tbuckley/cabot-search huggingface dataset:
Effect of an inpatient hematology-oncology ward rotation on medical house staff interest in pursuing hematology-oncology as a career.
Authors: Daniel Curtis McFarland, Jimmie Holland, Randall F. Holcombe
Journal: Journal of Clinical Oncology (2015)

e17559 Background: There is an oncologist workforce shortage. Medical sub-specialty training experiences influence residents’ career choices. We hypothesized that an inpatient ward rotation may increase residents’ interest in hematology-oncology. Resident distress, empathy, resilience, and patient death experiences were explored as reasons that would mitigate interest. Methods: Agreement with “I am interested in pursuing a career/fellowship in hematology and oncology”, was rated by residents before and after a hematology-oncology rotation where 0 = not true at all, 1 = rarely true, 2 = sometimes true, 3 = often true, 4 = true nearly all the time. Residents completed the Connors-Davidson Resilience Scale (CD-RISC), Impact of Events Scale-Revised (IES-R), and the Interpersonal Reactivity Index (IRI). Demographic information, number of dying patients, and derived meaning from working with dying patients were surveyed. Results: Fifty-six residents completed before and after rotation questionnaires (response rate 56%). The mean interest score was 1.43 initially and decreased to 1.24 after the rotation (p = 0.301). Female mean score was 1.13 initially and dropped to 0.81 after the rotation (p = 0.04). Male mean score was 1.71 initially and 1.81 after the rotation (p = 0.649). The attribution of ‘meaning’ had a protective effect on maintaining interest. Conclusions: The ward experience decreased residents’ interest in hematology-oncology. Encouraging outpatient rotations and cultivating resilience, empathy, and the ‘meaning’ of death-laden experiences may increase resident interest in hematology-oncology. Correlations Total n=56 Female n=32 Male n=24 Δ interest<->Distress ns ns ns Δ interest<->Empathy r = 0.338, p = 0.012 r = 0.381, p = 0.03 ns Δ interest<->Resilience ns ns r = -0.47, p = 0.03 Δ interest<-># dying patients ns ns ns ns=not significant, *p<0.05, r=correlation, Δ=change
Unresectable colorectal cancer liver metastases treated with radioembolization: Updated survival analysis of the MORE study.
Authors: Andrew S. Kennedy, Michael Cohn, Douglas M. Coldwell, Alain Drooz, Eduardo Ehrenwald, Adeel Kaiser, Charles W. Nutting, Steven C. Rose, Eric Wang, Michael Savin
Journal: Journal of Clinical Oncology (2017)

666 Background: In December 2011, the Metastatic Colorectal Cancer Liver Metastases Outcomes after Radioembolization (MORE) study retrospectively analyzed 606 patients with unresectable colorectal liver metastases treated with radioembolization using Y-90 resin microspheres. At a median follow-up of 8.6 months, 503 of these patients had died. Here, we summarize survival outcomes from extended follow-up of the remaining patients through September 1, 2016. Methods: Extended survival surveillance was abstracted from patient charts and public records. Survival time was compared for prognostic variables using Kaplan-Meier estimates. Results: Survival data were analyzed for 574 of 606 patients with median follow-up of 9.5 months (IQR 12.9 months). Patients received a median (range) of 2 (0 to 6) lines of chemotherapy. Additional death dates were obtained on 71 patients, and median survival was 10.0 months (95% CI 9.2-11.8) -versus 9.6 (95% CI 9.0-11.1) months originally reported. Data confirm ECOG PS, disease stage, extent of liver involvement, liver function, metachronous metastasis, and prior chemotherapy as predictors of post-radioembolization survival. Conclusions: Long-term follow-up confirms the originally reported prognostic factors for survival and that radioembolization offers a favorable survival benefit for patients with unresectable colorectal cancer liver metastases, even among those who already received 3 or more lines of chemotherapy. [Table: see text]
21-gene recurrence score assay (RS) and impact on adjuvant chemotherapy (CTx) use among lobular (L) and ductal (D) histology hormone receptor positive (HR+) early breast cancers (EBC).
Authors: Simon Daniel Baxter, Lovedeep Gondara, Caroline Speers, Ashley Davidson, Stephen K. L. Chia, Vanessa Bernstein, Susan Ellard, Scott Tyldesley, Caroline A. Lohrisch
Journal: Journal of Clinical Oncology (2015)

