tbuckley/cabot-search huggingface dataset:
Early thermal quantitative sensory testing to measure acute oxaliplatin neurotoxicity and predict chronic neuropathy in gastrointestinal malignancies.
Authors: Sangeetha Reddy, Nancy Kwon, Halla Sayed Nimeiri, Mary Frances Mulcahy, Robert Norm Harden, Al Bowen Benson, Judith A. Paice, Maxwell Thomas Vergo
Journal: Journal of Clinical Oncology (2012)

425 Background: Acute oxaliplatin neurotoxicity has been shown to be predictive of chronic oxaliplatin neuropathy. A recent study by Attal et al showed that tQST (thermal quantitative sensory testing) at cycle 4 provides a noninvasive method for predicting chronic neuropathy. A high risk population defined as those experiencing pain with a ≥ 20 degree cold stimulus had an OR of 39 for developing a severe chronic neuropathy at 1 year. Our study was designed to test the utility of tQST at earlier time points for predicting chronic neuropathy. Methods: Gastrointestinal cancer patients receiving FOLFOX were evaluated over a 1 year period for the development of acute and chronic oxaliplatin neurotoxicity: before starting FOLFOX, 1 hour into oxaliplatin infusion, before cycles 2, 4 and 12, and 1 year after start of treatment. Patients underwent a series of QSTs to measure thermal and mechanical sensitivities, fine motor skills, vibration detection, validated questionnaires, and presence of hyperalgesia. Results: Preliminary analysis of 13 patients using cycle 4 data as a surrogate for chronic neuropathy shows that cold pain (the temperature at which subjects report pain) prior to starting FOLFOX and at cycle 2 is predictive of cold pain at cycle 4, r s = 0.67 (p=.01) and 0.49 (p=0.09), respectively. There is a significant difference in cold pain across all time points between high and low risk populations(p=0.02 at baseline, p=0.04 during cycle 1, p=0.08 at cycle 2, and p=0.03 at cycle 4). Correlation between cycles 1 and 4 is seen for changes in cold sensitivity from baseline, r s = 0.52 (p=0.07). Conclusions: Baseline tQST correlates to cycle 4 measurements and may be an early predictor of patients at the highest risk for chronic neuropathy. These preliminary data indicate an inherent, pre-existing sensitivity to oxaliplatin induced chronic neuropathy for high risk patients which can be detected with tQST. Early identification of these patients can allow for preventive measures to decrease the incidence of this debilitating chronic adverse effect of oxaliplatin. A larger biomarker validation study is planned using tQST to stratify patients into high and low risk.
Use of the Notch signaling pathway to predict disease progression and distant recurrence-free survival in early stage colon cancer
Authors: R. D. Meng, L. Qin, C. C. Shelton, W. L. Gerald, F. Barany, D. Notterman, Y. Li, P. B. Paty, G. K. Schwartz
Journal: Journal of Clinical Oncology (2008)

14500 Background: The Notch pathway directs normal colonic development, but its aberrant activation may promote tumorigenesis. However, its expression in colon cancer is unknown. Therefore, we analyzed Notch receptors (1–4), ligands, and modifiers in colon cancers and suppressed this pathway with small interfering RNA (siRNA) and drug targeting. Methods: Gene chip microarrays were constructed from 308 normal and malignant colon tissues obtained at surgery, including normal mucosa (10%), polyps (15%), primary cancers (55%), and metastases from liver (13%) and lung (6%), using Affymetrix U133A arrays. Microarray data were normalized using the RMA method. Correlation analysis identified genes differentially expressed between sample classes, using Empirical Bayes t test, and genes associated with survival outcomes, using COX regression. In colon cancer cell lines (HCT116, SW620, and HT29), Notch receptors were downregulated by siRNA, and Notch activation was inhibited by gamma-secretase inhibitors (GSIs). Cell line viability was assessed by colony formation assays and apoptosis by DAPI staining. Results: Notch-3 expression increased with colon cancer progression and was highest in lung metastases (trend test, p<0.001). The Notch ligand JAG-2 increased significantly from polyps to Stage I cancers (p<0.001), whereas the negative Notch regulator Numb significantly decreased (p<0.001). The Notch targets cyclin D1 and survivin also increased with cancer progression. Overexpression of Notch-3 correlated with distant recurrence free survival in Stage III disease (p=0.074, HR=2.95); similar marginally significant correlation holds when adjusting for JAG-2 and NUMB expression. In vitro, siRNA to the Notch receptors inhibited growth but the greatest effect occurred with siRNA to Notch-3. GSIs significantly suppressed cell viability and induced apoptosis. Conclusions: Key elements of the Notch pathway are activated (Notch-3 and JAG-2) and suppressed (Numb) during early stage colon cancer progression. Targeting of this pathway could represent a new therapeutic strategy. Examination of the Notch pathway may have important prognostic significance in Stage III colon cancer and this requires prospective evaluation. No significant financial relationships to disclose.
Understanding treatment disconnect and mortality trends in renal cell carcinoma using tumor registry data.
Authors: Marc C. Smaldone, Brian Egleston, John M. Hollingsworth, Brent K. Hollenbeck, David Christopher Miller, Simon Kim, Elizabeth Handorf, Yu-Ning Wong, Robert G. Uzzo, Alexander Kutikov
Journal: Journal of Clinical Oncology (2014)

