tbuckley/cabot-search huggingface dataset:
O-desulfated heparin and chemotherapy for the treatment of AML.
Authors: Tibor Kovacsovics, Alice S. Mims, Mohamed E. Salama, Narayanam Rao, Jeremy Pantin, Michael W.N. Deininger, Thomas P Kennedy, Linda M. Bavisotto, Kenneth M. Boucher, Stephen Garrett Marcus, Paul J. Shami
Journal: Journal of Clinical Oncology (2015)

7053 Background: Acute myeloid leukemia (AML) therapy is associated with pancytopenia and a high failure rate due to resistant leukemia stem cells that use CXCL12/CXCR4 to home to marrow niches. Platelet factor 4 (PF4) negatively regulates megakaryopoiesis. O-desulfated heparin (ODSH), a low anticoagulant heparin derivative, inhibits PF4 and like other heparins, may inhibit CXCL12/CXCR4. This study combined ODSH with chemotherapy for the treatment of AML. Methods: Adults with newly diagnosed non-APL AML were enrolled. Induction consisted of cytarabine and idarubicin (7+3). Following a bolus, ODSH was given as a continuous infusion on days 1 – 7. Patients younger than 60 received consolidation therapy with high dose cytarabine along with ODSH. Growth factors were not used during induction. Primary endpoints were safety and tolerability of ODSH, and its effect on platelet count recovery. Secondary endpoints included the effect of ODSH on complete remission (CR) rate. The effect of ODSH on CXCL12/CXCR4 was studied using an ELISA assay. Results: Twelve patients were enrolled (median age 56, range 22 – 74, 3 women). Three, 5, and 4 patients had good, intermediate, and poor risk disease, respectively. Two patients did not finish induction due to events unrelated to ODSH. Day 14 bone marrows were available on 11 patients and were aplastic in all without detectable leukemia. Eleven patients had a morphologic CR after 1 induction (2 with minimal residual disease). Ten patients remain in CR1. One elderly patient relapsed 6 months after completing consolidation therapy off study. Four patients received an allogeneic stem cell transplant in CR1. All patients who received a full induction were evaluable for platelet recovery and had a median day to an untransfused platelet count ≥ 20,000/μl of 22 (range 18 – 23). Six patients who received a full induction were evaluable for neutrophil recovery and had a median day to a neutrophil count ≥ 500/μL of 23 (range 20 – 27). No ODSH-associated adverse events occurred. ODSH inhibited the CXCL12/CXCR4 axis in vitro at concentrations achievable in vivo. Conclusions: ODSH is well tolerated when combined with intensive therapy for AML. It may enhance count recovery and treatment efficacy. Further study of this strategy is justified. Clinical trial information: NCT02056782.
Current survival statistics for patients with newly diagnosed glioblastoma treated with radiation and temozolomide on research studies in the United States
Authors: S. A. Grossman, X. Ye, S. Piantadosi, S. Desideri, L. B. Nabors, M. Rosenfeld, J. Fisher
Journal: Journal of Clinical Oncology (2009)

2003 Background: Many novel agents are being studied in combination with radiation and temozolomide (RT+TMZ) in newly diagnosed glioblastoma using survival as the primary endpoint. These single arm phase II studies generally plan to compare their results with those reported from the phase III EORTC RT+TMZ study (Stupp, NEJM, 2005). Methods: The NABTT CNS Consortium has completed accrual to three RT+TMZ+ novel agent studies using the same eligibility criteria. A total of 281 patients with newly diagnosed glioblastoma were enrolled. The novel agents included talampanel (72 pts), poly ICLC (97 pts), and cilengitide (112 pts). The survival data emerging from these three single arm phase II studies was compared with the published EORTC data. Results: The median age, KPS, and percent undergoing debulking surgery for EORTC patients was 56, 86% (WHO 0–1), and 84% and for NABTT patients receiving talampanel 60, 90, and 77%, poly ICLC 56, 90, 86%, and cilengitide 55, 90, and 76%. A total of 247 patients (88%) were ages 18–70 making them comparable to the EORTC patient population. Currently available survival data for these NABTT and EORTC studies are provided below. MGMT methylation status and survival based on dose levels are not currently available. Conclusions: Survival of newly diagnosed glioblastoma patients treated with RT+TMZ + novel agents at 9 NABTT institutions accruing from 2005 to 2008 appears increased compared to RT+TMZ at 85 EORTC institutions accruing from 2000 to 2002. These results do not appear related to a specific effective agent. As a result, caution should be exercised when comparing outcomes from recently conducted Phase II studies in this patient population to published EORTC data. [Table: see text] No significant financial relationships to disclose.