543 Background: RS identifies lower risk HR+ EBCs that may avoid adjuvant CTx. L histology may influence CTx use in intermediate RS cancers given its association with high HR+ expression and hormone therapy benefit. We examined RS and its utility in clinical decisions among L relative to D EBCs. Methods: We identified BC Cancer Agency referred pts with a RS performed on their HR+ EBC between 2007 and 2014, as part of routine care (node negative only) or in clinical trials. Multifocal tumors and mixed L-D histology were excluded. Demographic and histopathological variables and rates of CTx were compared for D and L using univariate and multivariate analyses. Results: After exclusions, 577 cases (89% D, 11% L) were identified. Compared with D tumors, L tumors were larger, lower grade, had a lower mean RS (20 vs 16 p = 0.0002), and fewer had high RS (Table 1). These differences were not significant after adjustment for age, degree of HR+ expression, size, grade, nodal status, LVI. Among 289 pts (256 D, 33 L) with treatment not mandated in a trial based on RS, 82 (28.4%) had CTx, including 5 (15.2%) L and 77 (30.1%) D (p = 0.10). Of the 97 with intermediate RS cancers, CTx was given in 3/12 (25%) L and 26/85 (30.6%) D cases. Conclusions: The observed frequency of L and D histology in this series mirrors the incidence distribution described in EBC. The overall lower use of CTx in L cancers can be accounted for by lower RS and more favourable histopathological variables. Among intermediate RS cancers, histology did not appear to impact CTx use. In the absence of prospective data, L histology should not influence CTx use for intermediate RS cancers. Comparison of ductal and lobular cancers. Ductal Lobular P-value Pts, n (%) 512 (89) 65 (11) Age, mean (range) 55 (23-78) 58.5 (42-77) 0.008 Premenopausal, n (%) 232 (45) 19 (29) 0.01 Grade, n (%) 1 82 (16) 6 (9) < 0.0001 2 282 (55) 54 (83) 3 148 (29) 5 (8) Size, n (%) T1 328 (64) 24 (37) < 0.0001 T2 180 (35) 38 (58) T3 4 (1) 3 (5) Node negative, n (%) 375 (73) 50 (77) 0.53 LVI present 106 (20) 4 (6) 0.01 RS, mean (range) 20 (0-73) 16.4 (4-33) 0.0002 High, n (%) 82 (16) 3 (5) 0.047 Intermediate, n (%) 170 (33) 23 (35) Low, n (%) 260 (51) 39 (60)
Biomarker study of early death in patients with intermediate and favorable risk metastatic renal cell carcinoma.
Authors: Wayne Harris, Chao Zhang, Yuan Liu, Omer Kucuk, Bradley Curtis Carthon, Viraj A. Master
Journal: Journal of Clinical Oncology (2017)

530 Background: The primary objective of this study was to determine whether severe systemic inflammation (SSI) could serve as a biomarker for terminal disease progression and early death in patients with intermediate and favorable risk metastatic renal cell carcinoma (mRCC). Methods: Retrospective chart reviews of patients treated with targeted therapy for mRCC were conducted at the Winship Cancer Institute of Emory University (WCIEU) and the Atlanta Veterans Administration Medical Center (AVAMC) after obtaining institutional authorizations. The modified Glasgow Prognostic Score (mGPS) was used to quantify intensity of systemic inflammation (ISI) at baseline and at least two additional time points that were at least 10 days apart. Early death was defined as death within two years of Day 0, the first day ISI was quantified. Descriptive statistics were employed along with Kaplan-Meier survival analysis. Results: ISI was quantified 2,428 times in 135 patients at the WCIEU with a median of 16 per patient and a range of 3 to 51 versus 758 times in 46 patients at the AVAMC with a median of 12 per patient and a range of 3 to 48. Baseline risk stratification was as follows: favorable (mGPS=0), intermediate (mGPS=1) and poor (mGPS=2) with 96 (51%), 36 (19%), and 53 patients (29%) in the respective risk groups of the combined cohort (n=181). Sixty eight of the 90 patients who died in the time frame of the study did so within 2 years of Day 0. Of these early deaths, only 34 (50%) were among patients with poor risk at baseline versus 18 (26%) and 16 (24%) of the intermediate and favorable risk patients, respectively. Furthermore, 90% of these early deaths were associated with SSI as a terminal event as were 87% of all deaths in spite of the fact that 64% of poor risk patients had died as of Year 2 versus only 27% of patients in the combined group of intermediate and favorable baseline risk. Conclusions: Severe acquired systemic inflammation is a promising biomarker for terminal disease progression and early death in patients with intermediate and favorable risk mRCC. Prospective confirmatory studies are required.
An electronic prompt prior to myelosuppressive therapy to improve hepatitis B virus screening.
Authors: Jordan J. Feld, Lisa K. Hicks, Joshua Juan, Truong Judy, Urszula Zurawska, Angie Giotis, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2014)

