tbuckley/cabot-search huggingface dataset:
Impact of duration of adjuvant therapy (AT) on cancer survival.
Authors: Aalok Kumar, Renata D'Alpino Peixoto, Sharlene Gill, Hagen F. Kennecke, Daniel John Renouf, Howard John Lim, Caroline Speers, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2014)

6513 Background: Trials demonstrate that patients (pts) with specific cancers who complete AT experience better outcomes than those who do not. However, the magnitude of benefit in pts who discontinue AT early is poorly defined. Using a population-based cohort of stage III colon cancer (CC) pts, our aims were to (1) examine the rate of receiving all planned AT, (2) determine the factors associated with AT completion, and (3) explore the relationship between early AT discontinuation and survival. Methods: We analyzed pts diagnosed with stage III CC from 2006 to 2010 and initiated at least 1 cycle of adjuvant FOLFOX at any 1 of 5 regional cancer centers in British Columbia. Logistic regression models were constructed to determine the factors associated with AT completion, which was defined as receipt of >/= 10 cycles of FOLFOX. Kaplan-Meier methods and Cox regression that accounted for prognostic factors were used to evaluate the relationship between early AT discontinuation and disease-free (DFS) and overall survival (OS). Results: We identified 616 patients: median age 62 years (range 26-80), 52% men, 87% T3/4 tumors, and 40% N2 disease. Among them, 183 (30%) received < 10 and 433 (70%) underwent >/= 10 cycles. Adjusting for confounders, men and those with obstruction/perforation were more likely to discontinue AT early (OR for AT completion 0.62, 95%CI 0.43-0.89, p=0.01 and 0.55, 95%CI 0.33-0.92, p=0.02, respectively). In terms of survival, T3/4 stage, N2 disease and long post-operative recovery of >/= 1 week were correlated with worse DFS, while T4 stage and N2 disease were also associated with inferior OS. However, early discontinuation of AT did not impact DFS and OS (Table). Sensitivity analyses using different definitions for AT completion produced similar findings. Conclusions: Early discontinuation of adjuvant FOLFOX was not associated with significant survival differences, lending support to trials that are underway evaluating the utility of shorter durations of AT. DFS OS HR p HR p >/=10 cycles 1.0 .40 1.0 .76 <10 cycles 1.15 1.07 No obstruction/perforation 1.0 <.001 1.0 .13 Obstruction/perforation 1.95 1.47 T1/2 1.0 .02 1.0 .09 T3 2.31 <.001 2.19 .002 T4 3.72 4.44 N1 1.0 <.001 1.0 .002 N2 1.95 1.83 <7 days post-op stay 1.0 .049 1.0 .49 >/=7 days post-op stay 1.47 1.19
Efficacy of axitinib in patients with metastatic renal cell carcinoma previously treated with both VEGFR-TKI and mTORI.
Authors: Ryuichi Mizuno, Takeo Kosaka, Shuji Mikami, Mototsugu Oya
Journal: Journal of Clinical Oncology (2014)

e15585 Background: Developments of molecular targeted therapy, including VEGFR-TKI and mTORI, have achieved improvements in PFS in the treatment of mRCC. However, resistance to drugs will occur in most of patients. A reasonable approach to overcome drug resistance is the use of sequential therapy and some drugs which showed efficacy in the second line setting are in use. In view of the complete lack of information in the third or later line settings, we retrospectively evaluated the efficacy and tolerability of axitinib treatment in mRCC patients pretreated with both TKI and mTORI. Methods: A total of 12, 9 male and 3 female Japanese patients, with a mean age of 58 years (range 18–79), with mRCC, who progressed despite treatment with both at least one VEGFR-TKI and one mTORI, were treated with axitinib in the third or later line settings. Nine patients had clear cell, and remaining 3 patients had non-clear cell histology. They have received a median of 3 prior therapies. All patients had Karnofsky performance status 70–100. Results: In all patients axitinib was started with 5mg twice daily, and 4 patients experienced dose reduction. Response to axitinib was PR, SD, PD of 2 (17%), 8 (66%), and 2 (17%), respectively. The median PFS was 5.2 months. The median OS was not reached. The most common AEs were hypertension (n=9) and hoarseness (n=8), which were manageable. Severe AEs which resulted in cessation of axitinib were grade 3 proteinuria (n=1) and grade 2 perforated diverticulitis (n=1), which were managed with a conservative approach. Conclusions: Our findings suggest that although there is wide variability in the treatment and management patterns, axitinib seems to possess potency for the subset of patients pretreated with both TKI and mTORI.
