tbuckley/cabot-search huggingface dataset:
Preliminary safety data of an ongoing phase I-II clinical study with the tumor vaccine MGN1601 in patients with advanced renal cell carcinoma.
Authors: M. Tschaika, S. Weikert, E. Weith, V. Gruenwald, M. Schroff, M. Schmidt, B. Wittig
Journal: Journal of Clinical Oncology (2011)

e15157 Background: The clinical study with MGN1601 was initiated after proven prophylactic and therapeutic anti-tumor activity and good safety profile of the study drug shown in several in-vivo models and toxicity studies. MGN1601 is a cell-based renal cell carcinoma (RCC) tumor vaccine consisting of genetically modified allogeneic (human) cells transfected with four different MIDGE vectors encoding IL-7, GM-CSF, CD80 and CD154 and a synthetic DNA-based immunomodulator dSLIM-30L1, a TLR-9 agonist. The vaccine has been developed for treatment of patients with advanced RCC. Methods: This clinical study is conducted as multicentric, open Phase 1-2 study evaluating safety and efficacy of MGN1601 in patients with advanced RCC. A total of 24 patients have to be recruited into the study. The treatment consists of 8 MGN1601 applications administered weekly for the first 3 treatments and biweekly for the further 5 treatments. The treatment dose contains 107 transfected tumor cells and 5 mg dSLIM per administration. In this clinical study, safety and efficacy of the study treatment will be evaluated based on extensive clinical and laboratory assessments, monitoring of patients’ quality of life, immunological tests, and radiological investigations. Here, the first safety data are presented. Results: Six patients have been included into the study so far and received the first administrations of the MGN1601 (up to 6 treatments). Five adverse events are reported so far. Out of those five, four were judged as unlikely drug-related by the investigator and one as not drug-related. Local reactions in terms of mild redness and induration were reported in two of the six patients. The therapy is well tolerated – no treatment-limiting toxicities (TLT) or grade 2 toxicities occurred in these patients. Conclusions: The preliminary safety results of the ongoing clinical study in patients with advanced renal cell carcinoma (RCC) show that the cell-based tumor vaccine consisting of genetically modified allogeneic transfected RCC cells and the DNA-based immunomodulator dSLIM-30L1 is well tolerated and safe with no study drug-related adverse events reported so far.
PD-1 blockade in tumors with mismatch repair deficiency.
Authors: Dung T. Le, Jennifer N. Uram, Hao Wang, Bjarne Bartlett, Holly Kemberling, Aleksandra Eyring, Andrew Skora, Nilofer Saba Azad, Daniel A. Laheru, Ross C. Donehower, Brandon Luber, Todd S. Crocenzi, George A. Fisher, Steve M Duffy, James J. Lee, Minori Koshiji, James R. Eshleman, Robert A Anders, Bert Vogelstein, Luis A. Diaz
Journal: Journal of Clinical Oncology (2015)

LBA100 Background: Somatic mutations have the potential to be recognized as “non-self” immunogenic antigens. Tumors with genetic defects in mismatch repair (MMR) harbor many more mutations than tumors of the same type without such repair defects. We hypothesized that tumors with mismatch repair defects would therefore be particularly susceptible to immune checkpoint blockade. Methods: We conducted a phase II study to evaluate the clinical activity of anti-PD-1, pembrolizumab, in 41 patients with previously-treated, progressive metastatic disease with and without MMR-deficiency. Pembrolizumab was administered at 10 mg/kg intravenously every 14 days to three cohorts of patients: those with MMR-deficient colorectal cancers (CRCs) (N = 11); those with MMR-proficient CRCs (N = 21), and those with MMR-deficient cancers of types other than colorectal (N = 9). The co-primary endpoints were immune-related objective response rate (irORR) and immune-related progression-free survival (irPFS) at 20 weeks. Results: The study met its primary endpoints for both MMR-deficient cohorts. The irORR and irPFS at 20 weeks for MMR-deficient CRC were 40% and 78%, respectively, and for MMR-deficient other cancers were 71% and 67%, respectively. In MMR-proficient CRC, irORR and irPFS at 20 weeks were 0% and 11%, respectively. Response rates and Disease Control Rates (CR+PR+SD) by RECIST criteria were 40% and 90% in MMR-deficient CRC, 0% and 11% in MMR-proficient CRC, and 71% and 71% in MMR-deficient other cancers, respectively. Median PFS and overall survival (OS) were not reached in the MMR-deficient CRC group but was 2.2 and 5.0 months in the MMR-proficient CRC cohort (HR for PFS = 0.103; 95% CI, 0.029 to 0.373; p &lt; 0.001 and HR for OS = 0.216; 95% CI, 0.047 to 1.000; p = 0.05). Whole exome sequencing revealed an average of 1,782 somatic mutations per tumor in MMR-deficient compared to 73 in MMR-proficient tumors (p = 0.0015), and high total somatic mutation loads were associated with PFS (p = 0.02). Conclusions: MMR status predicts clinical benefit of immune checkpoint blockade with pembrolizumab. Clinical trial information: NCT01876511.
Generation of an automated tool for querying myeloma transcriptomics for multiple gene expression signatures used in risk-stratification.
Authors: R. Fonseca, E. Braggio, J. J. Keats, G. J. Ahmann, J. Mantei, A. K. Stewart, P. L. Bergsagel
Journal: Journal of Clinical Oncology (2011)

