tbuckley/cabot-search huggingface dataset:
The relationship between LHRH-agonist depot formulations and frequency of follow-up with health care providers in patients with prostate cancer
Authors: J. W. Moul, D. Wiederkehr, M. Connolly, V. Sendersky, E. Onel
Journal: Journal of Clinical Oncology (2008)

16002 Background: Several formulations of Luteinizing Hormone-Releasing Hormone Agonists (LHRH-A) of varying duration are available for treatment of prostate cancer (PCa). Previous reports suggest that utilization of longer acting LHRH-A may reduce the number of healthcare visits, thereby reducing the costs of managing PCa patients. In this study we investigated the frequency of patient follow-up with respect to use of 1, 3 and 4 month depot formulations in a cohort of patients with PCa from a large healthcare system in the United States. Methods: Data from PCa patients identified in the Henry Ford Health System (HFHS) as International Classification of Diseases for Oncology (ICD-O) code C61.9 in the tumor registry were extracted. The following patients were included: full staging information at index and the same dosage of LHRH-A during the duration of the follow-up. Patients with prior primary tumor types were excluded. Results: 653 patients receiving the same depot of LHRH-A through the duration of agonist treatment were identified (44.1 % Caucasians, mean age 72±9.2, mean Gleason score 7.2, median PSA 10.5). There was no significant difference with depot switchers excluded from the analysis. Patients receiving 1, 3 and 4-month depot formulations had 25, 29 and 41 days between any PCa related visits. Patients on the 1-month depot had 51 days between visits to urologists, while patients on 3 and 4 month depots had 46 and 60 days between urologist visits, respectively. For patients receiving 1-month depot, there was no significant difference between the actual time between PCa related follow-up visits and expected time between follow-up visits (mean difference -5 days; p=0.1923). However, patients receiving 3-month (mean difference -61 days; p<0.0001) and 4-month (mean difference -79 days; p<0.0001) depot formulations had significantly less time than expected between PCa related follow-up visits. Conclusions: Although it was expected that the depot formulation would have a significant impact on the interval between PCa related visits, the data did not support this. The results of this study suggest that patients’ frequency of follow- up with health care providers is not influenced by LHRH-A depot formulations. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Ferring Ferring Ferring Ferring
Interaction of <i>KRAS</i> somatic mutation and colorectal carcinoma and its association with differential DNA methylation.
Authors: Farzana Jasmine, Mohammed Kamal, Shantanu Roy, Mustafizur Rahman, Maruf Raza, Rupash Paul, Kamrul Hasan, Zahidul Haq, Habibul Ahsan, Muhammad Ghulam Kibriya
Journal: Journal of Clinical Oncology (2016)

577 Background: We examined if KRAS somatic mutation in colorectal carcinoma (CRC) is associated with differential tumor DNA methylation. Methods: We did a genome-wide methylation assay (450K) for a total of 250 paired samples from 125 CRC patients (m = 72, f = 53) at different stages (stage 1: 25, stage II: 33 and stage III: 67). Of them 101 had left-sided CRC (descending colon to rectum); 30 had MSI, and 34 had somatic mutation in KRAS (rs112445441). Results: Frequency of KRAS mutation was not different between right and left-sided CRC (29% vs. 27%). But, like other series, MSI was more frequent in the right-sided tumor (54% vs. 17%, p = 0.003). In patients with wild type KRAS tumor (n = 91), paired comparison between tumor and corresponding normal tissue identified a total of 1244 tumor-specific differential methylation loci (DML) covering 532 genes that were significant at FDR 0.001 and magnitude of difference ≥ 20%; But similar analysis in patients with KRAS mutation (n = 34) revealed 7612 tumor-specific DML covering 2357 genes - suggesting an association of KRAS mutation and DNA methylation. We also found that MSI in tumor tissue was associated with DNA methylation change too. Next, we identified 726 genes that are markedly differentially methylated in tumor compared to corresponding normal tissue only in presence of KRAS mutation, irrespective of MSI status, staging, and location of tumor (KRAS mutation associated tumor-specific genes – list enriched in GO ontology “developmental process”, “biological regulation”). We also identified 241 genes that are differentially methylated in tumor compared to normal tissue irrespective of KRAS mutation, MSI status, staging, and location of tumor. (common tumor-specific genes) Conclusions: KRAS somatic mutation is independently associated with methylation changes in a number of genes related to carcinogenesis in CRC.
Drug cost and outcome in metastatic colorectal cancer with emphasis on monoclonal antibodies.
Authors: Helmy M. Guirgis
Journal: Journal of Clinical Oncology (2015)