Defining a critical period in calvarial development for Hedgehog pathway antagonist-induced frontal bone dysplasia in mice
Authors: Yuanjing Jiang, Shixian Zhang, Chuanqing Mao, Yongzhen Lai, Di Wu, Hu Zhao, Caiyu Liao, Weihui Chen
Journal: International Journal of Oral Science (2019)

The Hedgehog (Hh) signalling pathway is essential for cellular proliferation and differentiation during embryonic development. Gain and loss of function of Hh signalling are known to result in an array of craniofacial malformations. To determine the critical period for Hh pathway antagonist-induced frontal bone hypoplasia, we examined patterns of dysmorphology caused by Hh signalling inhibition. Pregnant mice received a single oral administration of Hh signalling inhibitor GDC-0449 at 100 mg•kg-1 or 150 mg•kg-1 body weight at preselected time points between embryonic days (E)8.5 and 12.5. The optimal teratogenic concentration of GDC-0449 was determined to be 150 mg•kg-1. Exposure between E9.5 and E10.5 induced frontal bone dysplasia, micrognathia and limb defects, with administration at E10.5 producing the most pronounced effects. This model showed decreased ossification of the frontal bone with downregulation of Hh signalling. The osteoid thickness of the frontal bone was significantly reduced. The amount of neural crest-derived frontal bone primordium was reduced after GDC-0449 exposure owing to a decreased rate of cell proliferation and increased cell death.
Results of comprehensive molecular profiling of gliomas and the potential therapeutic implications.
Authors: Santosh Kesari, Joanne Xiu, David B. Spetzer, Anatole Ghazalpour, Zoran Gatalica, Nader Sanai
Journal: Journal of Clinical Oncology (2014)

2013 Background: Gliomas are the most common type of primary brain tumors with underlying molecular heterogeneity contributing to differential treatment response. Our retrospective study was designed to interrogate biomarkers from a large cohort of glioma patients to identify alterations with therapeutic implications. Methods: 871 glioma tumor samples (79% WHO grade IV glioblastoma, GBM) were analyzed with a multi-platform approach including sequencing, IHC, FISH/CISH and methylation assay to investigate actionable biomarker aberrations. Retrospective data analysis was performed on the complete cohort and molecular subgroups of patients. Results: In the 871 patient samples, mutations in 27 genes were seen. Both common TP53 (39%), IDH1 (22%), PTEN (13%) and previously unreported mutations in gliomas were observed, including JAK3, SMO and ABL1. Co-mutation of 2 or more genes occurred in 37% of cases. TP53 mutation was suggestive of genetic instability and was frequently associated with other concurrent mutations (p=0.0006). IDH1 mutations were associated with MGMT promoter methylation, low expression of TS, RRM1 and TOP2A (p from <0.0001 to 0.0036), suggesting different responses to temozolomide, fluoropyrimidine, gemcitabine and etoposide. IDH1 mutation was also associated with TP53 mutation; whereas wild type IDH1 was associated with PTEN mutation (p=0.0309) and showed some association with EGFR mutations (p=0.0543). Distinct biomarker profiles by IHC, FISH and sequencing were also observed when comparing GBM to grade II/III gliomas, suggesting different biology from GBM and thus different treatment implications. 20 GBM patients were identified with pre and post treatment analyses performed (comparative analysis ongoing). Conclusions: Gliomas exhibit a high degree of molecular heterogeneity as revealed by multi-platform profiling. IDH1 mutation identifies molecular subgroups of patients with different responses to therapeutic agents; while TP53 mutation suggests increased genetic instability. These results highlight the benefits of profiling in consideration of treatment options for glioma patients.
