tbuckley/cabot-search huggingface dataset:
Daily G-CSFs versus pegfilgrastim (PEG) in cancer patients (pts) undergoing chemotherapy (CT): A multivariate analysis from clinical practice.
Authors: D. Almenar-Cubells, C. B. ROIG, E. Jimenez, M. Á. Cruz, J. M. Cuervo, N. Diaz, A. B. Sánchez, A. Galan, V. Giner, M. Codes
Journal: Journal of Clinical Oncology (2011)

e19526 Background: Observational studies suggest that patterns of G-CSF use in current practice significantly influence their effectiveness. Methods: Multicentre, retrospective, observational study in pts with solid tumours that received G-CSF and CT in 2008. Multivariate analyses investigated the effectiveness of daily G-CSFs vs PEG. Results: The study included 391 pts (32.7% women, median age 61.7y (20.4-89.1), 81.2% stage III-IV, 211 daily G-CSF/180 PEG). 47.3% of pts received primary prophylaxis (PP) (57.8% with PEG), 26.3% secondary prophylaxis (SP) (51.5% PEG) and 26.3% reactive treatment. Only 43.1% of pts with daily G-CSF initiated administration within 72h after CT, compared to 63.5% with PEG. 10.5% of pts received ≥7 days of daily G-CSF. In the multivariate models, daily G-CSF was associated with higher risk of neutropenia and neutropenia-related hospitalizations vs PEG (table). Other factors associated with severe neutropenia (G3-4N) were: baseline neutrophils <1.5x109/L (odds ratio (OR):5.9; 95% CI: 2.1-16.5), creatinine >1.5 g/dL (OR: 4.8; 95% CI: 1.4-16.1); platinum-based CT (OR: 2.9; 95% CI: 1.4-5.9); anthracycline-based CT (OR: 3.3; 95% CI: 1.2-9.4); CT cycles (OR per cycle: 1.2; 95% CI: 1.03-1.3). Relative to SP, PP protected against G3-4N (OR for SP vs PP: 6.0; 95% CI: 3.2-11.4) and febrile neutropenia (FN) (OR: 3.4; 95% CI: 1.2-9.7). G-CSF initiation beyond 72h post-CT was associated with FN (OR: 2.2; 95% CI: 1.0-4.8). Better neutropenia-outcomes with PEG were translated into less antibiotic use (9.4% vs 23.7%). Conclusions: PEG was associated with a 70% decrease in the probability of severe neutropenia compared with daily G-CSF. Most pts did not receive daily G-CSF as per label in the current practice, which could compromise its efficacy. Study supported by Amgen S.A. Daily G-CSF % pts PEG % pts Daily G-CSF vs PEG OR* (95% CI) G3-4N 49.3 28.3 1.7 (1.004-3.0) FN 13.3 6.7 1.4 (0.6-3.0) Hospitalization due to neutropenia 14.7 3.9 3.6 (1.5-8.9) Hospitalization due to FN 10.9 2.8 3.7 (1.3-10.3) *Adjusted by: age, gender, stage, tumour type, intention of treatment, CT type and duration, prophylactic G-CSF use, G-CSF use within 72h after CT, baseline biochemistry.
Next-generation sequencing of circulating exosomal RNA from metastatic castrate-resistant prostate cancer patients.
Authors: Elisa M. Ledet, Ratish Gambhira, Aryeneesh Dotiwala, Diptasri Mandal, Oliver Sartor
Journal: Journal of Clinical Oncology (2015)