567 Background: Patients with wild type KRAS metastatic colorectal cancer (mCRC), treated with first-line cetuximab (Cet) or bevacizumab (Bev) and chemotherapy demonstrated similar overall survival (OS). In the Western world, costs of anticancer drugs ranged from $59,000 to $100,000 per life-year gain (LYG). Hazard ratios (HR) have rarely been integrated in cost/outcome evaluation. Objective: Weigh drug cost against survival and hazard ratio (HR) in mCRC with emphasis on monoclonal antibodies (MABs). Methods: Estimated costs in United States dollars (US$) were calculated for 70 kg or 1.7/m 2 patients. Costs were divided by the reported median OS gain over control in days (OSg) and by probability of survival (PoS) calculated as (1.0 – HR). Relative values (RV) were computed as 100,000/cost/outcome. Results: There was no significant difference in cost/outcome of Pan and Cet in first-line wild KRAS mCRC. At 12 week (w), the cost/LYG of panitumumab (Pan), Cet, and Bev were $64,947, $82,224, and $36,919 with RVs of 1.54, 1.22 and 2.71 respectively. Using HRs, the corresponding PoS were $140,082, $137,040, and $42,524 with RVs of 0.71, 0.73, and 2.35. Wild RAS testing improved the cost/outcome of Pan by 25%. Increasing number of cycles increased the cost/outcome and decreased the RVs of all MOAs. Conclusions: In first-line wild KRAS mCRC at 12 w, the cost/outcome of Bev was approximately 30% to 57% that of Pan and Cet. Cost/outcome of Pan significantly improved in RAS wild type. The cost/outcome of MABs was determined by the number of cycles.
Initial acute toxicity report of post-prostatectomy proton therapy for prostate cancer patients undergoing adjuvant or salvage radiotherapy.
Authors: Curtiland Deville, Stefan Both, Peter Edward Gabriel, Zelig Tochner, Neha Vapiwala
Journal: Journal of Clinical Oncology (2016)

154 Background: Purpose is to report acute genitourinary (GU) and gastrointestinal (GI) toxicities associated with post-prostatectomy proton beam radiotherapy (PBT). Methods: The first 50 patients undergoing post-prostatectomy PBT on a prospective, IRB-approved, institutional protocol for image-guided radiotherapy were assessed. Patients received a median dose of 70.2 Gy relative biological effectiveness (RBE) in 1.8 GyRBE daily fractions using traditional, laterally-opposed beams to the prostate bed only, as defined by RTOG consensus guidelines, passive scattering or pencil beam scanning technique, and 100 cc water-filled endorectal balloon, from 10/2011 to 7/2015. One patient received concurrent androgen deprivation. Acute toxicity was scored by CTCAE v4.0. Results: The Table summarizes the clinical characteristics. Median age was 62 years and median months from surgery were 23. Passive scattering was used for 16% of cases and pencil beam scanning for 84%. A GyRBE dose of 70.2 was used for 88% of cases, 66.6 for one case, and 75.6 for the remaining 10% with gross local recurrence. All patients completed treatment and there were no acute grade 3 or greater GU or GI toxicities. Regarding GU, most reported grade 1 (78%) toxicity, 18% grade 2, and 4% none (grade 0). Regarding GI, most patients (54%) reported no toxicity (grade 0), 36% grade 1, and 10% grade 2. Conclusions: Our results report for the first time to our knowledge, the clinical feasibility and favorable GU and GI toxicity profile of post-prostatectomy PBT. Future studies with larger patient numbers are planned to further validate our preliminary findings. [Table: see text]
Involvement of miRNAs in the formation and maintenance of self-renewing kidney cancer spheres with stem cell properties.
Authors: Zsuzsanna Lichner, Carol Saleh, Venkateshwaran Subramaniam, Gerard Prud'homme, George M. Yousef
Journal: Journal of Clinical Oncology (2013)