Investigation of the influence of zinc oxide nanoparticles on the neoplasm progression.
Authors: Polina Sergeevna Kachesova, Irina Aleksandrovna Goroshinskaya, Oleg Evgenevich Polozhentsev, Vladimir Borisovich Borodulin
Journal: Journal of Clinical Oncology (2014)

e14012 Background: There is concern that zinc oxide nanoparticles (ZnO NPs) induce selective killing of cancer cells in vitro. However the anticancer effect of ZnO NPs in vivo remains unclear. The objective of this study was to evaluate the effect of ZnO NPs on a transplantable neoplasm Methods: We investigated the influence of ZnO NPs on growth of the transplantable sarcoma-45 in rats (9.10-dimethyl-1.2-benzanthracene-induced fusiform cell fibrosarcoma, S-45). Outbred stocks of male rats were used in experiments. Tumors were developed by implantation of tumor tissue suspension obtained from tumor of a donor rat. The experimental animals were divided into three groups. Group 1: ZnO NPs in 0.9% w/v of NaCl were injected intratumorally. Group 2: ZnO NPs were injected intraperitonially. Group 3: control (rats received saline only). Nanoparticles were injected 1.25 mg/kg four times a week of a week's break, the procedure was repeated. The effect of ZnO NPs on tumor growth was determined by the measured tumor mass (M) and volume (V). The elemental composition, morphology and homogeneity of NPs were investigated by X-ray absorption near edge spectroscopy, scanning electron microscopy and measuring zeta potential. The used NPs of zinc oxide (II) are spherical in shape and the sizes are about 20 nanometers. Results: This study showed that administration of ZnO NPs enhanced the growth of fibrosarcoma in the 60.0% of experimental animals independently of injection way (arithmetic mean for group was: V=14.3±1.2 cm3, M=15.5±1.0 g). At the same time in the control group the tumor size and mass were V=9.08±1.92 cm3, M=10.43±2.4 g, respectively. Overall, for the entire group of animals tumor volume and mass increased over control at 58.0% (p<0.05) and 49.0% (p<0.05), respectively. The other 40.0% of rats with S-45 showed delay in tumor growth or partial tumor regression (V=0.56±0.18 cm3, M=0.83±0.26 g). Conclusions: Thus experiment indicated that in vivo effect of ZnO NPs with size 20 nm manifested in increase of the tumor growth in most of the animals. This result can be important for understanding of the implications of ZnO NPs use in cancer therapy. The reported study was supported by RFBR, research project No. 14-04-32046 мол_a.
Treatment of solid tumors with intratumoral poly-ICLC: A phase II clinical study.
Authors: Yvonne M. Saenger, Rachel Lubong Sabado, Rose Marie Holman, Deborah Lehrer, Andres M. Salazar, Nina Bhardwaj
Journal: Journal of Clinical Oncology (2014)

e14010 Background: Polyinosinic-polycytidylic acid (poly-ICLC) is stabilized double stranded RNA comprising carboxymethylcellulose, polyinosinic-polycytidylic acid, and poly-L-lysine RNA. Poly-ICLC is a ligand for toll like receptor 3 (TLR3) expressed on dendritic cells and is under clinical development for the treatment of viral infections and tumors. Pilot studies in pediatric brain cancer have shown efficacy.1 Poly-ICLC can be given intra-muscularly (IM) to induce systemic inflammation and/or intratumorally (IT) to induce immune infiltration of tumor. Methods: Three patients are currently enrolled on this study. The planned sample size is 15. Eligible patients include those ≥18 years old with unresectable melanoma, squamous cell cancer of the head and neck, breast cancer, squamous cell cancer of the skin or basal cell cancer. Patients with sarcoma are also eligible and must be ≥14 years old. Patients must have an ECOG performance status of 2 or better, a life expectancy of 6 months and must have progressed on prior systemic therapy or despite local irradiation. Brain metastases are allowable. 1 mg Poly-ICLC is administered IT three times a week for two weeks followed by biweekly IM injection for 7 weeks and 1 week of rest. If stable disease or better is observed, this 10 week cycle will be repeated and if there is continuous response than a maintenance cycle of IM poly-ICLC will be offered. The primary objectives of the study are to determine safety and evaluate therapeutic effect as assessed by progression free survival at 26 weeks. The secondary objectives are to determine whether injected and/or non-injected lesions will regress and to assess immunogenicity of this poly-ICLC regimen. Results: Not yet available. Conclusions: Not yet available. Clinical Trial Information: NCT01984892 1. Hartman LL, Crawford JR, Makale MT, et al. Pediatric Phase II Trials of Poly-ICLC in the Management of Newly Diagnosed and Recurrent Brain Tumors. Journal of pediatric hematology/oncology 2013. Clinical trial information: NCT01984892.
