tbuckley/cabot-search huggingface dataset:
Frequency of potential therapeutic targets identified by immunohistochemistry (IHC) and DNA microarray (DMA) in tumors from patients who have progressed on multiple therapeutic agents
Authors: D. D. Von Hoff, R. Penny, S. Shack, E. Campbell, D. Taverna, M. Borad, D. Love, J. Trent, M. Bittner
Journal: Journal of Clinical Oncology (2006)

3071 An important question that arises when caring for patients referred for phase I clinical trials is, if one studied the patients’ tumors carefully enough, would there be targets in those patients’ tumors for which a therapeutic agent might already be available. Perhaps treating the patient with that therapeutic agent would be better than trying the phase I agent. To address that issue we have performed IHC assays for up to 13 targets (e.g. Her2/neu, ER, c-kit, etc.) as well as a two color Agilent oligonucleotide microarray with 17, 085 unique probes, on tumors from patients with advanced cancer who have exhausted conventional therapy and who were undergoing a procedure for a cancer related matter (e.g. obstruction, ascites, etc.). Ninety-one patients had excess tissue submitted from the procedure, immediately frozen and subjected to microarray analysis and had IHC performed on sections obtained from the paraffin blocks prepared as part of their standard surgical workup. IHC was considered positive if ≥ 30% of tumor cells were scored as +1 or greater staining. For microarray studies the gene expressions were called significantly increased or decreased if the fold change in expression relative to the nominal tissue of origin reference was significant at p≤0.001. For the 91 patients where frozen tumor was submitted 89 (98%) of them had RNA that was of excellent quality. The findings were a surprise in that IHC identified an average of 1.2 targets (for which a conventional therapeutic agent is available) per patient (range 0 - 4 targets). The DMA identified an average of 3.3 targets per patient (range 0 - 8 targets). Overall, a target was found for 89 (98%) of the patients. This data indicates that using IHC and DMA one can consistently find a potential target for which we have a therapeutic agent in patients’ tumors even thought they have progressed on prior therapies. This has implications for patients’ planning on participating in phase I clinical trials. It is important to conduct a prospective clinical trial to determine whether the targets discovered using IHC and DMA can be used to select therapy which will further benefit the patient who would otherwise be participating in a phase I clinical trial. [Table: see text]
Topotecan-based induction regimen in high-risk neuroblastoma
Authors: A. Donfrancesco, I. Ilari, M. De Ioris, D. De Pasquale, R. Pessolano, A. Castellano, A. Serra, L. De Sio, C. Dominici, A. Jenkner
Journal: Journal of Clinical Oncology (2008)

21001 Background: Evaluate the impact of a topotecan-based induction regimen in high-risk (HR) neuroblastoma. Methods: Patients with HR and/or MYCN-amplified neuroblastoma received 2 courses of topotecan (TPT) 6 mg/m2 and cyclophosphamide (CPM) 4.2 g/m2, followed by 2 courses of ifosfamide 9 g/m2, carboplatin 800 mg/m2 and etoposide 500 mg/m2 (ICE). After resection of primary, a 5th course with vincristine 1.5 mg/m2, doxorubicin 75 mg/m2 and CPM 3 g/m2 was administered, followed by high-dose chemotherapy, PBSC rescue, local radiotherapy and cis-retinoic acid for 12 months. Primary tumor and bone marrow were evaluated after the second and the fourth course while skeletal disease was evaluated by MIBG scan at the end of induction. Results: 33 consecutive pts (18M/15F), median age 42 months (range 13–159), were enrolled April 2001- December 2006, 31/33 metastatic and 2 MYCN-amplified localized tumors. 28/33 showed skeletal involvement on MIBG and 22/31 had marrow disease. After two cycles 29 pts had evaluable primaries: 16/29 achieved PR with a RR of 55% and a median decrease of primary tumor volume of 54%. 8/22 marrows had turned negative. After four cycles the RR was 93% at the primary site with a median tumour reduction of 90%. One metastatic pt had died from surgical complication. At the end of induction, 27/32 pts achieved CR/VGPR or PR (84%). 3 metastatic pts suffered PD at the metastatic site after the fourth course. Bone marrow was cleared in 14/22 pts (64%). Complete remission of metastases was achieved in 11/30 (35%) and in 8/27 MIBG-positive cases. Toxicity was mainly haematological; CTC grade 4 in 100% of TPT/CPM courses and in 95% of ICE courses. Conclusions: The proposed induction regimen appeared feasible with good activity, without toxic deaths. At the end of induction the reported RR was 84% with a complete metastatic response in 35% and clearing of bone marrow in 64% of treated children. No significant financial relationships to disclose.
Physician and patient-related barriers to participation in genetic testing for breast cancer susceptibility
Authors: S. M. Domchek, A. J. Tweed, J. Stopfer, M. Weiner, B. L. Weber
Journal: Journal of Clinical Oncology (2004)

