tbuckley/cabot-search huggingface dataset:
Preliminary results of gemtuzumab ozogamicin (GO) during myeloablative conditioning for allogeneic stem cell transplantation (AlloSCT) or following reduced intensity alloSCT (RI-AlloSCT) in children with AML
Authors: P. Satwani, I. Waxman, M. Bhatia, Z. Jin, V. Kohl, L. Baldinger, J. Garvin, D. George, M. B. Bradley, J. Guerra, M. S. Cairo
Journal: Journal of Clinical Oncology (2008)

7038 Background: CD33 is expressed in 80–90% of childhood AML. GO, an immunotoxin targeting CD33, induces remission in 20–30% of relapsed/refractory childhood AML. Standard myeloablative conditioning (MAC) for AlloSCT in children with standard risk AML (SR-AML) is BU/CY. However, this regimen may be associated with 32% transplant related mortality (TRM) and 25% risk of relapse in SR-AML (Woods et al, Blood, 2001). Outcome following AlloSCT for high risk (HR) AML (≥CR3, induction failure [IF], refractory disease) is dismal (≤10% OS). There is a need for novel therapy during conditioning and after AlloSCT that can reduce TRM and relapse in SR-AML and improve outcome in HR-AML. Methods: We have performed 2 phase I studies of GO. In the first study of CD33+ HR-AML GO was dose escalated on day - 14 (3–7.5 mg/m2) prior to BU /CY MAC regimen. In the 2nd study of CD33+ SR-AML 2 doses of GO (4.5- 9 mg/m2) were administered ≥60d post reduced intensity conditioning (RIC) AlloSCT (8 wks apart). Results: In the HR-AML study, ten pts (2 CR3, 5 IF, 3 refractory) were studied. One pt died of chronic GVHD, 4 died of progressive disease, and 5 remain alive with no evidence of disease (NED). One pt developed mild VOD that resolved without therapy. In the SR-AML study, 11 pts, (8-CR1 and 3-CR2), received BU/FLU RIC. Nine pts received two doses of GO (Table) at mean d+78 and +153, respectively. One pt received one dose of GO but relapsed and died. One pt had primary graft failure. Nine pts are alive with NED; 1pt died from cGVHD. There has been no DLT secondary to GO and the MTD of GO in each study has not been reached. Conclusion: GO has been safe and well tolerated either added to MAC in children with HR-AML or as consolidation following RI-AlloSCT in SR-AML. We are currently accruing patients at the final dose level of GO in both studies. Study Conditioning GO Dose Median Age(range) Donors Myeloid Recovery (days) ANC>500/mm3× 2 days Platelet Recovery (days)(> 20,000/mm3 × 7 days UNTX) Mean Donor ChimerismDay-30 HR-AML Myeloablative 3mg/m2 [n=3] 8 yr 1 6/6 HLA-MSD, 24±10 54±49 96%±5 BU:12.8–16mg/kg 4.5mg/m2[n=3] (0.75-17) 1 10/10 MUD CY:120 mg/kg± ATG 6mg/m2 [n=3] 8 UCB (3 6/6, 2 5/6 and 3 4/6) 7.5mg/m2[n=1] SR-AML Reduced Intensity 4.5mg/m2[n=3], 11 years 8 6/6 HLA-MSD 15±4 16±16 97±2% BU:6.4–8mg/kg 6mg/m2 [n=4], (0.5-21) 1 5/6 MRD FLU: 150mg/kg ± ATG 7.5mg/m2 [n=3] 2 4/6 UCB. No significant financial relationships to disclose.
Phase I study of the multikinase prodrug SF1126 in solid tumors and B-cell malignancies.
Authors: D. Mahadevan, E. G. Chiorean, W. Harris, D. D. Von Hoff, A. Younger, D. M. Rensvold, F. Cordova, W. Qi, C. F. Shelton, M. D. Becker, J. R. Garlich, R. K. Ramanathan
Journal: Journal of Clinical Oncology (2011)