The utility of MR enhancement as a noninvasive predictor for high-grade histology in patients with progressive low-grade gliomas: Is histology needed to guide therapy?
Authors: Amol Narang, Kaisorn Chaichana, Weingart Jon, Kristin Janson Redmond, Michael Lim, Olivi Alessandro, Alfredo Quinones-Hinojosa, Lawrence Kleinberg
Journal: Journal of Clinical Oncology (2014)

2098 Background: In patients with low-grade gliomas, pathologic grade at time of progression has important therapeutic and prognostic implications. Whether surrogate radiographic variables such as new MR contrast enhancement can be used with high accuracy to predict malignant degeneration is uncertain. Methods: Patients with a pathologic diagnosis of low-grade glioma (WHO grade I or II) who underwent biopsy or resection at time of progression from 1995-2010 were retrospectively reviewed. Radiologic studies were examined to determine the presence of new MR contrast enhancement, which was analyzed as a predictor of high-grade transformation. Results: One hundred and eight patients underwent biopsy or resection for progressive low-grade gliomas, with 19 patients undergoing multiple repeat resections, allowing a total of 127 evaluable records. Median age at initial diagnosis was 36.2 years, while 10% of patients were under the age of 18. Initial pathology consisted of astrocytoma (43%), oligodendroglioma (39%), oligoastrocytoma (11%), and pilocytic astrocytoma (11%). Of the 127 instances of progression, malignant degeneration was present in 74 specimens (58%). Sensitivity (sens) and specificity (spec) of MR contrast enhancement for high-grade transformation were 89% and 57% respectively, while positive (PPV) and negative predictive values (NPV) were 74% and 79%. Values were similar when patients under 18 or with pilocytic astrocytoma were excluded (sens 89%, spec 57%, PPV 71%, NPV 81%), or when patients who only underwent biopsy at time of progression were excluded (sens 91%, spec 64%, PPV 79%, NPV 83%). Conclusions: Radiographic enhancement and pathologic grade were discordant in greater than 20% of cases, largely due to the lack of specificity of new MR enhancement for predicting malignant degeneration. As such, additional radiographic or clinical predictors are needed to better non-invasively identify tumors that have undergone malignant degeneration. Meanwhile, pathologic confirmation of grade at time of progression should be considered when safe.