9582 Background: Genetic testing is increasingly available for a number of diseases, but still has limited acceptance among physicians and patients. Clinical testing for BRCA1/2 mutations for breast and ovarian cancer susceptibility is widely available and allows targeted, effective interventions. In this study, we examined physician referral from a breast cancer (BC) clinic physically contiguous with a breast cancer risk evaluation program (CREP) as well as post-referral patient attendance patterns in order to better understand barriers to participation in genetic counseling. There is no charge for the clinical service. Methods: Chart review was completed on 166 individuals seen in BC clinic between 2000 - 2002 who: had BC under 40 (<40), were Ashkenazi Jewish and had BC under 50 (AJBr<50), had BC with ≥ 2 first-degree relatives with BC (2FDR), or had BC with a family history (FH) of ovarian cancer (BrOv), for documentation of referral to CREP. CREP schedules were reviewed to examine attendance following referral. Results: FH was documented by oncologists in 97%. 59 of 166 (36%) BC patients who met the above criteria had documented referral to CREP. Of these, 14 (24%) attended CREP. As BC stage increased, referral decreased (p=.01). BC <40 had fewer referrals than AJBr<50, BrOv, or 2FDR (p=.037). Differences in referrals between individual oncologists were highly significant (p<.001). Patient age, insurance status, and race were not significant predictors of referral. When examining those patient referred to CREP, AJBr< 50 had the highest rate of subsequent attendance (55%), followed by BC <40 (38%), BrOv (12%) and 2FDR (0%). Mean age of BC diagnosis for those attending CREP was 40.7 years compared with 48.2 among those who did not (p=.04). Current age, race, and insurance were not significant predictors of attendance. Nine of 107 (8%) individuals not referred by clinic physicians were seen in CREP by self-referral. Conclusions: Lack of referral from physicians, even those in the same clinic space as a CREP, is a significant limiting factor in participation in genetic counseling, but patients' decisions not to attend after referral also are significant. No significant financial relationships to disclose.
Phase I study of inotuzumab ozogamicin (INO) combined with R-GDP for relapsed CD22+ B-cell non-Hodgkin lymphoma (B-NHL).
Authors: Randeep S. Sangha, Andrew John Davies, Nam H. Dang, Michinori Ogura, M. Luisa Paccagnella, Revathi Ananthakrishnan, Erik Vandendries, Goh Yeow Tee
Journal: Journal of Clinical Oncology (2013)

2574 Background: CD22 is expressed on most B-NHL. INO, an anti-CD22 antibody linked to calicheamicin, has activity in refractory B-NHL. This study hypothesized that INO plus rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) for relapsed CD22+ B-NHL was safe and tolerable. Methods: Patients (pts) with relapsed CD22+ B-NHL treated with ≥1 prior R-chemo regimen were enrolled using an up-and-down independent dose-escalation schema for G and P. INO (0.8 mg/m 2 day 2) was combined with R-GDP (R 375 mg/m 2 , G, and P day 1; oral D 40 mg days 1-4) on a 21-d cycle for up to 6 cycles. Dose-limiting toxicity (DLT) included febrile neutropenia, grade (Gr) 4 ANC lasting ≥7 d, Gr 4 platelets ≥7 d, Gr ≥3 platelets with bleeding and transfusion support, Gr ≥3 QTc prolongation, Gr 4 AST/ALT, Gr 2 bilirubin ≥7 d, G-CSF during cycle 1, Gr ≥3 clinically significant or drug-related nonhematologic toxicity ≥7 d, and Gr ≥2 drug-related nonhematologic toxicity causing dose delay of ≥7 d. Results: Thirty-seven pts were treated: 15 DLBCL, 11 FL, 7 MCL, 1 MZL, 1 SLL, and 2 indolent B-NHL. Characteristics: aged 33 to 81 y (median 65 y); 34 with ECOG PS £1; median of 2 prior chemo regimens (range 1-6); 5 refractory to prior therapy. No DLTs were observed at the starting dose of G 500 mg/m 2 , P 37.5 mg/m 2 (n = 6); 2 DLTs (febrile neutropenia, Gr 2 platelets) at G 1000 mg/m 2 , P 37.5 mg/m 2 (n = 3); no DLTs at G 1000 mg/m 2 , P 0 mg/m 2 (n = 6); 2 DLTs (febrile neutropenia; Gr 4 ANC ≥7 d) at G 500 mg/m 2 , P 50 mg/m 2 (n = 8); and 2 DLTs (Gr 3 hypokalemia, Gr 4 neutropenic sepsis) at G 500 mg/m 2 , P 75 mg/m 2 (n = 4). In a maximum tolerated dose (MTD) confirmation cohort of 10 additional pts, 3 pts had DLTs (2 with Gr 4 platelets, 1 with febrile neutropenia); thus MTD was determined to be INO 0.8 mg/m 2 , R 375mg/m 2 , G 500 mg/m 2 , D 40 mg, P 50 mg/m 2 . Gr ≥3 adverse events included thrombocytopenia (68%), neutropenia (54%), lymphopenia (32%), anemia (27%), leukopenia (24%), hypokalemia (22%), fatigue (11%), and febrile neutropenia (11%). Median treatment cycle was 4 (range 1-6). There were 8 complete and 9 partial responses. Conclusions: INO 0.8 mg/m 2 with R-GDP is tolerable at reduced doses of G (500 mg/m 2 ) and P (50 mg/m 2 ). Preliminary efficacy is being explored in the ongoing MTD expansion cohort. Clinical trial information: NCT01055496.
Pharmacogenomics of childhood acute lymphoblastic leukemia (ALL)
Authors: William E. Evans, Mary V. Relling
Journal: Journal of Clinical Oncology (2009)