233 Background: PCa has proven to be an extraordinarily complex disease, with both genetic and phenotypic heterogeneity. Exosomes are membranous nano-sized (50-100nm) vesicles derived from both normal and tumor cells, and function in cell-to-cell communication. These vesicles and their nucleic acid cargo may serve as a peripheral biomarker for genetic risk assessment of PCa prognosis and therapeutic response. The goal of this study was to characterize exosome derived RNA (exoRNA) isolated from blood of metastatic CRPC patients. Methods: Blood samples from 18 consented clinically annotated mCRPC patients and 1 normal control; exosomes were isolated with ultracentrifugation and exoRNA extracted. Following library prep, paired-end sequencing was performed using Illumina Hi-Seq 2000. A bioinformatics pipeline was used for data pre-possessing including alignment, duplicate removal, normalization and variant calling. Visualization and differential analyses were performed with SNP &amp; Variation Suite v8.x. Results: Through preliminary analyses we identified 39 genes commonly expressed in the exosomes of these mCRPC patients. These include PDPK1, USP9X, MAGI2, HMGA2 and PTGFR all of which have been previously expressed in prostate cancer. In exoRNA there is evidence of extensive chromosomal rearrangement resulting in a myriad of gene fusions and isoforms. A diverse variety of lcnRNA, ncRNA and miRNA were also identified in circulating exosomes. Differential expression analyses will be presented. PCR validation is ongoing. Conclusions: The identification of PCa associated transcripts in blood derived exosomes provide evidence that exosomes and exosomal cargo may serve as biomarker in CRPC patients. Exosomes and exoRNA may provide otherwise unattainable insight into tumor evolution and disease progression. Additional studies evaluating the clinical relevance and prognostic value of exosomal RNA will be critical for biomarker development.
Safety, pharmacokinetics (PK), and cost-effectiveness of upfront genotyping of <i>DPYD</i> in fluoropyrimidine therapy.
Authors: M. J. Deenen, A. Cats, M. K. Sechterberger, J. L. Severens, P. H. M. Smits, R. Bakker, C. M. Mandigers, M. Soesan, J. H. Beijnen, J. H. M. Schellens
Journal: Journal of Clinical Oncology (2011)

3606 Background: Fluoropyrimidines, although generally well tolerated, can induce life-threatening toxicity. The major known cause of intolerance is deficiency of the detoxifying enzyme dihydropyrimidine dehydrogenase (DPD), which has an incidence of 1-3% in Caucasians. We determined the safety, PK and cost-effectiveness of pharmacogenetic guided dosing in DPYD*2A mutation carriers treated with fluoropyrimidines. Methods: Germline DNA was prospectively obtained from patients treated with capecitabine or 5-FU and screened before start of therapy for DPYD*2A polymorphism. DPYD*2A mutation carriers received an initial dose reduction of ≥50% plus further dose-titration in following courses based on clinical tolerance. Safety was compared with 45 historical DPYD*2A controls having received full dose treatment, identified among 3,391 patients in nine randomized studies. DPD enzyme activity and fluoropyrimidine PK were determined. In a decision analytical model the cost-effectiveness of this strategy was evaluated. Results: 1700 cancer patients were prospectively screened for DPYD*2A of whom 17 were heterozygous variant allele carriers (1.0%). In DPYD*2A mutation carriers the overall incidence of grade ≥3 toxicity was 14% and 13% was hospitalized due to treatment-induced toxicity. DPYD*2A mutation carriers could be safely treated with a median dose intensity of 48% (range 24-91%), resulting in a 15% incidence of grade 3 toxicity of short-lasting diarrhea. The genotype-predicted DPD deficiency was confirmed by DPD enzyme activity analysis, and was 50% reduced in DPYD*2A mutation carriers to 5.6 ± 2.1 nmol*hr-1*mg protein-1. Fluoropyrimidine exposure in DPYD*2A mutation carriers at reduced dose was comparable to fully dosed non-carriers. Cost-effectiveness analysis showed that total health care costs for screening (€ 5,839 or $ 7,929) were lower than of non-screening (€ 5,854 or $ 7,950). The risk of grade ≥3 toxicity thereby reduced from 68% in historical controls to 15% by genotype-guided dosing. Drug-induced death reduced from 10% to 0%. Conclusions: Upfront genotyping of DPYD*2A improves patient safety of fluoropyrimidine therapy, is feasible in routine practice and is cost-effective.
Everolimus plus bicalutamide for castration resistant prostate cancer (CRPC): Bench to bedside and back.
Authors: Helen Chow, Paramita Ghosh, Leandro S D'Abronzo,, Ralph de Vere White, Marc Dall'Era, Christopher P. Evans, Stanley A Yap, Primo Lara, Chong-Xian Pan
Journal: Journal of Clinical Oncology (2015)