Long-Term Clinical Benefit to Anti-CCR4 Mogamulizumab: Results from the Phase 3 Mavoric Study in Previously Treated Cutaneous T-Cell Lymphoma (CTCL)
Authors: Martine Bagot, Stéphane Dalle, Lubomir Sokol, Athanasios Tsianakas, Amy Musiek, Pablo Ortiz-Romero, Brian Poligone, Madeleine Duvic, Craig Elmets, Mollie Leoni, Karen Dwyer, Wei Sun, Elena Nikonova, Youn H. Kim
Journal: Blood (2018)
Prophylactic ciprofloxacin to prevent febrile neutropenia in adjuvant breast cancer patients receiving docetaxel (nonanthracycline) regimens.
Authors: Meena Okera, Ben W. Stevenson, Brian N. Stein, Nimit Singhal, Francis Parnis, Kerry A. Cheong, Carolyn L. Bampton, Sarwan K. Bishnoi, Dusan Kotasek
Journal: Journal of Clinical Oncology (2014)

1036 Background: Febrile neutropenia (FN) is a serious adverse effect of adjuvant chemotherapy for breast cancer. Primary GCSF prophylaxis is recommended for patients at > 20% risk of FN, but is not funded in Australia with docetaxel (non-anthracycline) regimens in adjuvant breast cancer patients (TC and TCH), despite literature reporting rates of FN of up to 50%. Prophylactic antibiotics can prevent FN, but are not routinely incorporated into chemotherapy guidelines for TC and TCH regimens. This retrospective study evaluates the usage and benefit of primary ciprofloxacin prophylaxis, in patients receiving TC and TCH chemotherapy. Methods: Retrospective review of breast cancer patients receiving adjuvant TC or TCH chemotherapy between 1.1.11 and 30.6.13 (single centre). Logistic regression analysis used to model the contribution of regimen, primary GCSF use (pegfilgrastim), and prophylactic antibiotic use on presence of FN. Results: 131 eligible patients, mean age 55 years (28-77). 96/131 (73%) received TC chemotherapy, 35/131 (27%) received TCH chemotherapy. 97/131 (74%) received primary ciprofloxacin prophylaxis from cycle 1. Primary ciprofloxacin prophylaxis was more frequently prescribed with TC rather than TCH chemotherapy (93% vs 26%). 26 admissions occurred with FN (24 patients). 21/26 admissions for FN occurred after cycle 1 or 2 of chemotherapy. Primary ciprofloxacin prophylaxis significantly reduced the risk of FN (12% vs 41%) and on logistic regression analysis, was the only predictive factor reducing risk of FN (p=0.019). There was no interaction between use of antibiotics and growth factors. Further evaluation of interactions was limited by small numbers. Conclusions: There is a high rate of FN amongst breast cancer patients receiving TC and TCH chemotherapy. Primary ciprofloxacin prophylaxis significantly decreases the risk of FN. Primary ciprofloxacin prophylaxis should be considered for patients receiving TC and TCH chemotherapy, where primary GCSF prophylaxis is unavailable. Admissions of FN. Number (%) patients Number (%) FN admissions Ciprofloxacin prophylaxis 97/131 (74%) 12/97 (12%) No ciprofloxacin prophylaxis 34/131 (26%) 14/34 (41%)
Molecular profiling of 267 pediatric cancers to identify potential clinically relevant targets.