463 Background: Cancer cells may acquire stem cell (CSC) properties by activated TGFβ-epithelial-mesenchymal transition (EMT) axis resulting in formation of cancer stem cells. miRNAs are involved in CSC formation in solid tumors, but their role has not been investigated in renal cell carcinoma (RCC). Methods: RCC spheres were generated and propagated in serum-free defined medium (SFDM). mRNA expression was assessed by qRT-PCR. miRNA expression was screened on a qRT-PCR based panel. Tumorigenicity was assessed by subcutaneous injection of RCC sphere or parental cells into immunodeficient mice in different dilutions. TargetScan and miRPath was used for target prediction and clustering. Results: We isolated self-renewing cancer spheres from ACHN and CAKI-1 RCC cell lines in the stem cell supporting media, SFDM. Spheres were highly clonogenic and tumorigenic in xenograft tumor model and expressed high levels of stem cell-related markers and mesenchymal markers. These spheres were enriched in the mesenchymal marker CD44 and the kidney progenitor maker CD24 indicating that EMT contributed to their formation or maintenance. We compared miRNA expression between the spheres and the parental cells and identified differentially expressed miRNAs. Functional clustering of their predicted targets indicates that TGFβ signaling is a potential regulator of CSC self-renewal and is regulated by the candidate miRNAs. Further, we show that transfection of ACHN and CAKI-1 cells with the miR-17 inhibitor resulted in rapid and highly efficient formation of cancer spheres that were indistinguishable from the spheres formed in SFDM. These spheres were stable and could be propagated indefinitely. Histologic examination and immunohistochemistry of the sphere-derived xenografts confirmed the presence of clear cell RCC with large areas of sarcomatoid dedifferentiation. Finally, we prove that the TGFβ receptor II, and the co-Smad Smad4 are possible direct targets of miR-17. Conclusions: The TGFβ-EMT axis likely contributes to the self-renewing potential of RCC spheres. miRNAs are differentially expressed in RCC spheres and miR-17 inhibition transformed ccRCC cells to highly tumorigenic RCC spheres.
S100A4 as a biomarker of resistance to gemcitabine: A secondary analysis of RTOG 9704.
Authors: Margaret A. Tempero, Jennifer Moughan, Grace E. Kim, Sanjay Kakar, Teresa S. Hyun, William Regine, Rex B. Mowat, Kevin Charpentier, William Small, Chandan Guha, David K. Chang, Andrew Victor Biankin
Journal: Journal of Clinical Oncology (2012)

165 Background: Preclinical studies suggest that nuclear expression of the Ca ++ binding protein S100A4 induces gemcitabine resistance in pancreatic cancer cell lines (Mahon et al, Cancer Research, 2007). As a consequence, we assessed the potential role of S100A4 protein expression as a clinical biomarker of gemcitabine resistance in the RTOG 9704 adjuvant trial, which compared gemcitabine to continuous infusion 5FU. Methods: Analyzable archival tissue samples were available for 184 patients on which the secondary analysis was based. Immunohistochemistry was used to detect S100A4 expression on a tissue microarray with triplicate samples from each specimen. Tissue was semiquantitatively scored for % labeled cells and intensity and dichotomized to negative or positive expression. DSS was estimated univariately with the Kaplan-Meier method and multivariate Cox proportional hazards models were used to determine if S100A4 expression correlated with DSS. Results: The analysis was based on 184 specimens; 97 from the 5FU arm and 87 from the gemcitabine arm (see table below). For S100A4 related DSS, the HR for negative vs. positive expression in the 5FU and gemcitabine treatment arms was 0.93 (95% C.I. = [0.53, 1.63], p=0.80) and 1.85 (95% C.I. = [0.96, 3.56], p=0.066), respectively. The 2-year DSS for S100A4-negative patients in the 5FU treatment arm was 26%, and 39% for S100A4-positive patients. In the gemcitabine treatment arm, 2-year DSS for S100A4-negative patients was 59% and 37% for S100A4-positive patients. Conclusions: The association with improvement in survival for S100A4-negative patients treated with gemcitabine, although not statistically significant, supports the hypothesis that S100A4 expression predicts for chemoresistance to gemcitabine. The small number of unique samples available from RTOG 9704, especially in subgroups of interest, was a limiting factor in this study. This project was supported by RTOG grant U10 CA21661, U24 CA114734, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and the RTOG Translational Research Program. [Table: see text]
The role of surgical resection for hepatocellular carcinoma in octogenarians: A population-based analysis.
Authors: Takintope Akinbiyi, Atuhani S. Burnett, Philip Ernst, Marisa Cevasco, Donald A. McCain, Suyog A. Mokashi
Journal: Journal of Clinical Oncology (2014)