Dose intensity comparison of African-American and white patients in NSABP breast treatment trials of postoperative doxorubicin and cyclophosphamide
Authors: J. W. Wilson, C. R. Thomas, E. P. Mamounas, P. C. Raich, A. Lagrange, N. Wolmark
Journal: Journal of Clinical Oncology (2006)

6111 Background: It has been proposed that ethnic neutropenia in African-American (AA) breast cancer patients leads to lower chemotherapy dose intensity (DI) compared to white (W) patients and hence to increased mortality from the disease [Hershman 2003]. Thomas et al. [2005] confirmed that AA patients in NSABP breast treatment trials had lower WBC and ANC than W counterparts and found that the total amount of chemotherapy received was no different in AA and W patients. The aim of the present study was to extend previous work to determine whether postop doxorubicin (A) and cyclophosphamide (C) DIs (as opposed to total doses) were lower in AA pts enrolled in NSABP breast cancer adjuvant treatment trials. Methods: Pooled data from AA and white (W) pts enrolled in NSABP trials B-15, B-16, B-18 (postop pts only), B-22, B-23, and B-25 (N=10,678 total: 1,040 AA pts and 9,638 W pts) were analyzed. Outcome measures were 1) total A received as a % of the total dose projected on the basis of BSA divided by total days of chemotherapy and 2) corresponding % of C divided by total days of chemotherapy. These quantities were compared in AA and W pts using ANOVA with adjustment for protocol, BMI, G-CSF use, C regimen (600mg/m 2 ×4, 1200mg/m 2 ×2, 1200mg/m 2 ×2, 2400mg/m 2 ×2, 2400mg/m 2 ×4), and significant pairwise interactions among these variables. Results: After adjustment for the above-listed factors, AA was not a significant predictor of dose intensity for either A or C (p = 0.24 for both comparisons). Conclusions: This retrospective exploratory analysis suggests that despite lower baseline WBC and ANC, AA pts enrolled in these NSABP trials did not receive substantially lower A and C DI than did W pts. Recommending identical dose regimens for AA and W patients in AC-based breast treatment trials is thus most likely clinically reasonable. No significant financial relationships to disclose.
Impact of pharmacogenetics on docetaxel as neoadjuvant treatment of breast cancer.
Authors: Hanjing Xie, Jonas C. S. Bergh, Mats Hellstrom, Thomas Hatschek, Sarah Sim
Journal: Journal of Clinical Oncology (2014)

1067 Background: Marked inter-individual variability of docetaxel has been reported previously. The pharmacogenetic contribution to variations of docetaxel-related toxicity and therapeutic response has not yet been thoroughly studied. The polymorphic cytochrome P450 (CYP) 3A4 plays en essential role in the metabolism of docetaxel. A comparatively frequent allele - CYP3A4*22, which was recently identified, has been shown to correlate with reduced enzyme activity. In this study, we aimed to investigate the effect of CYP3A4 as well as CYP3A5 genotype on docetaxel treatment in breast cancer patients. Methods: In the PROMIX trial, 151 patients with breast cancer received preoperatively six courses of docetaxel and epirubicin. In case of no change or partial response after the first two courses, bevacizumab was added for the remaining four courses. Grade 3 or 4 adverse events (AEs) and data on clinical/radiological and pathological response were addressed in relation to CYP3A4 genotype. Blood samples were used to extract DNA for genotyping analyses. Results: The allelic frequency of CYP3A4*22 and CYP3A5 *3 were 3 % and 8 %, respectively. Seven patients had decreased catabolic activity of docetaxel (PM), 22 patients had increased activity (EM), and 121 patients had normal activity (IM). Regarding the toxicity, a clear genetic influence was seen. The frequency of grade 3/4 AEs was significantly higher in the PM group, compared to that in the EM and IM group (P=0.02). 71.4 % of the patients in the PM group reported grade 3/4 AEs, while the frequency for the EM and IM groups were only 45.5 % and 44.6 %, respectively. One single patient was homozygote for both CYP3A4*22 and CYP3A5 *3, thus lacking enzyme activity, experienced a fatal colon necrosis shortly after the first course of treatment. After a median follow up of 25 months, there were in total 33 relapses, but none of them reported from PM group. Conclusions: The allelic variants CYP3A4*22 and CYP3A5 *3 contribute significantly to the inter-patient variations of docetaxel treatment. The impact of pharmacogenetics on a widely used drug as docetaxel must be considered in the era of individualized therapies. Genotyping should be considered as a valuable tool for dose optimization. Clinical trial information: NCT00957125.
Clinical and molecular characteristics of <i>NF1</i> mutant lung cancer.