6627 Background: Hepatitis B virus (HBV) reactivation is a potentially fatal and yet preventable complication of myelosuppressive therapy. However, HBV screening rates have been low despite the recommendation from the Centre of Disease Control (CDC) to screen all patients prior to myelosuppressive therapy. We evaluated the effectiveness of an electronic prompt on HBV screening rates. Methods: An electronic prompt was established in Nov 2010 at a large academic oncology centre in Toronto (study centre). The electronic prompt reminded ordering physicians to order HBV surface antigen (HBsAg) at the time of booking a new patient’s first chemotherapy electronically. For physicians who agreed, HBsAg was automatically ordered. The prompt was not implemented at another large academic oncology centre in Toronto (control centre). Both centres received the same educational rounds in Nov 2010. The primary endpoint was the rate of HBV screening. Actual HBV screening rates were determined in both centres both prior to the intervention (Nov 2009 to Oct 2010) and during the intervention (Nov 2010 to Oct 2011). Multivariable logistic regression with random effects was conducted to assess the effect of the electronic prompt adjusting for potential confounders and clustering of patients by physicians. Results: 6,116 patients received first chemotherapy during the study period (2,095 study centre, 4,021 control center). In the pre-prompt period, the screening rate was 17% in the study centre and 25% in the control centre. In the prompt period, the screening rate increased to 61% in the study centre and was unchanged at 25% in the control centre. The overall screening rate for patients with hematological (heme) malignancies was higher (62.3% vs. 20.4% in non-heme patients, p<0.0001). After adjusting for study period, centres and heme malignancies, the electronic prompt improved the HBV screening rate significantly (odds ratio 11.0, 95% CI 8.3-14.7, p<0.0001), which remained significant adjusting for clustering of patients by physicians (p<0.0001). Conclusions: An electronic prompt increased the rate of HBV screening, however screening rates remained relatively low. Educational rounds did not appear to improve the HBV screening rate.
Quality of Cancer Surveillance Clinical Practice Guidelines
Authors: Ryan P. Merkow, Deborah Korenstein, Rubaya Yeahia, Peter B. Bach, Shrujal S. Baxi
Journal: JAMA Internal Medicine (2017)

Primary care clinicians, who are increasingly responsible for caring for the growing population of cancer survivors, may be unfamiliar with appropriate cancer surveillance strategies. Clinical practice guidelines can inform cancer follow-up care and surveillance testing. Vague recommendations and inconsistencies among guidelines can lead to overuse and underuse of health care resources and have a negative impact on cost and quality of survivorship care.
Expression and function of the four and a half LIM-only protein 2 (FHL2) in breast cancer
Authors: B. T. Martin, K. Kleiber, M. Kaufmann, K. Strebhardt
Journal: Journal of Clinical Oncology (2006)

10109 Background: FHL2 belongs to the expanding family of proteins that possess highly conserved double Zn-finger motifs, CX 2 CX 16–23 HX 2 CX 2 CX 2 CX 16–21 CX 2 (C/H/D), and are involved in protein-protein interactions and transcriptional regulation. FHL2 was primarily described as “down regulated in rhabdomyosarcama cells LIM domain protein” (DRAL). Further studies also indicated a connection of FHL2 with the tumor biology. Its expression has been shown to be increased in tumors of epithelial and melanoma cell origin. A recent publication describes the interaction of FHL2 with the breast cancer susceptibility gene 1 (BRCA1) but to date little is known about the function of FHL2 in breast cancer. Methods: Tumor samples of 61 breast cancer patients and 8 normal breast tissues were lysed and subjected to Western blot analysis using a monoclonal FHL2-specific antibody; Tissue specimens of normal breast and breast cancer were histologically examined with the monoclonal antibody used for the Western blot analysis; Luciferase assays were carried out in MCF-7 breast cancer cells, using AP1-dependent reporter plasmids. Anchorage-independent growth was assayed by colony formation in soft agar. Results: FHL2 is overexpressed in almost all human breast cancer tissues tested but not in normal breast tissues and only low levels of FHL2 expression were present in four premalignant ductal carcinoma in situ (DCIS). Co-immunoprecipitation assays and GST-pull down experiments revealed that FHL2 interacts with the proto-oncogene c-jun in breast cancer cells. Reporter gene assays demonstrated that FHL2 represses c-jun-mediated activation of an idealized AP-1-regulated reporter gene in a dose-dependent manner. This repression was also seen on the naturally occurring AP-1-dependent IL2 promoter. The repression domain was identified within the N-terminal half of the FHL2 molecule. Finally, we show that stable expression of FHL2 leads to anchorage-independent growth of breast cancer cells in soft agar. Conclusions: Taken together, our data suggest that by modulating the activity of transcription factors such as c-jun, the expression of FHL2 in breast cancer might contribute to the malignant potential of breast tumors. No significant financial relationships to disclose.
Advanced colorectal carcinoma
Authors: C. G. Gennatas, G. Papaxoinis, N. Tsavaris, D. Mouratidou, C. Andreadis, D. Voros, A. Fotopoulos, V. Smyrniotis, E. Mallas
Journal: Journal of Clinical Oncology (2004)