3015 Background: SF1126 is a peptidic prodrug that converts to LY294002, a widely studied dual PI3K/mTOR inhibitor that historically suffered from poor solubility. LY294002 is conjugated to an RGD peptide via a cleavable linker to form SF1126, which demonstrates improved solubility and site selectivity. LY294002 also inhibits other cancer target kinases including DNA-PK, PIM1, and PLK1 and induces oxidative stress in cancer cells. Methods: 39 pts with advanced solid tumors were enrolled in sequential cohorts in a standard 3+3 design. SF1126 was administered days 1, 4 weekly by 90 min i.v. infusion in 4 wk cycles. The maximum administered dose (MAD) level cohort (1,110 mg/m2) was expanded to allow pts with B-cell malignancies. Clinical response was evaluated according to standard disease-specific criteria. Primary objectives were to determine safety and a recommended phase 2 (RP2) dose. Results: Part 1 Solid Tumors. Toxicities were generally grade 1/2 with only 1 DLT (transient G3 diarrhea at 180 mg/m2 dose level). Stable disease (SD) was the best response in 19 of 33 (58%) of evaluable pts. Prolonged SD over 1 yr was noted in one GIST pt (18 cycles) and one renal cell carcinoma pt (21 cycles) who had progressed on temsirolimus representing possible evidence of effect of SF1126 on mTORC1 resistance. Part 2 B-Cell Malignancies. Four CLL pts and 1 DLBCL pt have been treated. One CLL pt who had progressed on rituximab achieved SD after two months of SF1126 alone. SF1126 plus rituximab led to a partial response with decreased absolute lymphocyte count, lesion sum products and spleen size. Flow cytometry and Western blotting of CLL cells showed that SF1126 reduced expression of p-AKT over time and increased late apoptosis demonstrating pharmacodynamic inhibition of activated PI3K signaling. Conclusions: SF1126 is well tolerated at doses up to 1,110 mg/m2 given by i.v. infusion twice weekly and showed significant disease stabilization in multiple solid tumor pts. MTD was not reached. The RP2 dose of 1,110 mg/m2 is the MAD and was reached based on the findings of safety, PK, PD, toxicity, and activity profile in solid tumor pts. In B-cell malignancies promising preliminary activity alone and in concert with rituximab was noted.
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanoma
Authors: K. B. Kim, J. Saro, S. S. Moschos, P. Hwu, A. A. Tarhini, W. Hwu, G. Jones, Y. Wang, H. Rupani, J. M. Kirkwood
Journal: Journal of Clinical Oncology (2008)

9026 Background: TKI258 is an inhibitor of type III to V RTKs including VEGF-Rs, FGF-Rs (FGF-R1, 2 and 3), PDGFR-β, c- KIT and FLT3 with preclinical pharmacology profile consistent with these targets. In experimental mouse models for melanoma, TKI258 has shown efficacy as a single agent and in combination with chemotherapeutic agents. Methods: A phase I study was conducted to determine the maximum tolerated dose (MTD), the biological activity and the preliminary efficacy of TKI258 in patients with advanced melanoma. TKI258 was administered orally on a once daily continuous dose schedule in 28 days cycle. Dose escalation was governed by a two- parameter Bayesian logistic regression model. Plasma biomarkers and DCE-MRI imaging were analyzed. Results: As of November, 19 patients have been treated at the following dose levels: 200 (2), 300 (2), 400 (8) and 500 mg/d (7). Median number of cycles was 2 (0–10). Median age was 63 years (33–81), and 10 patients were male. All patients were evaluable for toxicity. 3 patients experienced DLT at 500 mg/d (G3 and G4 fatigue and G3 diarrhea despite therapy), other toxicities ≥ G2 included fatigue (4), N/V (2), dehydration (2) and diarrhea (1). MTD will range between 400 - 450 mg/d, the study is continuing. 14 patients were evaluable for efficacy (two too early). 6 patients experienced SD from 4 to 10 months. Pharmacokinetic (Pop-PK) studies at 400 and 500 mg/d (n=10) showed a median T ½ = 17h (range:11–45), mean AUC = 2,894 ng/mL (range: 900–11,890) and mean CL/F= 95 L/h (range: 30–310). Significant VEGF induction was shown at 400 and 500 mg/d. Six out of ten patients treated at the above doses achieved DCE-MRI objective vascular response (defined as Change in Ktrans and/or AUCBN >2 SD ). VEGF induction tended to correlate with DCE-MRI responses and with tumor stabilization. Conclusions: TKI258 is safe and well tolerated at doses below 500 mg/d and has shown in metastatic melanoma patients treated at 400–500 mg/d preliminary biological activity that tended to correlate with disease control. 20 additional patients will be enrolled at the MTD to confirm these preliminary findings. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Pharmaceuticals Novartis Pharmaceuticals
Relationship of colorectal cancer incidence rate and age of diagnosis in eastern Kentucky.
Authors: Adnan Koura, Raymond Elsoueidi, Mark Dignan
Journal: Journal of Clinical Oncology (2012)