Authors: Amanda J. Redig, Stacy L. Mach, Marzia Capelletti, Caitlin Fontes, Yunling Shi, Poornima Chalasani, Suzanne Eleanor Dahlberg, Pasi A. Janne
Journal: Journal of Clinical Oncology (2015)

8022 Background: NF1 is a tumor suppressor that negatively regulates Ras, thus NF1 mutant tumors may also be sensitive to inhibitors of MAP kinase signaling. NF1 variants occur in lung cancer, but their clinical significance is unknown. We evaluated clinical and molecular characteristics of NF1 mutant lung cancers, with comparison to KRAS mutant tumors. Methods: From 07/13-10/14, 591 lung tumors at our institution underwent targeted next generation sequencing (NGS) for mutations and copy number alterations in a 275 gene panel. NF1 and KRAS cohorts were identified, with clinical and genomic analysis. Fisher’s exact test was used to compare frequency of gene mutations between cohorts. Results: Among 591 pts, 60 had NF1 mutations (10%) and 143 (24%) had KRAS mutations (Stage IV: NF1 26, 43%; KRAS 58, 41%). 15 NF1 mutations (25%) occurred with other driver mutations (BRAF (2); ERBB2 (2); KRAS (9); XRAS (2)). There were 73 unique NF1 variants: single copy deletion (1), splice site (12), loss of function/predicted damaging (49), predicted benign (11). 10 tumors had > 1 mutation. Tumor pathology was diverse: adenocarcinoma (38, 63%); squamous cell carcinoma (11, 18%); large cell neuroendocrine (2, 3%); mixed small cell carcinoma (2, 3%); other (7, 11%). In contrast, KRAS mutations (G12C:51, G12D:22, G12V:27, Q61H:8, other:35) occurred in adenocarcinomas (138, 97%) and seldom with other driver mutations (2, 1%). Both mutations were common in former ( > 10 pack years) or current smokers (NF1 49, 82%; KRAS 120, 84%). Among pts without co-mutation, TP53 mutations/2-copy deletions occurred more often with NF1 mutation (33, 65%) than KRAS mutation (47, 35%) (p < .001). Similarly, LKB1 mutations occurred in 8 (16%) NF1 mutant tumors and 33 (25%) KRASmutant tumors (p = .24). Conclusions: NF1 mutations define a unique population of 10% of non-small cell lung carcinoma (NSCLC). NF1 and KRAS mutations present in similar pt populations. NF1 mutations occur more often with other driver mutations and with coexisting TP53 mutations than KRAS mutations. Therapeutic strategies targeting KRAS activation, such as MEK inhibitors, may warrant investigation in NF1 mutant tumors. Tumor suppressor inactivation patterns in these tumors may help further define novel treatment strategies.
Effect of addition of docetaxel (D) to hormonal therapy (HT) versus HT alone on quality of life: Results from a phase III study in non-metastatic high-risk prostate cancer (PC) patients (pts) with a rising PSA status.
Authors: Stephane Oudard, Florence Gillaizeau, Severine Peyrard, Igor Latorzeff, Philippe Beuzeboc, Emmanuel Sevin, Frederic Rolland, Loic Mourey, Franck Priou, Stephane Culine
Journal: Journal of Clinical Oncology (2013)

e16009 Background: Around 75% of non-metastatic high risk PC pts undergo PSA recurrence within 2 years after local therapy. Effect of D in addition to HT on Quality Of Life (HRQoL) was assessed using QLQ-C30. Methods: HRQoL was assessed every 3months: baseline, 3m, 6m, 9m and 12m for this multicenter, randomized phase III study comparing arm A: HT+D (70 mg/m 2 Q3W, 6 cycles) and arm B: HT (triptorelin) every 3m for 1 year in non-metastatic PC pts at high-risk of recurrence after radical prostatectomy (RP) and/or radiotherapy (RT). Stratification factors (SF) were RP vs RT and PSA-doubling time &lt; or &gt;6m. Inclusion criteria were at least 1 of: Gleason &gt;8, PSA-DT &lt;6m, positive surgical margins, PSA velocity &gt;0.75ng/mL/year, pathological pelvic lymph nodes, time from RP/RT to inclusion &lt; 12m. Primary endpoint was PSA PFS (ASCO2011, abs 84423); secondary endpoints: PSA response, time to metastasis, overall survival, QoL and safety. Treatment effect on QoL was analyzed using 1) linear (L) and non-linear (NL) mixed models with continuous and discrete time points from baseline to 12m. Covariates were: SF, an