s3 Childhood ALL is a model for drug-responsive cancer: it is successfully cured with medications in 85%–90% of patients, but relapse remains unacceptably high for some subgroups, and therapy is complicated by the occurrence of adverse effects. Human germ-line genomic variability is common, with ∼1 in every 300 nucleotides (at least 10 million polymorphisms among humans) differing among individuals. Identifying the important genomic variants for purposes of optimizing anticancer therapy is the current challenge in cancer pharmacogenomics. Our research has been focused on elucidating the germ-line and acquired genomic variations that influence the effectiveness of and toxicity to chemotherapy regimens, with the long-term goal of individualizing therapy based on genetics to maximize cure and minimize toxicity. We and our many collaborators are pursuing candidate gene and whole genome approaches to this end, studying children enrolled on front-line ALL protocols at St. Jude and through the Children's Oncology Group. Based on these studies, candidate gene genotyping has been already incorporated into the treatment of childhood ALL and integrated with electronic medical records at St. Jude to optimize use of a few medications. This includes genetic testing for TPMT to adjust thiopurine doses and CYP2D6 to optimize use of codeine for vincristine neuropathy. Additional genotyping is conducted on a research basis and has identified SLCO1B1 as important for methotrexate disposition, IL15 as related to antileukemic drug response, ITPA as important for thiopurine toxicity, and a genomic basis to race-related differences in relapse risk. Gene expression analyses of ALL cells show expression signatures associated with resistance to chemotherapy and relapse. The principles and techniques of pharmacogenomics also have implications for adult malignancies. Because prognostic factors (including genomic variations) depend upon the details of therapy, collection of blood (for germ-line DNA) should be part of every cancer clinical trial to advance genomic research.
Patterns of failures after definitive conformal radiation therapy for head and neck cancers
Authors: S. Jain, T. Gupta, P. Reenadevi, J. Agarwal, S. G. Laskar, S. K. Shrivastava
Journal: Journal of Clinical Oncology (2009)