189 Background: We previously reported that the mammalian target of rapamycin (mTOR) pathway was upregulated in CRPC, and that simultaneous blockade of both androgen receptor (AR) and mTOR pathways synergized in killing CRPC cells. Methods: Eligible patients (pts) must have progressive CRPC with serum testosterone &lt;50 ng/dl. No prior bicalutamide (except to prevent flare) or everolimus was allowed. Treatment regimen included daily bicalutamide 50 mg and everolimus 10 mg orally. Primary endpoint was prostate specific antigen (PSA) response (defined as ≥30% reduction). Sample size of 23 pts would have the power of 0.8 and alpha error of 0.05 (one-sided) if the combination had a PSA response rate of 50% vs. a historical rate of 25% with bicalutamide alone. Molecular correlative studies including serum ERBB3 levels were performed by ELISA. LNCaP and C4-2 cells, modeling bicalutamide-sensitivity and resistance, respectively, were transfected with ErbB3 or an empty vector and subjected to western blotting. Results: Of 24 pts enrolled, the mean number of treatment cycles was 7.9 (1.0-23.0). Eighteen pts had a PSA response (75%, 95% CI: 0.53-0.90). Median overall survival was 28 months (95% CI 14.1-42.7). Fourteen pts (54%, 95% CI 0.37, 0.78) developed Grade 3 (13 pts) or Grade 4 (1 pt with sepsis) adverse events attributed to study treatment. Pts with partial response showed a greater decline in ErbB3 (P=0.037) compared to those with stable disease or disease progression. Consistent with these findings, everolimus induced a decline in ErbB3 in hormone-sensitive LNCaP cells but failed to affect ErbB3 in CRPC C4-2 cells, which expressed 8-fold higher levels of ErbB3. Increased expression of ErbB3 in LNCaP cells resulted in resistance to everolimus, whereas bicalutamide initially prevented this effect. Prolonged exposure to bicalutamide also resulted in an increase in ErbB3 which correlated with increased growth rates and cell invasion. Conclusions: The combination of bicalutamide and everolimus has very encouraging efficacy in men with bicalutamide-naïve CRPC, but with substantial everolimus-related toxicity. ERBB3 may contribute to resistance and deserves further study. Clinical trial information: NCT00814788.
MD Anderson experience with off-study regorafenib in patients with advanced colorectal cancer.
Authors: Diogo Bugano Diniz Gomes, Hesham M. Hassabo, Salwan S. Al Mutar, Ibrahim Halil Sahin, Jane Rogers, D. Van Nguyen, Ryan M. Bolonesi, Tunghi May Pini, Arvind Dasari, Scott Kopetz, Michael J. Overman, Cathy Eng, Bryan K. Kee, Manal Hassan, Chris R. Garrett
Journal: Journal of Clinical Oncology (2014)

635 Background: Regorafenib was approved by the FDA on September 27, 2012 following the CORRECT trial demonstrating an overall survival (OS) benefit compared to placebo in pts with advanced treatment-refractory CRC (Grothey A. et al: Lancet. 2013;381:303-12). Little data exists regarding patient treatment outcomes outside of reported clinical trial data. Methods: Pts seen at MD Anderson Cancer Center with a diagnosis of gastrointestinal malignancies since October 1, 2012 were evaluated for regorafenib therapy; electronic clinic records were reviewed for pt treatment data, toxicity, and survival outcomes. Results: 61 pts were identified; 4 pts were determined to have GI malignancy other than CRC [appendiceal cancer (n=3) and duodenal cancer (n=1)] and were omitted from this analysis. Median age was 58 years (range 30.5-83.3), M:F 37:20 (65%:35%), KRAS non-mutant/ KRAS mutant 26/31 (46%:54%), BRAF mutant n=3 (5%); Median time from diagnosis of metastatic disease to initiation of regorafenib therapy was 27.7 months (range 5.9-112.3); 8 pts (14%) had enrolled in clinical trials prior to starting regorafenib. The initial starting dose was 160 mg (n= 38, 66.7%), 120mg (n=18, 31.5%), and 80mg (n=1, 1.8%) respectively. Dose reductions or interruptions were required in 25 pts (43.8%); 14 patients (24.5%) discontinued therapy due to toxicity. The most common grade 3 adverse event was hand-foot reaction (n=12; 21%). One pt initiated on 120 mg was able to tolerate dose escalation to 160mg. Seven pts (12.2%) had stable disease radiographically for more than 2 months and 2 had a confirmed partial response (3.5%). Median OS was 9.1 months (95% C.I. 5.3-12.8) and median time on regorafenib therapy was 2.2 months (range 0.2-10.3). Following regorafenib discontinuation 12 pts (21%) were enrolled on phase I trials. Conclusions: In this pt population palliative regorafenib therapy was associated with modest efficacy and significant toxicity. Dose reductions or interruptions were common (43.8%) even despite a large number of pts being initiated on a dose lower than the recommended initial dose (33.3%). Further studies may be required to determine the optimal tolerable dose in pts with advanced CRC.
Predicting Response to Immunosuppressive Therapy By the Combination of Minor Paroxysmal Nocturnal Hemoglobinuria Clones and Lymphocyte Telomere Length in Children with Aplastic Anemia
Authors: Atsushi Narita, Yuko Sekiya, Hirotoshi Sakaguchi, Nobuhiro Nishio, Hideki Muramatsu, Yusuke Okuno, Nao Yoshida, Xinan Wang, Yinyan Xu, Nozomu Kawashima, Sayoko Doisaki, Michi Kamei, Masahiro Irie, Asahito Hama, Yoshiyuki Takahashi, Seiji Kojima
Journal: Blood (2014)
Characteristics of breast cancer tumors in Lebanon: Where do we stand?
Authors: L. A. El Hajj, R. M. Dimassi
Journal: Journal of Clinical Oncology (2005)