3655 Background: The purpose of this study was to compare the activity and toxicity of a CPT-11, LV, 5-FU combination with a standard regimen of 5-FU and low dose LV. Methods: One hundred and twelve patients, all with measurable disease and previously untreated with chemotherapy for advanced disease, have been randomized so far; 55 patients (group Á) received LV 20mg/m2 i.í. bolus and 5-FU 425 mg/m2 i.í. bolus ïn days 1–5, with cycles repeated every 28 days. 57 patients (Group Â) received CPT-11 80mg/m2 (30–90min i.í. infusion), followed by LV 20mg/m2 i.í. bolus and 5-FU 425mg/m2 i.í. bolus ïn days 1, 8, 15, 22, 29, and 36, with cycles repeated every 8 weeks. Response was assessed every 3 months or when clinically indicated. The primary end point of this study was the overall objective tumor response rate (CR and PR). The study was designed principally to determine whether CPT-11, LV and 5-FU was a least as active as 5-FU/LV in the induction of tumor responses. A sample size of 302 patients per treatment group was considered sufficient to achieve 80% power to demonstrate at least equivalence in overall response rates, assuming a 20% response rate in both treatment groups, a margin of equivalence of 10%, with alpha equal to 0.025. Results: Responses were as follows; Group Á: Complete response (CR)=0–Partial response (PR)=10, Group Â: CR=2–PR=15. Median durations of response and survival have not yet been calculated. The main hematological toxicity was grade III/IV neutropenia, which occurred in 2 Group Á and 4 group Â patients. The main Grade III/IV non-hematological toxicities were diarrhea in 6 Group Á and 11 Group Â patients. No toxic death was observed and no patient was hospitalized because of febrile neutropenia. Conclusions: The preliminary results of this ongoing study suggest that the combination of CPT-11, LV and 5-FU is more effective than the combination of LV+5-FU. It is a well tolerated outpatient regimen for the treatment of advanced colorectal cancer. Because of its effectiveness, ease of administration and good patient tolerance, further investigation in the adjuvant setting is warranted. No significant financial relationships to disclose.
Use of liquid biopsy for detection of renal cell carcinoma.
Authors: Dean Laganosky, Charles Lorentz, Usama Al-Qassab, Kenneth Ogan, Viraj A. Master, Muta Issa, John Pattaras, David Roberts, Sharon Bergquist, Michael R. Rossi, Rebecca Arnold, Jeremy Goecks, John Petros
Journal: Journal of Clinical Oncology (2017)