interaction term between time and treatment and 2) time to 20% degradation of QoL upon Cox regression model. Results: Included =254, ITT=251. Arm A (125) vs B (126): median age(y) 64 vs 66, time(m) initial diagnosis to inclusion 35 vs 34, ECOG=0: 96% vs 93%, Gleason score (%) &gt;8: 32 vs 27, RP (%): 69.6 vs 71.4, RT (%): 37.6 vs 38.1, PSA-DT (%) &lt;6m: 53.6 vs 53.2, respectively. At baseline, mean (SD) Global Health status was 76.8 (19.4) and 81.6 (16.9) for arm A and B respectively (p=0.10). Fatigue dimension score was different at 3M (p&lt;0.0001). Upon linear and non-linear longitudinal analysis, addition of D to HT had no effect on QoL (L: p=0.29; NL: p=0.25). Time to 20% QoL degradation was not significantly different between the 2 arms (p=0.44). Conclusions: Addition of docetaxel to hormonotherapy at an early stage after local therapy in non-metastatic high-risk PC pts with a rising PSA status does not significantly impact QoL during the first 12 months.
Association of prior epidemiologic exposures with cytogenetic risk in adult acute myeloid leukemia (AML).
Authors: Laura Elizabeth Finn, Lisa Ostrosky Sproat, Michael Heckman, Liuyan Jiang, Nancy N. Diehl, Rhett P. Ketterling, Riccardo Valdez, James M. Foran
Journal: Journal of Clinical Oncology (2013)

7047 Background: In addition to secondary AML (sAML), important lifestyle and environmental exposures associated with increased risk of AML development have been identified in recent case-control studies including obesity (BMI&gt;30kg/m 2 ), smoking, regular acetaminophen use, and rural/farm habitat. The association of these exposures with AML cytogenetic risk groups is unknown. We therefore evaluated relevant exposures in a cohort of 301 AML patients with confirmed central cytogenetics analysis diagnosed and treated at Mayo Clinic FL and AZ since 1995. Methods: Documented patient exposures were extracted from central electronic medical records, including: prior chemotherapy/radiation or hematologic malignancy, occupation, select medications, “toxins” (esp. benzene) and solid organ transplantation (SOT). Standard cytogenetic risk categories (including intermediate abnormal) were applied. The association of epidemiologic exposures with cytogenetic risk was evaluated on multivariable analysis using logistic regression models. Results: sAML was significantly associated with cytogenetic risk groups, as was prior SOT, healthcare occupation, farm habitat and toxin exposures [see Odds Ratios (OR), Table). In contrast, prior radiation for epithelial malignancies, smoking and BMI were not independently associated with specific cytogenetic risk categories. Conclusions: Specific epidemiologic exposures are significantly associated with AML cytogenetic risk categories suggesting a unique clinical phenotype. This supports a link to leukemogenesis and requires validation in a controlled prospective therapeutic study. [Table: see text]
Survival analysis in breast cancer's women in Santa Catarina, south of Brazil
Authors: I. J. Schneider, E. D. Orsi, C. M. Furtado, A. Vianna, T. S. Silva
Journal: Journal of Clinical Oncology (2009)

e22149 Background: Overall survival after breast cancer diagnosis is influenced by the characteristics study's group, the study's place and biological factors. The prognostic factors are directly related to the survival of women with breast cancer. The studies indicate that the incidence and survival of breast cancer are influenced by socioeconomic factors and demographics. Methods: Define overall survival in five-years and the associated factors with the prognosis of breast cancer's women in Santa Catarina, Brazil. This is a historic cohort study, with data from diagnoses from January 2000 to December 2002 from Registro Hospitalar de Câncer of the Centro de Pesquisas Oncológicas, SC and the Hospital de Caridade, both in south Brazil, and complemented with data from the Mortality Information System until December 2007. The time of survival was calculated as the range of the date of diagnosis (biopsy or surgery) until