e17037 Background: The primary objective of the study is to analyze patterns of failure in patients with head and neck cancer treated with definitive conformal radiotherapy with a focus on the location of failures in relation to the target volume coverage. Methods: Sixty patients with squamous cell carcinoma (stage: T1–3, N0–2b) were treated definitively on a prospective protocol with conformal techniques to conventional dose-fractionation equivalent of 70 Gy to the gross disease using standardized contouring guidelines. The recurrent or persistent tumor volume (Vf) was defined using positron imaging tomography (PET) and surgical-pathologic findings, and analyzed using dose-volume histograms. The failure was considered marginal when 20%-95% of Vf was within 95% isodose line. Results: At median follow-up of 12 months (range, 4–30) the 3-year actuarial local control, loco-regional control, disease-free survival, and overall survival Kaplan-Meier estimates were 86.4%, 80.5%, 62.6%, and 46.4% respectively. Of 12 (19.3%) patients with disease related events, 10 have loco-regional failures with a median time of 4 months (range, 0–22). Of 10 patients, 8 had in-field, one had marginal and one had failures of both patterns. Of seven (11.3%) local failure events, two were isolated and one had marginal failure. Of seven regional failure events, two were marginal including one with failure at peri-parotid contra-lateral neck. Another one had bilateral multiple nodal levels with supraclavicular recurrence. The remaining events were in-field were “true failures” with no apparent technical cause, none had out-field failures. Two patients were detected to have distant metastases and two developed second malignancies, one out-field and other marginal with upper esophagus carcinoma at gradient zone of previous radiation. Conclusions: Conformal radiotherapy does not compromise loco-regional control as compared to historical controls treated with conventional techniques. PET scans are useful in delineation of failure volumes. The majority of recurrences were ‘in-field‘ motivate studies of dose escalation to the highest risk regions and marginal failures in the high-dose gradient region highlight the potential hazard of high precision techniques and warrants careful consideration. No significant financial relationships to disclose.
High response rates with isolated pelvic perfusion (IPP) with a pneumatic anti-shock garments (PASG) and low-dose TNF-α for locally advanced pelvic sarcomas and carcinomas: A phase II unicenter trial
Authors: S. Bonvalot, J. Muret, T. Debaere, L. Drouard-Troalen, G. Bonniaud, P. Morice, D. Elias, J. Y. Blay, T. Tursz, A. Le Cesne
Journal: Journal of Clinical Oncology (2008)

10586 Background: Previously irradiated and pre-treated locally advanced pelvic cancers, particularly when unresectable, have limited treatments options. IPP by the balloon occlusion technique provides high-dose regional chemotherapy, but the degree of systemic leakage prohibits the addition of TNF-α. The use of a PASG in a basithoracic position increased the perfusion ratio between pelvic and systemic compartment on a bovine model (Bonvalot, 2007). In addition to melphalan (M), low and high doses of TNF-α were equally effective in an isolated limb perfusions phase II trial, with a lower systemic toxicity (T) for the lower doses (Bonvalot, 2005). Methods: Patients (pts) with non resectable locally advanced pelvic sarcoma or carcinoma were included in this phase II trial. IPP with PASG inflated progressively to 90 mmHg, in mild hyperthermia 38°. Balloon catheters were inserted percutaneously and placed above the aortic and vena cava bifurcations. Injection of 0.3 mg TNF-α and 1.5 mg/kg M, during 30 mn. Treatment will be considered effective if 30% of complete response (CR) were obtained. CR is defined by a complete necrosis or the disappearance of the tumor evaluated on dynamic MRI, 1 and 2 months post treatment. Results: To date, 22/25 pts were included (18 females, 4 males): 7 sarcomas, 10 recurrences of cervix carcinomas and 5 recurrences of rectal/anal carcinomas. The median age was 45 yrs. No toxic death and no surgical morbidity were observed. Median ratio AUC 0–30 mn between pelvic and systemic compartments was 14. During procedure: all pts had a grade 2 cardiac and respiratory T. After procedure: 90% pts had a grade 4 hematologic T, 32 % a grade 1 cardiac T, 10% had a grade 3 hepatic T, 100% had a grade 1 pulmonary T, 47% pts had an alopecia. One pt had a fracture and 4 pts had a fistula due to the clinical response. A CR, PR, SD and PD were observed in 47%, 7%, 33%, 13% of pts, respectively. Conclusions: IPP with PASG allows the use of TNF-α with an acceptable systemic toxicity and yields a high CR rate. Final results of this innovative local-regional approach will be presented during the meeting. No significant financial relationships to disclose.
Time dependence of biomarkers
Authors: Jacqueline Stephen, Gordon Murray, David Cameron, Jeremy S Thomas, Ian Kunkler, Wilma Jack, Gill Kerr, Tammy Piper, Cassandra Brookes, Daniel Rea, Cornelis van de Velde, Annette Hasenburg, Christos Markopoulos, Luc Dirix, Caroline Seynaeve, John Bartlett
Journal: Cancer Research (2015)
A phase II evaluation of imatinib mesylate (G) in stage M0 prostate cancer (PC) patients (pts) on hormonal therapy (HT) with evidence of biochemical relapse
Authors: V. J. Sinibaldi, M. A. Carducci, K. Elza-Brown, E. Rosenbaum, S. Denmeade, R. Pili, J. Walczak, E. Garrett-Mayer, S. Moore-Cooper, M. A. Eisenberger
Journal: Journal of Clinical Oncology (2006)