403 Background: Previous research has demonstrated a rise in overall and cancer specific mortality over time despite increased detection and treatment of kidney cancer, termed “treatment disconnect.” Our aim was to assess the impact of missing data and rising incidence on mortality trends using national tumor registry data. Methods: Using Surveillance, Epidemiology, and End Results (SEER) data, we identified all patients with a kidney cancer diagnosis from 1973-2009. We estimated overall mortality rates by tumor size after accounting for lags from diagnosis to death and using multiple imputation for missing data. Mortality rates for all patients irrespective of tumor size were also estimated after adjustment for prior cumulative incidence using ridge regression. Results: 73,647 patients met inclusion criteria, of which 22.7% had missing tumor size data. Compared to observed rates, significant decreases in the change in mortality rate per 100,000 US population from 1983 to 2009 were noted for 2-4cm (Δ obs 1.58 versus Δ imp 1.34; p=0.003), 4-7cm (Δ obs 1.61 versus Δ imp 0.79; p&lt;0.001), and &gt;7cm (Δ obs 1.55 versus Δ imp 0.19; p&lt;0.001) tumors following missing data imputation, while no differences in change of rate were noted for tumors &lt;2cm (Δ obs 0.29 versus Δ imp 0.25). In a separate analysis, holding the incidence of kidney cancer constant over time, the temporal increase in overall mortality for all patients was attenuated (p&lt;0.001 for test of difference in slope) when comparing observed (3.9 to 6.8) and estimated (5.9 to 7.1) rates, suggesting that rapidly rising incidence may also influence reported mortality trends. Conclusions: Missing data and rising incidence rates may contribute substantially to the “treatment disconnect” phenomenon when examining mortality rates in kidney cancer using tumor registry data.
Molecular analysis of the epidermal growth factor receptor (EGFR) gene and protein expression in patients treated with erlotinib in National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial BR.21
Authors: M. S. Tsao, A. Sakurada, I. Lorimer, J.-C. Cutz, S. Kamel-Reid, J. Squire, K. Ding, R. Frank, L. Seymour, F. Shepherd
Journal: Journal of Clinical Oncology (2005)