521 Background: Circulating tumor DNA (ctDNA) displays characteristics of an ideal serum biomarker. We sought to develop whole-exome sequencing of ctDNA to interrogate commonly mutated genes in renal cell carcinoma (RCC) for early tumor detection through a single blood sample. Methods: Patients with solid renal tumors and healthy controls provided 40 mL blood from which purified plasma cell-free DNA was prepared. A multiplex bar-coded polymerase chain reaction amplification using the Fluidigm Access Array was performed to prepare sequencing libraries for the Illumina HiSeq platform. Galaxy workflow was then utilized to identify mutations within the plasma cell-free DNA samples and results were compared to buffy coat sequencing containing control DNA for each individual’s sample. The following genes were queried: VHL, PBRM1, SETD2, BAP1, KDM5C, KIT, NFE2L2, MET, TP53, CDKN2A, FGFR3, PIK3CA, BRAF, and MUC4. Criteria for calling mutations included adequate frequency by overall count and percentage of reads, identification in all overlapping sequences and presence of buffy coat-derived control DNA for comparison with &lt;0.5% containing the mutation. Results: Of the preoperative RCC patients, 20/30 (67%) had detectable somatic mutations compared to 2/48 (4.2%) controls. These included nonsynonymous, frameshift, stop-gain, and splice site mutations. Mutations were detected in RCC patients with both early and advanced stage disease, including a patient with a 1.1 x 0.7 x 0.5 cm tumor. Mutations were seen in all genes assayed. Conclusions: The majority of RCC patients of various stages and histology had ctDNA detected in a single preoperative blood sample. Comparatively, only two of the control patients sampled were ctDNA positive. Controls will be followed to identify the possible sources of ctDNA. Developing such non-invasive methods for RCC detection has the potential to enhance both diagnosis and surveillance of renal malignancy, even in the setting of small renal masses.
Development of an Optimized rAAV2/6 Human Factor 8 cDNA Vector Cassette for Hemophilia a Gene Therapy
Authors: Brigit E. Riley, Jeff Boonsripisal, Alicia Goodwin, Dominique Cartier, Eudean Garces, Kate Nesbitt, Courtney Dwyer, Stephen Ballaron, Kassandra Hebert, Hung Tran, Andrea Kang, Lei Zhang, Kathleen E. Meyer, Judith Greengard, Christine Hough, Richard Surosky, Dale Genji Ando, David Lillicrap, Geoff Nichol, Michael C. Holmes
Journal: Blood (2016)
A phase I study of cabozantinib (XL184) in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: A Children’s Oncology Group phase I consortium trial.
Authors: Meredith K. Chuk, Brigitte C. Widemann, Charlotte H. Ahern, Joel M. Reid, AeRang Kim, John Joseph Wright, Maya Lodish, Elizabeth Fox, Brenda Weigel, Susan Blaney
Journal: Journal of Clinical Oncology (2014)

10078 Background: Cabozantinib, an oral inhibitor of tyrosine kinases including MET, VEGFR2 and RET, is approved for adults with progressive, metastatic medullary thyroid carcinoma (MTC). We conducted a phase I and pharmacokinetic (PK) trial of cabozantinib in children with refractory solid tumors. Methods: Cabozantinib was administered daily (28 day cycles) using the rolling 6 design; 3 dose levels were evaluated. If a cohort was filled, patients (pts) with MTC could be enrolled at the previous lower dose. PK and pharmacodynamic (PD) studies were conducted in all patients, including an expanded cohort at the recommended phase 2 dose (RP2D). Results: 29 eligible (25 evaluable) pts, median age 14 yr (range, 4-18) [CNS tumor (n=6), MTC (n=3), hepatocellular carcinoma (HCC, n=2), Ewing sarcoma (EWS, n=2), other sarcomas (n=8), or other (n=8)] have received a median of 3 (range, 1-10) cycles, with 6 pts still on study. During the dose escalation phase dose-limiting toxicities (DLT) occurred in 0/6 pts at 30 and 40 mg/m2 and 1/6 pts at 55 mg/m2 [Gr3 fatigue and headache]. Other first cycle DLTs in expansion cohorts included: Gr 2 palmar plantar erythrodysesthesia (PPE) and oral mucositis (n=1; 40 mg/m2); Gr3 proteinuria and Gr2 hypertension (HTN) (n=1; 55 mg/m2); and Gr3 HTN and reversible posterior leukoencephalopathy syndrome (n=1; 55mg/m2). Later cycle DLTs in 10 pts include: Gr3 weight loss (n=2), Gr3 PPE (n=2), Gr3 and 4 lipase increase (n=1 each), Gr4 neutropenia (n=1), Gr2 fatigue (n=1), Gr2 arthralgia (n=1) and Gr3 anorexia, dyspnea, skin ulcer (n=1). Cabozantinib exposure was not dose proportional. The mean ± SD steady state AUC0-24h at 30 mg/m2 (n=6), 40 mg/m2 (n=6) and 55 mg/m2(n=6) was 31.9 ± 7.8, 33.3 ± 11.3 and 33.7 ± 15 µg·h/mL, respectively. The median accumulation index was 3.0 (0.5-8.7). Responses will be reported. Conclusions: Based on DLTs observed in later cycles, the recommended dose of cabozantinib in children with solid tumors is 40 mg/m2 (adult fixed dose ≈72 mg). Enrollment is ongoing to further assess PK and PD at the RP2D. A phase II trial is planned. Clinical trial information: NCT01709435.