14612 Background: Imatinib mesylate (Gleevec, G) is a potent inhibitor of the tyrosine kinases and other signaling mediated events. Preclinical models suggest that G inhibits platelet derived growth factor (PDGF) and stem cell factor (SCF) which are important for prostate cancer growth. This trial was designed to evaluate the safety and efficacy of G in PCA pts on HT with stage M0 disease. Methods: Eligible PCA pts included: stage M0 disease with rising PSA levels while on hormonal therapy, no prior chemotherapy. Planned treatment included G 400 mg PO BID given up to a maximum of 12 months. The statistical endpoint for this trial was the% of pts with a ↓ in prostate specific antigen (PSA) ≥ 50% lasting ≥ 4 wks. A 2 stage trial was designed where the study would terminate if the% of pts meeting the endpoint was not convincingly &gt; 30% with 5% chance for error. Pts with a &gt; 50% rise in PSA from baseline were removed from study. Follow-up included monthly toxicities and PSA (specimens frozen/stored until completion of each 3 months of therapy). Results: From 10/1/02–10/11/04, nine pts were enrolled. Pt characteristics included median: age of 67 years (range 52–80), ECOG performance status of 0 (range 0–1), baseline PSA of 29.6 ng/ml (range 2.69–39.52), # prior hormonal manipulations of 3 (1–5). Prior local therapies included: 1 status post (s/p) RP alone, 2 s/p RT alone, 2 s/p neoadjuvant HT plus RP, 2 s/p neoadjuvant HT plus RT. Two pts had no prior local therapy. Two pts had prior salvage RT, 1 had prior palliative RT. Eight of 9 pts evaluable for response and toxicity. One patient never received treatment. None of the pts had a decline 50% decline in PSA level lasting ≥ 4 weeks. Three of 8 pts (38%) had rapid increases in PSA and 4/8 pts (50%) developed metastatic disease after 3 months of therapy. Only one pt completed 12 months of planned therapy. Grade 3/4 toxicities included: fatigue (25%), rash (25%), arthralgias (12.5%), peripheral edema (25%), depression (12.5%), necessitating dose delays and/or discontinuation of G in 4/8 pts (50%). Conclusions: These data suggest significant toxicity and low clinical benefit. Further evaluation of Gleevec in this pt population is not warranted. No significant financial relationships to disclose.
Renal insufficiency in cancer patients: Results of the BIRMA study
Authors: Nicolas Janus, Hans Wildiers, E. Byloos, Jean Pascal Machiels, Lionel Duck, Joseph Kerger, W. Wynendaele, Jean-Luc Canon, Willem Lybaert, Joëlle Nortier, Gilbert Deray, Vincent Launay-Vacher
Journal: Journal of the American Society of Nephrology (2008)
A phase I/II study of tegafur-uracil (UFT) plus oral leucovorin (LV) and biweekly CPT-11 therapy for patients (pts) with metastatic colorectal cancer (CRC)
Authors: H. Uetake, H. Tetsuro, M. Enomoto, K. Sugihara
Journal: Journal of Clinical Oncology (2004)

3736 Background: 5-fluorouracil plus leucovorin (5-FU/LV) and CPT-11 therapy is recently widely used as a first line chemotherapy for the treatment of metastatic CRC. We performed a phase I study of UFT/LV, all oral administration regimen, plus biweekly CPT-11 therapy for metastatic CRC and reported that the maximum tolerated dose and the recommended dose (RD) of CPT-11 were 140 and 130mg/m2, respectively (ASCO 2003). Objectives of the present trial were to estimate the response rate (RR) of this regimen. Methods: Eligibility criteria were as follows; histologically proven CRC with measurable metastatic lesions, PS 0–2, age< 80, adequate organ functions, and written informed consent. No prior chemotherapy except adjuvant setting was allowed. UFT/LV was administered orally (UFT: 400 mg/m2/day, LV: 15 mg/body/day) on 5 consecutive days with 2 days' rest for 4 weeks, and CPT-11 was infused at the RD in phase I trial (130mg/m2) on days 1 and 15. This schedule was repeated every 6 weeks. Results: Fourteen of 16 cases were treated by two or more courses of this regimen. Objective responses according to RECIST criteria were observed in 6 of the 14 pts (1 CR and 5 PRs. RR=43%). Six pts were treated without hospitalization, and for other pts 8–14 days of hospitalization in each course was necessary because of the adverse effects. Conclusions: High RR and mild toxicity profile of UFT/LV plus biweekly CPT-11 therapy may be favorable for outpatient clinic. No significant financial relationships to disclose.