439 Background: Colorectal cancer is the third most commonly diagnosed cancer in US among men and women. Approximately 150,000 new cases of colorectal cancer are diagnosed each year and about 50,000 of them die. Nationally, it is documented that the highest percent of patients with colorectal cancer are diagnosed between the ages of 75-84. However, rates are higher in Eastern Kentucky and a larger proportion of cases appear to be diagnosed at a younger age. Methods: Data on newly diagnosed cases of colorectal cancer were collected from the Appalachian Regional Healthcare Cancer Registry, a registry serving seven county regions in Eastern Kentucky, and compared to data from Surveillance Epidemiology and End Results (SEER). Results: The age-adjusted incidence rate for SEER, 2004-2008, was 47.2 per 100,000 compared to 59.22 per 100,000 for Eastern Kentucky. The median age of diagnosis with colorectal cancer was 65 years in Eastern Kentucky, compared to age 70 in SEER and the proportion of patients diagnosed between age 35 and 64 was higher in Eastern Kentucky than in SEER: 6.96% vs. 3.90% for 35-44 and 25.35% vs. 19.60% for 45-64 (p &lt; 0.05. For residents age 75-85+, the proportion in Eastern Kentucky was lower than SEER: 75 - 84 yrs 19.50% vs. 26.20% and 85+ yrs 5.85% vs. 12.20% (p &lt; 0.05). Conclusions: The results of this study reflect an increase incidence of colorectal cancer among the younger population in Eastern Kentucky compared to US national data. Also there was a decrease incidence of newly diagnosed cases among the elderly population. This could be attributed to many domestic risk factors including genetic, diet, obesity, smoking or other factors. Further studies to stratify above possible factors are warranted.
High-risk osteosarcoma (OS): Preliminary results of the ISG-SSG II protocol
Authors: A. Brach Del Prever, S. Smeland, A. Tienghi, K. S. Hall, M. Aglietta, G. Bernini, T. Bohling, M. Berta, O. Brosjo, S. Ferrari, T. Alvegard
Journal: Journal of Clinical Oncology (2005)

9002 Background: The ISG-SSG II study was undertaken to explore the effect of adding high-dose chemotherapy (HDCT) with peripheral blood stem cells support (PBSC) to conventional chemotherapy (CT) in patients with primary metastatic and/or axial localized OS. Methods: From May 1996 to Dec 2003, 57 patients, median age 17 years (range 2–38) entered the study. 46 patients had metastases at presentation, 39 with extremity localized tumors and 7 with axial tumors. All 46 had lung metastases (> 2 nodules in 31 cases), 3 additional lymph node involvement and 6 bone metastases. 11 patients had pelvic OS without metastases. Preoperative CT included two courses of Methotrexate 12 g/m2, Cisplatin 120 mg/m2 + Adriamycin 75 mg/m2 and Ifosfamide 15 g/m2. Stem cells were harvested after the first course of Ifosfamide (day 28). Post-operatively patients received 2 cycles of Adriamycin 90 mg/m2, Cyclophosphamide (CTX) 4000 mg/m2 + VP16 600 mg/m2, and 2 cycles of HDCT containing VP16 1800 mg/m2 + Carboplatin 1500 mg/m2 with PBSC rescue. Results: Surgery of primary tumour was performed in 46 (81%) patients. A median of 2 (range 1–7) aphaereses were performed, with a median collection of 6.9x106 CD34+/kg. 3 patients needed additional bone marrow harvest. 27 patients received 2 HDCTs and 9 patients 1 cycle. Conditioning regimen was well tolerated (median time to Neutrophils > 0.5x109/l and Platelets > 25x109/l: 10 days). One patient developed renal failure after Ifosfamide and 1 veno-occlusive disease after CTX + VP16. 38 (67%) patients (30 metastatic and 8 pelvic) achieved complete remission (C.R.). With a median follow-up of 26 months (range 4–101 months), 14 patients are alive in 1st C.R., 5 in 2nd or higher C.R., 3 patients are alive with disease and 35 have died of disease. The projected overall and event free survival (EFS) at 3-year are 39% and 21% respectively. For the group with metastatic disease (n=46) the 3-year overall and EFS rates are 34% and 16% respectively, and for the group of patients (n=38) who achieved C.R. 58% and 33%. Conclusions: The ISG-SSG II study demonstrates that HDCT in addition to conventional CT is feasible in high-risk OS patients. The reported survival rates do not support the use of HDCT in this subset of patients. No significant financial relationships to disclose.
Magnetic resonance elastography for prediction of radiation‐induced liver disease after stereotactic body radiation therapy
Authors: Shintaro Ichikawa, Utaroh Motosugi, Mitsuhiko Oguri, Hiroshi Onishi
Journal: Hepatology (2017)