Authors: Todd Maney, Sherri Z. Millis, Josiah Winkler, Leonard S. Sender
Journal: Journal of Clinical Oncology (2014)

10037 Background: Even though only 1% of cancers occur in children, it is the 2nd leading cause of death in children. Survival rates depend on the type of cancer, the majority of which arise from the central nervous system, bone, or neuroblasts. Methods: 267 cases referred to Caris Life Sciences were tested per physician request, including sequencing (Sanger, next generation [NGS]), protein expression (immunohistochemistry [IHC]), gene amplification (CISH or FISH), and/or MGMT methylation. Diagnoses were collected from referring physicians at intake; for this analysis, cases were initially grouped into carcinomas (CA), n=40, sarcomas (SA), n=117, neuroendocrine (NET), n=12, germ line (GL), n=11, or central nervous system (CNS), n=37. Within those groups the specific diagnoses were further delineated. Results: In this pediatric cohort, biomarker alterations included higher AR protein expression in CA and SA, higher ER expression in CA, GL, and NET, and EGFR amplification in all but GL. MGMT loss was highest in CNS, PTEN loss was highest in GL and both were lowest in CA. PGP was expressed at less than 15% in CNS and SA and 68% in CA. No HER2 protein overexpression, amplification, or gene mutations were seen. TP53 mutations were lowest in SA (9%) and varied between 25 and 50% in the others. Of the gene panel tested, CTNNB1 was mutated in 1 patient in CA and SA, while AKT1, CSFIR, and MPL were mutated in 1 patient each in GL. KRAS was mutated at least once in all but CNS. All other mutations (MT) were exclusive to the CNS group, and included PTEN, SMO, VEGF, ERBB4, EGFR, ALK, and APC. These were specific to the astrocytomas, which also had the only MGMT methylation event, except for ALK MT (neuroblastoma) PTEN MT (medulloblastoma), and EGFR MT (ganglioglioma). Conclusions: The mutations in the CNS group suggest MEK and mTOR pathway involvement. Biomarker profiling to identify therapeutic targets has potential in pediatric patients and warrants further investigation. Comparison to adult onset of these types of cancers may yield different molecular profiles for a subset of these cancers. Because children typically respond well to chemotherapy, targeting specific molecular alterations identified in childhood cancer could prove very effective.
A phase II trial of combined chemotherapy with oral S-1 and 24-hour infusions of irinotecan plus bevacizumab in patients with metastatic colorectal cancer.
Authors: Sotaro Sadahiro, Toshiyuki Suzuki, Akira Tanaka, Kazutake Okada, Gota Saito, Akemi Kamijo
Journal: Journal of Clinical Oncology (2014)

3544 Background: Irinotecan causes S-phase-specific cell killing. Its active metabolite, SN-38, is catalyzed by carboxylesterases. Prolonged exposure to low concentrations of irinotecan is associated with less carboxylesterase saturation, thereby enhancing therapeutic effectiveness (Houghton PJ, 1995, Rothenberg ML, 1998). We previously reported that combined chemotherapy with oral UFT/leucovorin or S-1 plus 24-hour infusions of irinotecan is very effective. We examined the effectiveness and safety of combined chemotherapy with S-1 and 24-hour infusions of irinotecan plus bevacizumab in patients with metastatic colorectal cancer (mCRC). Methods: Patients who had mCRC, an age of ≥ 20 years, and an ECOG PS of 0-1 were eligible. S-1 (40 mg/m2) was given orally twice daily on days 1 to 14. Irinotecan was given as continuous 24-hour intravenous infusion on days 1 and 15. On the basis of the results of a previous phase I study, patients who were homozygous for the UGT1A1*28 allele received 100 mg/m2 of irinotecan, and those with other genotypes received 125 mg/m2of irinotecan. Bevacizumab (5 mg/kg) was given intravenously on days 1 and 15, followed by a two-week rest. This four-week regimen was regarded as one cycle and was repeated. The primary endpoint was overall response (OR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: 79 patients were enrolled; median age, 68 years (range, 38-85); 42% female; ECOG PS 0/1, 58%/42%; and first line/second line therapy, 58%/42% (adjuvant chemotherapy, 16%). Three patients (4%) were homozygous for the UGT1A1*28 allele. Median follow-up time was 18.1 months. The median number of treatment cycles was seven. The OR rate was 77.2% (95% confidence interval, 66.4-85.9; first line, 80.4%; second line, 72.7%). Median PFS was 15.7 months (first line, 16.4 months; second line, 16.5 months). Median OS were not reached. Grade 3 or higher adverse events that occurred at an incidence of ≥ 10% were neutropenia (43.0%), leukopenia (20.3%), anorexia (19.0%), and diarrhea (10.1%). Conclusions: This regimen appears to be highly active and well tolerated, both as first-line and second-line chemotherapy for mCRC. Clinical trial information: 10R-121.