7007 Background: BR.21 demonstrated a significant survival benefit for patients with advanced NSCLC who received erlotinib vs placebo (Shepherd, ASCO 2004). While EGFR expression is common in NSCLC, protein expression by immunohistochemistry (IHC) does not appear to predict response to EGFR tyrosine kinase inhibitors (TKI). Point mutations and/or short deletions in exons 18–22 of the EGFR gene may predict response to EGFR TKIs. In BR.21, EGFR expression by IHC did not predict response. The predictive value of EGFR mutations (MUT) or gene amplification (AMP) on survival have not yet been reported. Methods: 731 patients were randomized to BR.21 (488 erlotinib, 243 placebo). IHC for EGFR expression was evaluated for 325 patients in formalin-fixed, paraffin embedded tumor specimens. 213/325 samples were suitable for molecular analyses for MUT and/or fluorescent in situ hybridization (FISH) studies for AMP. Results: 184/325 samples showed >10% EGFR staining by IHC. The HR for survival was 0.7 for patients with >10% EGFR expression compared to 0.9 for those without. EGFR gene data presently are available for 106/213 patients; this subset was significantly more likely to have had adenocarcinoma (adeno), >1 prior regimen, > time from diagnosis to randomization. 12 mutations/deletions in exons 19 and 21 were identified (10 adeno) in the 106 patients. FISH was performed successfully in 68/106 patients; 20 samples had AMP arising from polysomic gain or high copy number AMP (14/20 adeno). 4 patients had MUT + AMP, 3 MUT without AMP and in 5 patients with MUT, FISH was not successful. In this preliminary subset of 106 patients, 3 had complete or partial response; all 3 patients had AMP but no MUT. Analyses of additional EGFR gene exons and of the remaining samples are ongoing and will be correlated with survival. Conclusion: Erlotinib appears to have a greater effect on survival in patients with EGFR protein expression. In a small, preliminary subset, EGFR amplification appears a better predictor of response than EGFR mutation. Additional gene assays and survival analyses will be completed shortly. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI OSI
A shared decision support system for localized prostate cancer.
Authors: Pavan Dadlani, Jingyu Zhang, Sebastian P. M. Dries, Colleen M. Ennett, Esther Toet
Journal: Journal of Clinical Oncology (2012)

326 Background: In the US, about 1 in 6 men is diagnosed with prostate cancer (PCa). Over 90% of them are localized PCa patients, which have the most controversial treatment decisions with few certainties about outcomes such as survival years and quality of life (QoL). Shared decision making is emerging, where patients need to make trade-offs between longevity and QoL based on personal preferences and treatment outcomes. Methods: By collaborating with leading PCa centers, medical psychologists and health economists, we investigate, iteratively design, and eventually test a decision support solution that could enhance treatment decision making and patient-clinician interaction. We interviewed 7 PCa clinicians and 13 patients and survivors, and observed 4 patient-clinician consultations. Results: Key insights from the user research: 1) existing decision aids are very generic and not personalized to the patient’s preferences, are not integrated in the clinical workflow, and involve a complex user experience; 2) there is a significant amount of unwarranted variation in PCa treatment (i.e. not preference sensitive, or patients lack the confidence to choose non-aggressive options that could lead to similar or better outcomes, e.g., active surveillance; and 3) clinicians need to understand what the patient’s preferences are (verbally discussed only), which consumes significant time in consultations. These insights led to developing a shared decision support system based on algorithms that use quantitative computations of quality adjusted life years (QALYs) and patient-friendly interactions. This system can be integrated in the clinical workflow, allow patients to make better informed decisions, and increase their confidence to choose the best treatment option according to their own preferences. We aim to increase patients’ involvement and satisfaction, enhancing consultation efficiency, and reducing unwarranted variation. Conclusions: Our ongoing research, motivated by user insights, focuses on developing shared decision support technology that is personalized to the patient’s profile and sensitive to their preferences. We will deploy validation studies at clinical sites and evaluate the system across the predefined outcome measures.
Combination of antiangiogenic therapy and cytotoxic chemotherapy for sarcomatoid renal cell carcinoma.
Authors: M Dror Michaelson, David F. McDermott, Michael B. Atkins, Daniel C. Cho, Kara M. Olivier, Abraham B. Schwarzberg, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2013)

