of MBC patients (n=509), who received chemotherapy with DOX (60 mg/m 2 every 3 wks) or PLD (50 mg/m 2 every 4 wks) [O'Brien, 2004]. NC were defined as an absolute neutrophil count (ANC) = 1.5 x10 6 cells/L, febrile neutropenia or neutropenia with infection. Patient, treatment and hematological factors potentially associated with NC were evaluated. Factors with a p-value of ≤ 0.25 within a cycle were included in a generalized estimating equations (GEE) regression model. Using backward elimination, we derived a risk scoring algorithm (range 0–63) from the final reduced model. Results: Risk factors retained in the model included poor performance status, ANC = 2.0 × 10 6 cells/L at some point in the previous cycle, the first cycle of chemotherapy, DOX vs. PLD and older age. A precycle risk score from = 25 to &lt; 40 for a given patient was identified as being the optimal threshold for sensitivity (58.0%) and specificity (78.7%). Patients with a score at or beyond this threshold would be considered at high risk for developing NC in later cycles. Risk scores below, within, or above this threshold predict a 0.3%–2%, 3%–8% and a 9%–45% probability risk of NC, respectively. Conclusion: This risk prediction tool demonstrated acceptable internal validity and can be readily applied by the clinician prior to a given cycle of chemotherapy. The application of this prediction tool may allow for identification and targeted intervention (such as growth factor support or the use of PLD) for those most likely to experience NC during anthracycline-based chemotherapy for MBC. No significant financial relationships to disclose.