Ichikawa, Shintaro1; Motosugi, Utaroh*,1; Oguri, Mitsuhiko1; Onishi, Hiroshi1 Author Information
Systematic survey of therapeutic trials for metastatic colorectal cancer.
Authors: Zhiyu Chen, Michael J. Overman, Chris R. Garrett, Zhi-Qin Jiang, Robert A. Wolff, James L. Abbruzzese, Cathy Eng, Scott Kopetz
Journal: Journal of Clinical Oncology (2012)

523 Background: The FDA’s 2004 “Critical Path Initiative” encouraged novel clinical trials and incorporation of biomarker-based enrichment studies to improve drug development. A survey of metastatic colorectal cancer (mCRC) trials from 2006 (Kopetz et al. JCO) demonstrated a very low utilization of novel therapies and minimal biomarker integration. The extent of change of mCRC clinical trials 5 years later is unknown. Methods: The NIH clinical trials database was searched for enrolling phase II or III treatment trials in mCRC, using previously published search strategies. Enrichment studies were defined by the presence of a tumor-based biomarker in the eligibility criteria. Trials were categorized according to FDA approval status and mechanism of action of the included agents, with novel agents being defined as ones not targeting the same protein or cellular mechanism as an existing agent that is FDA-approved for mCRC. Results: 162 trials were identified for mCRC pts with planned enrollment of 31,050 mCRC patients, representing a 58% and 45% increase from the 2006 survey, respectively. Fewer studies used only agents already FDA-approved for mCRC in 2011 compared to 2006 (39% vs 54%, respectively, P=0.02), with a substantial increase in the number of trials that included agents against novel therapeutic targets (n=49 vs 13, P=0.001). Enrichment trial designs were identified in 64 studies, compared with 13 in 2006 (P=0.0001). While the majority of these designs were for KRAS-wild type tumors and EGFR monoclonal antibodies, there has been a 5-fold increase in novel biomarker-directed trials (n=3 vs 15). However, 101 trials (62%) with an anticipated enrollment of over 21,000 mCRC pts, neither incorporate a novel agent nor biomarker in their trial design. Conclusions: Compared with trial in 2006, current mCRC trials are more likely to evaluate novel agents and incorporate enrichment designs with tumor-based biomarkers. Yet despite the rapid development of biomarker technology for pt enrichment and wider acceptance of innovative trial designs, most clinical trials are empiric in design and fail to integrate recommendations from the FDA Critical Path Initiative.
Human papillomavirus (HPV) and rising oropharyngeal cancer incidence and survival in the United States.
Authors: A. Chaturvedi, E. Engels, R. Pfeiffer, B. Y. Hernandez, W. Xiao, E. Kim, B. Jiang, M. Goodman, M. Sibug-Saber, W. Cozen, L. Liu, C. Lynch, N. Wentzensen, R. Jordan, S. Altekruse, W. F. Anderson, P. Rosenberg, M. L. Gillison
Journal: Journal of Clinical Oncology (2011)

5529 Background: Recent increases in incidence and survival of oropharyngeal cancers in the United States (U.S.) have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking. Methods: HPV status was determined for 271 oropharyngeal cancer cases (1984-2004) collected by population-based cancer registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results program in Hawaii, Iowa, and Los Angeles. Tumor HPV status was determined by PCR and genotyping (Inno-LiPA), HPV16 viral load, HPV16 mRNA expression, and HPV16 in situ hybridization. Trends in HPV prevalence across four calendar periods were estimated using logistic regression. Survival of HPV-positive and HPV-negative cases was compared by Kaplan-Meier and multivariate Cox regression analyses. Results: HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay (p-trend<0.05). For example, HPV prevalence by Inno-LiPA increased more than 4-fold from 16.3% during 1984-1989 to 72.7% during 2000-2004. Median survival was significantly greater for HPV-positive vs. HPV-negative cases (131 vs. 20 months; log-rank p<0.001; adjusted hazard ratio=0.31; 95%CI=0.21-0.46). Survival significantly increased across calendar periods for HPV-positive (p=0.003) but not for HPV-negative cases (p=0.18). The difference in survival between HPV-positive and HPV-negative cases was greater for cases treated by radiation (HR= 0.23; 95%CI=0.09-0.59) than those not treated by radiation (HR=0.80; 95%CI=0.40-1.60; p-interaction=0.002). Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% during 1988-2004 (0.8/100,000 to 2.6/100,000), while incidence for HPV-negative cancers declined by 50% (2.0/100,000 to 1.0/100,000). Should recent incidence trends continue, the annual number of HPV-positive oropharyngeal cancers among men is expected to surpass that of cervical cancers among women by the year 2020 in the U.S. Conclusions: Increases in the population-level incidence and survival of oropharyngeal cancers in the U.S. since 1984 are caused by HPV infection.
The effect of perioperative transfusion on recurrence and survival following gastric cancer resection: A seven-institution analysis of 765 patients from the U.S. Gastric Cancer Collaborative.
Authors: Malcolm Hart Squires, David A. Kooby, George A. Poultsides, Sharon M. Weber, Mark Bloomston, Ryan C. Fields, Timothy M. Pawlik, Konstantinos I. Votanopoulos, Carl Richard Schmidt, Aslam Ejaz, Alexandra W. Acher, David J. Worhunsky, Neil Saunders, Doug S. Swords, Linda X. Jin, Clifford Suhyun Cho, Emily Winslow, Maria C. Russell, Charles A. Staley, Shishir K. Maithel
Journal: Journal of Clinical Oncology (2014)