4512 Background: Numerous treatment options exist for metastatic renal cell carcinoma (mRCC), but optimal treatment for patients (pts) with sarcomatoid features remains undefined. Sarcomatoid differentiation is a particularly unfavorable prognostic feature in mRCC. Cytotoxic chemotherapy has modest activity, with a response rate of 16% for doxorubicin plus gemcitabine (Gem). Retrospective data has suggested a response rate of 10% for antiangiogenic therapy. We prospectively studied the combination of antiangiogenic therapy, sunitinib (Su), with Gem chemotherapy in this mRCC subpopulation. Methods: Pts with mRCC and sarcomatoid differentiation were enrolled in a phase 2 clinical trial at 3 institutions. Treatment consisted of 21-day cycles of Su, 37.5 mg on a 2 weeks on/1 week off schedule, along with Gem 1000 mg/m2 on days 1 and 8. The primary endpoint was radiographic response rate (RR) by RECIST. Secondary endpoints included time to disease progression (TTP), safety, and overall survival (OS). Results: Among 35 pts treated in total, 7 were classified as MSKCC good risk, 26 as intermediate risk, and 2 as poor risk. There were 10 partial responses and 1 complete response, for a confirmed RR of 30%. An additional 10 pts exhibited stable disease (clinical benefit rate 60%). Among the 10 pts who had progressive disease as their best response, the majority had underlying non-clear cell histology. Median TTP was 3.5 months (range 0.5-12). Eight pts discontinued due to adverse events (AEs). The most common treatment-emergent grade 3 or higher AEs were neutropenia (8 pts), fatigue (5), anemia (2), and hypertension (2). No treatment-related deaths occurred. Median OS was 11 months (range 1-38+). Conclusions: To our knowledge, this is the largest prospective trial combining cytotoxic chemotherapy and antiangiogenic therapy in patients with RCC and sarcomatoid features. Our results suggest that combination therapy may be more efficacious than either treatment alone in this subtype of mRCC and supports an ongoing intergroup trial (NCT01164228). Further research is necessary to define prognostic factors, including histologic and molecular biomarkers, for distinct subpopulations within this heterogeneous disease. Clinical trial information: NCT00556049.
Circulating tumor cell (CTC) detection, N-terminal androgen (AR) characterization, and PTEN loss in metastatic or advanced castration resistant prostate cancer (CRPC).
Authors: Shidong Jia, Sarah Baird, Amanda K. L. Anderson, Shannon L. Werner, Jane Petersen, Ling Huw, Dena C. Marrinucci, Premal H. Patel
Journal: Journal of Clinical Oncology (2016)

195 Background: Detection and characterization of CTCs offers a minimally invasive mechanism for understanding patient response to therapy and disease evolution. Here we describe a proprietary technology platform to examine CTC incidence, N-terminal AR expression, and PTEN loss in metastatic or advanced CRPC patient samples from a phase II clinical trial (GO27983) testing the combination of the AKT inhibitor ipatasertib and abiraterone. Methods: Blood samples from CRPC patients (n = 283) were collected at screening and shipped to Epic Sciences. Upon receipt, the nucleated cells were plated onto microscope slides and stored at -80C. Two slides were thawed per patient and analyzed with an N-terminal AR CTC assay. CTCs were detected using a combination of CD45 exclusion, CK and N-terminal AR expression, and morphologic criteria. Traditional (CD45-, CK+, DAPI+) and Non-Traditional (CD45-/CK- with distinct morphology or CD45-/CK+ with fragmented nuclei) CTCs were enumerated and N-terminal AR expression was quantified for each CTC. Samples with &gt; 2 Traditional CTCs enumerated per slide were further evaluated for PTEN loss by FISH (n = 170). Results: Traditional CTCs were detected ( ≥ 1 cell/ml) in 86% (242 of 283) of samples. Non-traditional CTCs were detected in 93% (263 of 283) of patients. N-terminal AR positivity was detected ( ≥ 1 AR+ cell/ml) in 53% (128 of 242) of Traditional CTC-positive samples, with the % positivity ranging from 0.4-100%. PTEN status was determined for 66% (160 of 243) of patients with Traditional CTCs detected. Patients with homozygous (HO) PTEN loss had a significantly higher mean CTC/mL (p = 0.0013) and AR+ CTC/mL value (p = 0.0014) than patients with PTEN non-deleted status. Conclusions: The ability of the Epic Sciences platform to detect AR+ CTCs and PTEN loss at screening provides a non-invasive approach to characterizing and monitoring CTCs identified in advanced CRPC patients. The study is ongoing to monitor longitudinal changes in CTC incidence and AR expression in relation to PTEN status. Clinical trial information: NCT01485861.
Predicting chemotherapy-induced hematotoxicity elderly patients with metastatic breast cancer treated by pegylated liposomal doxorubicin (PLD): A population-based analysis on data coming from the DOGMES phase II GINECO study.
Authors: A. Sostelly, C. Falandry, E. Pujade-Lauraine, G. Freyer, M. Tod
Journal: Journal of Clinical Oncology (2011)