8024 Background: Multiple myeloma (MM) is characterized by a remarkable heterogeneity in outcome following standard and high-dose therapies. In MM, gene expression profiling (GEP) has a key role in establishing clinically relevant disease subgroups. Methods: To molecularly stratify disease-risk groups, we performed GEP on purified plasma cells from 469 MM cases in different stages of the disease using the Affymetrix U133Plus2.0 array. A total of 162 probes were analyzed using an in house automated script to generate a GEP report with the most used risk stratification indices and signatures, including the UAMS 70-gene, TC classification, proliferation and centrosome signature, and NFKB activation indices. In a subset of samples, IgH translocations were analyzed using FISH and results were correlated with GEP data. Results: All signatures identified around a third of patients with high-risk disease, ranging from 26% by using high proliferation index to 28% with high centrosome signature and 31% with high 70-gene index. High proliferation index and high centrosome signature significantly correlates with 70-gene high-risk group (p<0.0001). Conversely, the activation of NF-kB pathway was not significantly different between high- and low- risk subgroups. TC subgroups D1 (p<0.0001) and 11q13 (p=0.01) were significantly more common in the 70-gene low-risk group. Similarly, TC subgroups 4p16 (p=0.0004), Maf (p=0.02), D2 (p=0.05), and None (p=0.08) were enriched in the high-risk group. Translocations t(4;14)(p16;q32), t(11;14)(q13;q32) and t(14;16)(q32;q23) were precisely predicted by the TC classification (100% correspondence). Cases with IgH translocations without known partner were classified in subgroups D1 (33%), D2 (25%), 6p21 (25%) and Maf (16%). Conclusions: Here we summarized the associations between the most significant gene expression indices and signatures relevant to MM risk-stratification. The multiple variables simultaneously analyzed in an automated way, provide a powerful and fast tool for risk-stratification, helping in the therapeutic decision-making.
Improving the patient experience for cancer patients in Ontario through real-time measurement.
Authors: Nancy Kraetschmer, Alysha Glazer, Esther Green, Laura Macdougall, Simron Singh
Journal: Journal of Clinical Oncology (2014)

240 Background: Cancer Care Ontario (CCO) is an Ontario government agency that drives system wide quality improvement in disease prevention and screening, the delivery of care and the patient experience (PE), for cancer, chronic kidney disease and access to care for key health services. CCO partners with 14 Regional Cancer Programs across the province. CCO measures the cancer PE retrospectively through a paper-based Ambulatory Oncology Patient Satisfaction Survey but there are limitations such as the delay in reporting of results. CCO is developing and implementing a province-wide electronic real-time PE survey to measure PE. An electronic survey tool will enable the collection, analysis and reporting of PE data more quickly to drive quality improvement. Methods: A current state assessment was undertaken in fall 2013 to understand support for and readiness of CCO’s Regional Cancer Centres (RCCs) to move forward with measuring PE in real-time, at point of care. 14 semi-structured interviews were conducted with RCCs Regional Vice Presidents (RVP); over 800 patients participated in focus groups in 11 of 14 regions; a targeted online survey was completed by 16 administrators in 14 regions. Results: Interest in a real-time measurement (RTM) approach was overwhelmingly positive – 94% of patients and 100% of RVPs thought that measuring PE in real-time is important. Patients want the real-time survey to be short - 61% of patients reported that the number of questions they are willing to answer is 5-10, with 18% indicating 15 questions. 62% of patients reported that they were willing to spend 2-6 minutes answering a survey, with 24% reporting 10 minutes. 36% of the RCCs have ad hoc RTM strategies and 21% have utilized an electronic tool. There was no co-ordination or data sharing between RCPs. Conclusions: CCO is implementing a province-wide RTM strategy which includes the validation of a RTM PE survey and procurement of an electronic solution to capture, analyze and report PE data. CCO will initially pilot the survey and electronic tool with the intention of a provincial rollout to cancer centres upon a post-pilot evaluation.
Laboratory evaluation of hepatic synthetic function as a predictor of ethiodol retention during transarterial (chemo) embolization in hepatocellular carcinoma (HCC).
Authors: Brandon Alan Dyer, Raluca McCallum, Leah Savitsky, Catherine Kato, Martin Fuss, Charles R. Thomas, Wilscott Naugler, Kenneth Kolbeck, John Kaufman, Khashayar Farsad, Alice Fung, James Tanyi
Journal: Journal of Clinical Oncology (2015)