the date of death or end of monitoring (5 years). The survival curves were estimated by the Kaplan-Meier method, using the log-rank test for comparison of the curves. The effect of co-variable model was estimated by the semi- parametric risk proportionate, Model Cox, with the Schoenfelder analysis of residuals to assess whether the co-variables of the final model respect the principle of proportionality over time. The analysis was made using R 2.5.0. Results: 1002 women were included, and 262 deaths occurred, this 235 by breast cancer. The overall survival after 5 years was 76,2% (73,6–78,9%). Variables were associated with survival by the Kaplan-Meier curves: age, race/color, education, clinical stage, treatments received. This includes these variables in the model of Cox, remaining in the final model, as independent factors: age until 30 years (HR: 3,09) illiterate (HR 3,70), staging III (HR 5,27) and staging IV (HR 14,07).The Cox model variables respect the principle of proportionality over time (p=0,25). Conclusions: The overall survival in breast cancer, proved to be better than in other Brazilian states. The instruction presents itself as a strong influence on survival, where illiterate women have worse prognosis. The diagnosis in advanced stages is one of the most important factors for worse survival, and modifiable through campaigns of early detection and mammography screening. No significant financial relationships to disclose.
Gaining biomarker insights from existing stage II colorectal cancer (CRC) patient cohorts in the United Kingdom: Using real-world data to guide treatment decisions.
Authors: Sarah Jane Fleming, Eva Morris, Mike Shires, Gemma Hemmings, Lisa Wang, Andrea Muranyi, Shalini Singh, Margaret Elizabeth McCusker, Kandavel Shanmugam, Philip Quirke
Journal: Journal of Clinical Oncology (2017)

614 Background: Trial data, while valuable, does not reflect the importance of a biomarker or treatment in the general population as trials generally exclude patients (pts) due to age or comorbidities. We used merged large population datasets to validate a linked anonymized stage II CRC pt cohort as representative of the population to identify the prognostic and predictive value of deficient mismatch repair (MMR) and a new biomarker Ga-interacting vesicle-associated protein (GIV). Methods: English national data on stage II CRC pts surgically treated from 2001-2015, n = 92,147, were analyzed for survival and clinicopathological parameters. Anonymized data were then linked to pathology and a subset of 405 unselected pts surgically treated from 1990-2003 at the Leeds Teaching Hospitals NHS Trust. These were investigated for 5 antibodies. 4 identified deficient MMR status and one was a new marker; GIV. Results: Population data vs the cohort of 405 pts showed a median age of 73 vs 74 yrs, M:F 55%:45% vs. 53%:47%. These are older than seen in most clinical trials and more reflective of the general stage II CRC population. The median survivals of 108 vs 92 months are as expected based on relative time periods covered. 374 patients yielded valid MMR status on immunohistochemistry (92%); 17% were dMMR and 83% were proficient. dMMR vs pMMR pts did not differ in age (median age 75 vs 74.5) or distribution of T3 (69% vs 66%), but were more likely to be female (71% vs 42%), sited in the right colon (76% vs 30%) and poorly differentiated (42% vs 8%). 11% of dMMR and 8% of pMMR received adjuvant chemotherapy in this cohort. GIV scoring status was also evaluated (405): 30% (121) were negative, 65% (264) positive and 5% (20) were not scored. Survival and risk scores by MMR and GIV status will be presented. Conclusions: Population based data has been created to validate the representativeness of a stage II biomarker cohort. This approach using large, population based data-sets provides opportunities to understand the generalizability of biomarker cohorts. The creation and expansion of such cohorts will more effectively validate existing and new biomarkers and treatments in real-world populations.