202 Background: Hepatocellular carcinoma (HCC) is a significant source of morbidity and mortality amongst the elderly population. In appropriately selected patients, surgery is known to confer a survival advantage. Octagenarians, however, given their remaining life expectancy may receive limited benefit from surgery. Nevertheless, insufficient information is available in the literature on the survival benefit of surgery in octagenarians with HCC. Methods: Octogenarians with HCC were selected from the Surveillance, Epidemiology, and End Results (SEER) database between 1998 and 2009. We evaluated patients who underwent surgical resection and those that declined to assess the impact surgery has on overall survival in this population. Results: A total of 8,614 with HCC were identified in the SEER database, of which surgery was recommended for 3,529 (41%). A total of 1,002 patients (28%) underwent surgery and 2,497 (71%) declined. Although there was a trend towards improved survival in the surgery group (7.91 months) vs the non-surgical group (7.03 months), there was no statistically significant difference in survival between the two groups (p = 0.09). Conclusions: Our study demonstrates that octagenarians as a whole do not experience a survival benefit from surgical resection for HCC. Subgroup analysis, however, may ultimately identify benefit in specific disease stages or patients with fewer comorbidities.
Bevacizumab therapy in recurrent high grade glioma: Impact on local control and survival
Authors: A. Narayana, S. Raza, J. G. Golfinos, G. Johnson, E. A. Knopp, D. Zagzag, I. Fischer, P. Medabalmi, P. Eagan, M. L. Gruber
Journal: Journal of Clinical Oncology (2008)

13000 Background: Anti-angiogenic agents have recently shown impressive radiological responses in high grade glioma. However, it is not clear if the responses are related to vascular changes or due to anti-tumoral effect. We report the mature results of a retrospective study of bevacizumab based therapy in recurrent high grade gliomas. Methods: Fifty four patients with recurrent high grade gliomas received therapy with Bevacizumab at 10 mg/kg every two weeks for four doses in an 8 week cycle along with Irinotecan at 125 mg/m2. Treatment evaluation was done with neurological examination, conventional magnetic resonance and perfusion imaging subsequently. The survival was calculated from the time of starting bevacizumab based therapy. Results: The median progression free survival (PFS) and overall survival (OS) were 5 (95% confidence interval, 1.0–6.9) and 9 (95% confidence interval, 7.5–10.5) months respectively. Radiological responses following therapy were noted in 72.2% of cases. The Patients who received > 2 cycles of bevacizumab based therapy had a PFS and OS of 7 and 11 months compared to 3.5 and 5 months for the patients who received < 2 cycles of therapy (p=0.02 and P<0.0001) respectively. Neither the grade of the tumor nor the surgical resection prior to therapy had an impact on survival. Although the predominant pattern of relapse was local, twelve patients (22.2%) failed as diffuse disease. Conclusion: Bevacizumab therapy improves the survival in recurrent high grade glioma. A possible change in the invasiveness of the tumor following therapy is worrisome and needs to be closely monitored. No significant financial relationships to disclose.
Combination external beam radiotherapy and brachytherapy for radical treatment of esophageal carcinoma in patients not suitable for surgery or chemoradiation.
Authors: Ajay Aggarwal, Mark Harrison, Ricky Sinharay, Derek Cooper, Robert Glynne-Jones, Peter Hoskin
Journal: Journal of Clinical Oncology (2013)