892 Background: To examine tumor characteristics of breast cancer patients in Lebanon and draw orientations to increase the rate of early stages at presentation in accordance with international standards. Methods: A sample of 271 patients is chosen by drawing lots from a larger population of breast cancer patients treated between January 2000 and November 2004. Patients are of all ages and sex, from the 4 different regions of the country, presenting breast cancer disease for the first time and seeking treatment in 50 different medical centers. Females represent 98.15% (266 patients) and males represent 1.84% of this sample. Statistical profiles are drawn for tumor size at presentation and type of surgery performed. The figures are compared to those from developed countries to determine where our patient population stands compared to figures in developed countries. Results: Considering the sample of 266 female patients, the majority of cases (204 of 266) present T1 (37.2%) and T2 (39.5%) tumors. Advanced tumors are found in 21.0% with 7.5% T3 and 13.5% T4 tumors. Early cases represent 1.5% having 0.3% T0 and 1.2% Tis tumors. 60.5% of the female population has tumors larger than 2 cm. This percentage is significantly higher than that for white American women. Radical modified mastectomies are done in 125 (46.99%) women. Conservative surgery is done in 144 (54.13%) women. The rate of conservative surgery compares with a model from developed countries. Conclusions: These results suggest that Lebanese women do not sufficiently refer to breast cancer screening probably because there are not enough public educational campaigns and due to socioeconomic status. Public health measures should be implemented to increase the use of breast cancer screening facilities. No significant financial relationships to disclose.
Patterns of post-treatment care among non-Hodgkin lymphoma (NHL) survivors.
Authors: L. P. Forsythe, N. Arora, K. E. Weaver, A. L. Potosky, C. M. Alfano, N. Aziz, A. S. Hamilton, J. H. Rowland
Journal: Journal of Clinical Oncology (2011)

e19512 Background: With the growing debate about who should oversee cancer survivors’ medical care, information on who survivors see post-treatment is needed. This study describes non-Hodgkin’s Lymphoma (NHL) survivors’ self-reported patterns of post-treatment care. Methods: Using a population-based sample from the Los Angeles County Surveillance Epidemiology and End Results (SEER) registry, we surveyed survivors of aggressive NHL 2-5 years after diagnosis. Our analytic sample included NHL survivors whose cancer was in remission at study enrollment (N=363). Results: Nearly all survivors (N=334, 92%) received cancer-related follow-up care in the past year; most (N=297, 89%) were followed primarily by an oncologist and only 23 (7%) were followed primarily by a primary care physician (PCP). Of those followed by an oncologist, 92% reported more than one visit; 15% reported >5 visits. 263/297 (89%) survivors followed by an oncologist reported on additional care. Four distinct patterns of care emerged: 13% saw only oncologists; 19% saw oncologists plus other specialists; 20% saw oncologists plus PCPs; and 48% received care from oncologists, other specialists, and PCPs. Survivors with a history of recurrence, radiation treatment, or bone-marrow/stem cell transplant were more likely to see only oncologists (p < .01). Survivors who reported greater limitations due to comorbidities (p=0.001) or greater symptom burden (p<0.05) were more likely to also see other providers (PCP, other specialists, or both). Time since diagnosis, grade of NHL, health information needs, perceived health competence, perceived risk of recurrence, and sociodemographics were not related to patterns of care. Conclusions: Most NHL survivors receive regular follow-up care from an oncologist 2-5 years after diagnosis. Survivors with greater disease risk (recurrence, radiation therapy, transplant history) are cared for in oncology only, while those with greater comorbidity and symptom burden also received care from other specialists and PCPs. Patterns of care appear to be matched to patient needs. The high proportion of NHL survivors receiving care from multiple providers suggests that special attention may need to be paid to coordinating care across specialties.
Association of DNA repair factors with overall survival in advanced urothelial carcinoma treated with platinum-based chemotherapy.
Authors: Elizabeth Ann Guancial, Lillian Werner, Edward Stack, Rosina Lis, Sabina Signoretti, Massimo Loda, Enrique Gallardo, Federico Rojo, Jose Lloreta, Meredith M. Regan, Rachel Park, Robert O'Brien, David M. Berman, Joaquim Bellmunt, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2012)