100 Background: Whether perioperative blood transfusion has a negative prognostic effect on recurrence and survival in patients undergoing resection of gastric adenocarcinoma (GAC) is unknown. Methods: All patients who underwent resection for GAC from 2000-2012 at 7 institutions were identified. The effect of transfusion on recurrence-free (RFS) and overall survival (OS) in the context of adverse clinicopathologic variables was examined by univariate (UV) and multivariate (MV) regression analyses. Results: Out of 965 pts, 765 underwent curative intent, R0 resection. Median FU for survivors was 44 mos; 30-day deaths were excluded. Median estimated blood loss (EBL) was 250cc and 166 pts (22%) received perioperative RBC transfusions. 5-yr RFS was 51% in transfused and 61% in non-transfused patients (p=0.01). Median OS was decreased in patients receiving transfusions (19 vs 50 mos, p&lt;0.001). On MV analysis, transfusion remained an independent risk factor for decreased RFS (HR 2.8; 95% CI: 1.2-6.5; p=0.01) and decreased OS (Table), regardless of EBL or need for splenectomy. Timing (intraop vs postop) and volume (# of units) did not alter the effect of transfusion on survival. Non-transfused pts were more likely to receive adjuvant therapy (56% vs 44%; p=0.01). Conclusions: Perioperative blood transfusion is associated with decreased recurrence-free and overall survival following resection of gastric cancer, independent of adverse clinicopathologic factors. This supports the judicious use of perioperative transfusion during resection of gastric cancer. [Table: see text]
Association of Complement with Microvascular Endothelial Cell Injury in Thrombotic Microangiopathy In Vivo and in In Vitro Model Systems.
Authors: Brian A. Di Carlo, Radu Stefanescu, Kelvin Lee, Wei Yin, Rozbeh Modaressi, Ellinor I.B. Peerschke, Jeffrey Laurence
Journal: Blood (2006)
Provider perceptions of burnout while engaging in end-of-life care conversations: A pilot study using the Serious Illness Conversation Guide.
Authors: Anna Catherine Beck, Allison Miraglia, Deepthi Rajeev, Rita Hanover, Joshua Steenstra, Shaida Talebreza, Holli Martinez, Emily Looney
Journal: Journal of Clinical Oncology (2016)

19 Background: Studies recommend improved attention to patient end-of-life (EOL) care preferences and there is evidence that effective provider-patient EOL care conversations yield positive patient outcomes and reduce stress, anxiety, and depression for providers. Providers lack training to elicit patients’ EOL care goals and hence are reluctant to initiate EOL conversations. Methods: The Serious Illness Conversation Guide (SICG) was used to train providers and data were collected based on the Maslach Burnout Inventory to assess provider burnout, determine satisfaction of SICG training, and change in confidence/knowledge related to EOL conversations. Results: 18 providers were trained with a median work experience of 15 years. 41% spent 8+ hours/week interacting with seriously ill patients, 50% initiate EOL conversations &lt; twice/month, and 19% reported burnout. 10 providers responded to the post-training evaluation, 80% reported burnout (Table). Conclusions: Providers reported high satisfaction of SICG training and increased knowledge and confidence related to EOL care conversations. However, provider burnout increased, possibly due to their increased awareness of an appropriate way to elicit patients’ EOL care goals. To explore this further, we will be conducting additional training sessions in the future. [Table: see text]