431 Background: Image-guidance for HCC suffers due to a lack of contrast between tumor and liver parenchyma. To compensate for the inability to directly visualize the radiation target other IGRT strategies have been employed for target optimization. Transarterial embolization (TAE) and transarterial chemoembolization (TACE) are level 1, evidence-based treatments for HCC and improve survival by several months; however, local failure occurs in up to 50% of treated lesions by 6 months. The lack of durable local control provides a rationale to add a second treatment modality. If Ethiodol is used as an embolizing agent, the treated HCC becomes radio-opaque. In the current assessment, we correlated the quality of Ethiodol tumor stains with liver function parameters as prognosticators for Ethiodol stain retention prior to simulation for SBRT. Methods: Records of 31 patients undergoing staged TAE/TACE prior to SBRT (50 Gy/5) were evaluated under an institutional protocol. The quality of Ethiodol stains in simulation CT were graded as excellent (mean HU of &gt;300), good (mean HU of 225-300), fair (mean HU 150-225), and poor (mean HU &lt;150). A liver function panel, general labs, Child-Pugh and MELD scores prior to TACE/TAE were also recorded and correlated with the quality of Ethoidol stain at simulation. Results: Duration between TACE/TAE and simulation was 124+120 days. Simulation scans showed excellent, good, fair and poor tumor stains in 7 (mean HU =360+48), 3 (mean HU =262+17), 15 (mean HU =184+24) and 6 (mean HU =130+16) cases, respectively. Of all laboratory testing, only Child-Pugh score showed strong statistical correlation (p&lt;0.0012) with the retention of Etioldol. Conclusions: TACE/TAE-based Ethiodol tumor stain facilitates tumor visualization for SBRT of HCC. While it is not conclusive that laboratory testing can serve as a predictor of Ethiodol stain retention between TACE/TAE and simulation for SBRT, the Child-Pugh score presents a unique matrix for patient stratification.
Impact of health care costs on utilization of needed health care in the Childhood Cancer Survivor Study (CCSS).
Authors: Douglas Beaty Fair, Anne C. Kirchhoff, Ryan David Nipp, Wendy M. Leisenring, Paul C. Nathan, Kevin C. Oeffinger, Gregory T. Armstrong, Leslie L. Robison, Elyse Park
Journal: Journal of Clinical Oncology (2016)

20 Background: Survivors of childhood cancer face increased risks for morbidity and premature mortality due to the sequelae of their primary disease and its treatment. Survivors may be socioeconomically vulnerable, which could negatively impact their healthcare utilization. We investigated sociodemographic factors associated with forgoing needed healthcare due to cost among long-term survivors within the CCSS. Methods: From a survey of insured and uninsured survivors conducted in 2011-12, forgoing needed healthcare due to cost was determined by the question “In the past year, was there a time when you did any of the following because you were worried about the cost? (Yes/No)” with 10 response categories (e.g., skipping a test/treatment, postponing medical care, taking a smaller cost of a prescription). ‘Yes’ responses were summarized using a categorical outcome variable of 0, 1-2, or ≥ 3 instances of forgoing healthcare. Ordinal logistic regression models assessed the association of sociodemographic factors with increased instances of forgoing healthcare due to cost, including survey weights to account for stratified sampling. Results: Of 1,110 mailed surveys, we received 698 (64%) responses. Mean age at time of survey was 39.6 (range 24-60) years and average time since diagnosis was 31.3 (SD = 4.6) years. 23% of survivors reported 1-2 instances of foregoing needed healthcare and 31% reported 3 or more. Odds of more forgone needed healthcare due to costs were increased for those who were uninsured, female, and had a chronic medical condition. [Table: see text]
High Dose Chemotherapy with Autologous Stem Cell Transplant in Treatment of Germ Cell Tumors: A Systematic Review and Meta-Analysis
Authors: Muhammad Husnain, Irbaz Bin Riaz, Muhammad Umar Kamal, Farva Razia Gondal, Zeeshan Ali, Qurat-ul-Ain Riaz Sipra, Asad Javed, Sara Akbar, Parminder Singh, Faiz Anwer
Journal: Blood (2016)
Phase II study of AZD2171 for the treatment of patients with acute myelogenous leukemia.
Authors: M. Juckett, B. LaPlant, P. J. Flynn, A. Jumonville, A. Moreno-Aspitia, C. Erlichman
Journal: Journal of Clinical Oncology (2011)