291 Background: DNA repair factors are hypothesized to mediate chemosensitivity to cytotoxic agents that produce DNA damage and may be predictive for response to platinum-based chemotherapeutic regimens. Primary urothelial carcinoma (UC) tumors of patients who developed metastatic disease were evaluated for expression of a panel of DNA repair factors by immunohistochemistry (IHC). Methods: A cohort of 132 clinically annotated, uniformly-treated (platinum-based combination chemotherapy) UC patients who subsequently developed distant metastases with FFPE primary tumor tissue available was identified. Tumor bearing areas were evaluated by a single urologic pathologist. Tissue arrays were constructed for IHC analysis of the following DNA repair factors: ERCC1, Rad 51, BRCA1/2, PAR and PARP1. Tumor was deparaffinized and specific antigen retrieval determined for individual antibodies. Pathologist supervised IHC analysis of nuclear versus cytoplasmic expression was performed using spectral imaging analysis. Overall survival (OS) was defined from start of chemotherapy for metastatic disease to death (N=67) or censored on the last known alive date. Percent of positive nuclear staining was categorized as quartiles or previously identified cut-points. Cox regression evaluated the associations of percent positive nuclear staining levels and OS in multivariable analysis (HRs and 95% CIs included) that controlled for known prognostic variables (performance status and visceral metastases). Results: Higher percentage of nuclear staining of ERCC1 [HR=2.7 (1.5, 4.9), p=0.0007]; Rad51 [HR=5.6 (1.7, 18.3), p=0.005]; and PAR [HR=2.2 (1.1, 4.4), p=0.026] in tumor tissue were associated with poor outcome; each was independent of the other two repair factors and known prognostic variables. Neither nuclear nor cytoplasmic staining for BRCA1/2 or PARP1 reached statistical significance for an association with OS. Conclusions: DNA damage repair factor levels measured by IHC impact outcomes in advanced UC. External validation is ongoing and will be presented. Further studies are required to determine whether these biomarkers are prognostic or predictive in this setting.
Downstaging in pancreatic cancer: A matched analysis of patients resected following systemic treatment of initially locally unresectable disease.
Authors: K. A. Bickenbach, M. Gonen, M. F. Brennan, M. I. D'Angelica, R. P. DeMatteo, Y. Fong, W. R. Jarnagin, P. J. Allen
Journal: Journal of Clinical Oncology (2011)

257 Background: Patients with locally unresectable pancreatic cancer (AJCC stage III) have a median survival of 10–14 months. Standard treatment for these patients is systemic therapy with or without radiation. The objective of this study was to evaluate outcome of patients who respond to this treatment and undergo resection. Methods: Using a prospectively collected database (2000-2009), we identified patients who were initially deemed unresectable due to vascular invasion and had sufficient response to non-operative treatment to undergo resection (initial stage III). Overall survival (OS) was compared between this group and a matched group of patients who were resected during the same time period without receiving preoperative treatment (stage I and II). Case-matching was performed using a previously validated pancreatic cancer nomogram. Results: A total of 36 patients with initial stage III disease were identified who underwent resection after treatment with chemotherapy or radiation therapy. Initial unresectability was determined by operative exploration (n=15, 42%) or by cross-sectional imaging (n=21, 58%). All patients received chemotherapy prior to resection and 58% of patients received radiation. Resection consisted of pancreaticoduodenectomy (n=31, 86%), distal pancreatectomy (n=4, 11%), and total pancreatectomy (n=1, 3%). Pathology revealed T3 lesions in 27 patients (73%), nodal positivity in 6 patients (16%), and a negative margin in 30 patients (83%). There were no operative mortalities. Median follow-up was 13 months (range 2 to 44 months). The median OS in this series was 25 months from resection and 30 months since treatment initiation. There was no difference in OS from time of resection between the initial stage III patients and matched patients who presented with resectable disease (p=0.35). Conclusions: In this study, patients who were able to undergo resection following treatment of initial stage III pancreatic cancer experienced similar survival as those who presented with stage I and II disease. Resection is indicated in this highly select group of patients. No significant financial relationships to disclose.