e19740 Background: Use of anthracyclines is often limited in older patients due to cardiac toxicity and hematotoxicity (HT). Thanks to its improved toxicity profile, PLD allows use of doxorubicin in this population. We aim at modeling HT of PLD in MBC patients older than 70 years and at finding predictive factors of neutrophil nadir value. Methods: sixty patients, enrolled in the DOGMES prospective multicenter phase II trial, were treated with PLD 40 mg/m2 every 28 days for 6 cycles. Trial design included geriatric covariates assessment at inclusion and monitoring of blood counts every weeks for 3 cycles. Due to the long half-life of PLD, it was assumed that drug effect was constant over time. A non-linear mixed effects model as suggested by Friberg et al (J Clin Oncol 2002) was applied to neutrophil count. The model includes inter-occasion (IOV) and inter-individual (IIV) variabilities. Best model choice was based on goodness of fits plots and Akaike criteria. Results: Final model includes 1 IOV parameter on the mean transit time (MTT) and 4 IIV parameters on baseline count, MTT, proliferation rate, and power. Based on model, exact neutrophil nadir values from 53 patients and their 3 first cycles were computed. Then, predictive factors were assessed among the 66 measured covariates. Minimal estimated nadir value was 0.82x109/L and maximal value 8.38x109/L, median time in grade 2 was 4 days (1.1; 4.8). Conclusions: Three factors were predictive of the nadir value (diabetes, p = 0.00012; assistance at home, p = 0.037; frailty syndrome, p = 0.065) and explained 18.5% of variability in this value. These factors can be used to identify patients with higher risk of toxicity.
Treatment strategy for intrahepatic cholangiocarcinoma: From optimal surgical management to adjuvant therapy.
Authors: Yuji Morine, Mitsuo Shimada, Satoru Imura, Tetsuya Ikemoto, Yu Saito, Shinichiro Yamada, Masato Yoshikawa, Hiroki Teraoku
Journal: Journal of Clinical Oncology (2016)

392 Background: Surgical strategy for intrahepatic cholangiocarcinoma (IHCC) including systemic lymph nodes (LN) dissection is still controversial. Also, as adjuvant chemotherapy, we adopted this GFP regimen (GEM, 5-FU, and Cisplatin). We demonstrate the adequate surgical strategy, the effect of adjuvant therapy and the tumor malignancy evaluation. Methods: Study 1: Surgical strategy) In period 1 (1994.4-2004.3, n = 20), extended surgery was basically performed. In period 2 (2004.4~, n = 34), extent of hepatectomy is conducted according to tumor conditions. Swelling LN exterpation for macroscopic curability and bile duct resection for positive surgical margin are performed. Study2: Adjuvant GFP therapy) Induction of 2 cycles of GFP for advanced IHCC with prognostic factors (LN metastasis, intrahepatic metastasis and R2 resection). Study 3: Malignancy evaluation) Significance of serum CA19-9 levels, the relationships its levels and expressions ( immunostaining ) of hypoxic inducible factor 1 (HIF-1) /Histone deacetylase 1 (HDAC1) were evaluated. Results: Study 1) In period 2, LN dissection and extrahepatic bile duct resection were significantly infrequent. Surgical outcome is rather good regardless of limited surgery in recent periods (Period 1 vs. Period 2: 5yrs survival 24.9% vs. 34.9%, p = 0.119). There was no significant difference in recurrent pattern. Study 2) There were 32 cases had some kind of prognostic factors, and of these 11 patients received adjuvant GFP. Patient’s prognosis received adjuvant GFP was significantly prolonged (GFP vs. non GFP: 1yrs survival 71.6% vs. 45.0%, p &lt; 0.02). Study 3) CA19-9 ( &gt; 300U/ml) high group revealed the independent prognostic factor with stepwise model, as well as LN metastasis and vessels invasion. CA19-9 levels significantly correlated to HDAC1 and HIF-1 expressions. Conclusions: Extended surgery including LN dissection might not control malignant behavior of IHCC, and adjuvant GFP should be introduced in patients with poor prognostic factors.