6574 Background: Inhibition of vascular endothelial growth factor receptors (VEGFR) can block growth and trigger apoptosis in leukemia cells. AZD2171 (cediranib) is a highly potent, orally bioavailable, VEGFR-1/2 inhibitor. We conducted a phase II study of the efficacy of AZD2171 for the treatment of AML. Methods: Adults with AML (relapsed, refractory, or untreated > 60 years) were eligible if they had ≤ 2 prior induction courses, adequate organ function, and ECOG 0-2. The primary endpoint was proportion of responses according to the IWG criteria assessed at one and every 3 months. Pts with stable disease could remain on treatment. Pts were initially treated with cediranib 45 mg daily but due to toxicity, the starting dose was lowered to 30 mg daily. Results: 7 pts were treated at 45 mg; 4 of 7 pts experienced grade 3 toxicity (1 mucositis, 2 fatigue, and 1 hypertension) prompting lowering the starting dose to 30 mg for an additional 16 pts. A total of 23 pts (median age 70 years) were enrolled, and all are evaluable. 12 pts had relapsed/refractory disease and 11 were > 60 years with new AML. Median baseline marrow blasts were 30% (range 0 to 95); 4 pts (17%) had low, 8 (35%) intermediate, and 11 (48%) had high risk cytogenetics. Prior therapy included azacitidine (n=3), induction chemo (n=12), or none (n=11). Patients were treated for a median of 1 cycle (range 1 to 5). There were no responses. Median OS was 3.7 mo (95% CI: 2.2, 5.7). Median TTP was 2.8 mo (95% CI: 1.0, 3.8). Grade 3-4 toxicities at least possibly related to cediranib were: neutropenia (n=2), thrombocytopenia (n=8), anemia (n=1), fatigue (n=3), asthenia (n=1), and hypertension (n=1). Among those on trial for 4 weeks and who had the bone marrow repeated, the blast count fell in 4 of 4 pts taking 45 mg and 3 of 8 of pts taking 30 mg. Because the study met the stopping rule in the first stage of enrollment, it was closed to accrual. Conclusions: Cediranib was poorly tolerated at a dose of 45 mg daily and a dose of 30 mg daily was associated with better tolerance. Although marrow blast percentage declined in some patients, there is insufficient efficacy to warrant further investigation as a single agent in AML. Supported by NCI N01-CM62205, NCI P30-CA014520 and the UW Carbone Comprehensive Cancer Center.
Development of a sensitive COLD-PCR method for the detection of the EGFR mutations in plasma or serum.
Authors: Y. Shi, G. Wu, K. Echtenkamp, R. Candau, P. Eastlake, B. J. Legendre, K. Richardson
Journal: Journal of Clinical Oncology (2011)

e13614 Background: Several variations of the COLD-PCR method have been used for mutation detection. To enrich for all types of substitutions, insertions and deletions in a single assay, we have developed specific Ice COLD-PCR assays for analysis of genes of interest in oncology. Ice COLD-PCR is a method that preferentially amplifies low levels of mutant DNA in a sample containing a vast excess of wild-type DNA. The use of a reference sequence oligonucleotide (RS-oligo) complementary to one of the wild-type strands results in linear amplification of the wild-type sequences but exponential amplification of any the mutant sequences present. Methods: NSCLC tumors harboring the EGFR L858R mutation and the exon 19 deletions respond to anti-EGFR therapy. The methods developed used RS-oligos containing locked nucleic acids (LNA’s) complementary to the wild-type sequence in the L858 mutation or the exon 19 deletion regions. Results: Ice COLD-PCR amplification of control and mutant plasmids containing the exon 19 deletion or the L858 region followed by Sanger sequencing confirmation had a limit of detection (LOD) of 0.1-0.5%. This LOD indicates the methodology shows great promise for detection of low abundance mutations. Ice COLD-PCR with an LNA-RS oligo was also used for detecting exon 19 deletions. Coupled with Sanger sequencing, an LOD of 0.5% mutant DNA was achieved. Thirty-three DNA samples extracted from plasma were tested for both the L858R mutation and exon 19 deletions by Ice COLD-PCR. These samples had previously been analyzed for mutations using SURVEYOR Nuclease digestion. Anaylsis of these samples using the Ice COLD-PCR methodology confirmed previously detected mutations and additional samples with mutations. The detection of these additional mutant samples is due to the greater sensitivity of Ice COLD-PCR. Conclusions: The results demonstrate the utility of using Ice COLD-PCR for the highly sensitive detection of EGFR exon 19 deletions and L858R mutations in DNA derived from serum. Coupled with mutation detection methods such as Sanger sequencing, Ice COLD-PCR provides a new model for highly sensitive, economical testing of EGFR mutations to aid patient treatment decisions and disease monitoring.
Understanding the interaction between physicians and pharmacists as a method of quality improvement.
Authors: Jessica Lynn Fontaine Calder, Vivian Choy, Denise Kwan, Sophia Li, Melissa Lo, Vishal Kukreti
Journal: Journal of Clinical Oncology (2014)