115 Background: Standard curative therapy for esophageal cancer is surgery or chemoradiotherapy. Many patients are not suitable for this approach due to significant co-morbidity.This study evaluates a combination of external beam radiotherapy and High-Dose-Rate (HDR) brachytherapy as a sole modality of treatment for patients in whom tumour characteristics would indicate radical treatment was appropriate. All patients had previously been discussed in a multi-disciplinary setting in which standard radical therapies had been discounted. Methods: 59 patients were treated between October 2000 and October 2011. 40 (58%) were male. Median age was 77 (53 – 88). 39 (66%) adenocarcinoma, 19 (31%) SCC and 1 undifferentiated tumour. 49 (83%) were lower third esophagus. Tumour stage: 1 12(20%), 2 25(43%), 3 19(32%) and 4 2(3%). 30 (50%) had Adult Comorbidity Score – 27 (ACE) of 2 or 3. External beam radiotherapy was conformally planned. Doses of either 27 Gy/6F or 30 Gy/10F were delivered. HDR brachytherapy was delivered utilising an Ir 192 source dosed at 1cm. Doses of either 10 or 15 Gy were delivered. Results: The Median OS, of all treated patients estimated by the Kaplan Meier methods was 373 days (12.3 months). (Fig 1) The 1-, 2- and 3-year survival rates for treated patients were 51%, 19% and 7% respectively. Patients with stage I disease had a median survival of 16 months compared with 10 months for patients with stage III disease. Review of pre treatment dysphagia score demonstrated that patients with no dysphagia prior to treatment (score =0) had a median survival of 17 months compared to 12.5 months and 10 months for patients with scores of 2 and 3 respectively. Conclusions: This demonstrates the value of a purely radiation based approach in a population unsuited to other radical approaches. The median survival exceeds by several months that seen in patients treated palliatively. Treatment is deliverable without significant co-morbidities and offers a survival advantage comparable to radical chemoradiotherapy.
Use of adjuvant chemotherapy (AC) and outcomes in stage II colon cancer (CC) with versus without poor prognostic features.
Authors: Aalok Kumar, Hagen F. Kennecke, Howard John Lim, Daniel John Renouf, Ryan Woods, Caroline Speers, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2013)

338 Background: AC is frequently considered in patients (pts) with "high risk" stage II CC, defined by the presence of &gt;/=1 poor prognostic features such as obstruction or perforation, T4 stage, &lt;12 lymph nodes removed, positive resection margins, and lymphovascular or perineural invasion. Survival benefits associated with AC use in high risk pts remain largely unproven. Our aims were to examine patterns of AC use in stage II CC and to explore the impact of AC on survival in high vs. low risk pts. Methods: All pts with stage II CC in British Columbia from 1999 to 2008 and evaluated at 1 of 5 regional cancer centers were reviewed. Kaplan-Meier and Cox regression methods were used to correlate high vs. low risk status and receipt of AC with relapse-free (RFS), disease-specific (DSS), and overall survival (OS). Results: We identified 1,697 pts: 1,236 (73%) high risk and 461 (27%) low risk among whom 363 (29%) and 61 (13%) received AC, respectively. Individuals with high risk disease who received AC were younger (median 62 vs. 72 yrs, p&lt;0.01) and had better performance status (ECOG 0/1 47% vs. 34%, p=0.02). For high risk pts, AC was associated with improved 5-year OS (Table). Adjusting for confounders, an OS advantage from AC persisted for high risk pts (HR 0.67, 95CI 0.52-0.86, p=0.002), with no significant RFS or DSS benefits. Subgroup analyses revealed individuals with T4 lesions had significantly improved RFS (HR 0.63, 95CI 0.42-0.95, p=0.03), DSS (HR 0.59, 95CI 0.37-0.93, p=0.03), and OS (HR 0.50, 95CI 0.33-0.77, p=0.002). For low risk pts, AC was associated with worse RFS (HR 2.27, 95CI 1.03-4.97, p=0.04) and DSS (HR 2.97, 95CI 1.10-8.02, p=0.03). Conclusions: In this population-based cohort study, AC was associated with an OS advantage in high risk pts, likely due to pt selection. RFS and DSS benefits were mainly seen in T4 lesions, suggesting a limited role for AC in pts deemed high risk. A possible trend towards harm was seen in the low risk group receiving AC. Better risk stratification schemes including those that incorporate molecular testing are warranted. [Table: see text]