Atezolizumab in Combination with Obinutuzumab and Lenalidomide Demonstrates Favorable Activity and Manageable Toxicity in Patients with Relapsed/Refractory Follicular Lymphoma (FL): An Interim Analysis of a Phase Ib/II Trial
Authors: Gilles Salles, Nilanjan Ghosh, Izidore S. Lossos, Maria Lia Palomba, Amitkumar Mehta, Olivier Casasnovas, Don Stevens, Ana Abajo, Tina Nielsen, Surya Chitra, Michael Wenger, Franck Morschhauser
Journal: Blood (2018)
A feasibility study of dynasplint to prevent trismus in head and neck cancer patients receiving radiation therapy.
Authors: Lauren Azure Zatarain, Clayton Smith, Mary S. Dietrich, Kenneth J. Niermann, Jill Gilbert, Mersiha Hadziahmetovic, Sheila H. Ridner, Barbara A. Murphy
Journal: Journal of Clinical Oncology (2014)

e20676 Background: Lymphedema & fibrosis is a late effect of head and neck cancer (HNC) treatment negatively affecting quality of life. Trismus is a fibrotic process of mastication structures. Incidence varies but reported up to 60% in HNC patients receiving XRT. Once trismus develops response to treatment with stretching exercises is poor, thus preventive strategies may be beneficial. Dynasplint is a mechanical device used to stretch contracted muscles & fibrotic soft tissues. This is a pilot trial to assess the feasibility of Dynasplint for prevention of XRT induced trismus. Methods: Eligible patients had locally advanced HNC, normal interincisor distance (IID) > 35 mm & high trismus risk (planned primary or adjuvant XRT dose ≥ 6 Gy to masticator muscles). Patients were randomized 1:1 to Dynasplint (30 min 3 x day) during XRT & for 3 months post-treatment or standard of care with jaw exercises. Daily patient logs were used as a measure of compliance. The Vanderbilt Head & Neck Symptom Survey version 2.0 & IID were measured weekly thru XRT +1, 2, 3 & 6 months post-XRT. The primary outcome was feasibility & the secondary outcome was trismus (IID < 30 mm). Crossover from standard of care to Dynasplint was allowed if trismus developed. Results: We report results from the first 32/40 patients enrolled. Dynasplint patients had increased withdrawal rates. Dynasplint arm had lower compliance rates across the entire study. Compliance dropped to < 50% at weeks 6 & 16 for Dynasplint & control patients respectively. Reasons for non-compliance included: mucositis, gagging, fatigue, & device fit issues. A decline in IID was noted in both groups over time (p=0.021). A similar trajectory was noted for the VHNSS item "Do you have difficulty opening your jaw." The overall incidence of trismus was 13%. Conclusions: Preventive use of a mechanical stretching device during cancer treatment & early recovery was not feasible in HNC patients receiving primary or adjuvant XRT. There were overall lower trismus rates compared to historic controls despite a high risk population. Aggressive stretching with ROM exercises alone appears feasible & sufficiently powerful to prevent trismus in this population. Clinical trial information: NCT01649583.