90 Background: Pharmacists and pharmacy technicians are essential to safe medication delivery. Filling prescriptions can be time consuming when the prescription is not complete or clear and requires inter-professional communication. To improve the quality and efficiency of dispensing medication we performed an audit of callbacks to physicians in the outpatient pharmacy associated with our cancer center with a focus on oral chemotherapy. Methods: The Princess Margaret is one of the largest cancer centers in the world, with an outpatient pharmacy on the premises that fills over 70,000 prescriptions a year. The pharmacists have access to the hospital’s Health Information System and chemotherapy prescribing system. A Prescription Audit Form was developed to track the mode of oral chemotherapy prescription (handwritten, preprinted, computerized physician order entry (CPOE), verbal) and reason for callback. The form was implemented from February 10th until March 7th, 2014 with coded data collection. The form was incorporated into the normal workflow of the outpatient pharmacy and concurrently used to document pharmacy interactions for billing purposes. Results: A total of 5,546 prescriptions were filled with 1,166 prescriptions for oral chemotherapy. Nine percent of prescriptions for oral chemotherapy required a callback to a physician and accounted for 32% of the total callbacks made to physicians. Of the 1,166 oral chemotherapy prescriptions; 39% were refills, 34% were handwritten, 22% were CPOE, 4% were verbal, 1% were preprinted, and 1% were not documented. The top two reasons for callbacks were; drug interaction (32%) and incorrect dose (24%). In the 9% of cases where the physician was contacted to clarify a prescription, the prescription was changed 43% of the time. Conclusions: Understanding the reasons for callbacks can be used to determine optimal data fields required in oral chemotherapy prescribing. Ensuring that prescriptions are appropriately completed will reduce the number of callbacks to physicians - significantly impacting the workflow and efficiency of the pharmacy. Reducing unnecessary callbacks will allow the pharmacy team to deliver timely, safe and effective patient centered care.
Pushing the envelope beyond a centimeter in rectal cancer: Oncologic implications of close but negative margins.
Authors: T. L. Fitzgerald, J. Brinkley, E. E. Zervos
Journal: Journal of Clinical Oncology (2011)

487 Background: Advances in surgery, adjuvant therapy and understanding of the natural history of rectal cancer has enabled sphincter preservation surgery for most patients. A 1 cm margin is commonly accepted as minimal distal margin, when not achievable many are relegated to permanent colostomy. Our purpose was to determine if distal margins of &lt; 1 cm is justified by the world's published experience. Methods: Studies were identified with a MEDLINE search using terms rectal cancer, colorectal cancer, margins and distal margins with an additional manual search. There were no restrictions on data type or year of publication. All studies were retrospective or prospective, none were randomized controlled. Studies were excluded if specific margins, local recurrence rates or case level data could not be extracted. Extracted variables included year of publication, time span, number of patients, standardized surgery, radiotherapy, margins, follow up, local recurrence rates and overall survival. Meta-analysis was performed using a random weighting scheme. Values were aggregated across studies to determine overall impact and p-values. Results: Seventeen studies reported margins with thirteen studies, 3,232 patients, reporting outcomes when &lt; 1cm. Meta-analysis of all studies indicated a nonsignificant trend favoring greater margins. However, in order to understand distal margins in the context of current standards additional analyses were performed. Of the thirteen studies 4 reported neither TME nor use adjuvant radiotherapy and 9 studies reported use of one or both. When either total mesorectal excision and/or adjuvant radiotherapy was reported there was no significant increase in local recurrence with distal margins &lt; 1 cm. In studies that used neither therapy &gt; 1 cm margins were statistically less prone to recurrence. Conclusions: Sphincter preservation is possible with &lt; 1 cm distal margin when optimal surgical and adjuvant therapy are applied. [Table: see text]