tbuckley/cabot-search huggingface dataset:
Patterns of relapse in poor-prognosis germ cell tumors in the GETUG 13 trial: Implications for assessment of brain progression.
Authors: Yohann Loriot, Lance C. Pagliaro, Aude Flechon, Jozef Mardiak, Lionnel Geoffrois, Pierre Kerbrat, Christine Chevreau, Remy Delva, Frederic Rolland, Christine Theodore, Binh Bui, Gwenaelle Gravis, Jean-Christophe Eymard, Jean-pierre Malhaire, Claude Linassier, Muriel Habibian, Christopher Logothetis, Stephane Culine, Agnes Laplanche, Karim Fizazi
Journal: Journal of Clinical Oncology (2014)

365 Background: GETUG 13 investigated personalized chemotherapy based on tumor marker decline in patients with poor-prognosis GCT and demonstrated that a dose-dense regimen improves progression-free survival in patients with an unfavorable decline (Fizazi K, ASCO 2013). We investigated the pattern of relapse for patients included in GETUG 13. Methods: We conducted an analysis of relapse events in patients from GETUG 13 and an unfavorable decline of tumor markers (n=203). Baseline procedures before inclusion in the trial comprised a thoraco-abdomino-pelvic CT scan and an MRI of the brain: 22 patients (10%) had evidence of brain metastases at presentation. Results: With a median follow-up of 4.1 years (0.3 ; 8.8 years) when the analysis was performed, a progression event was observed in 94/203 patients (46%). First event consisted in a marker progression only in 41 patients (43%), a radiographic progression only in 29 patients (31%), a mix progression on both markers and imaging in 11 patients (12%), and death in 13 patients (14%). In patients with radiographic progression only, brain was the predominant site (n=16/29, 55%). Among all patients who experienced a radiographic progression (as first and subsequent progression event, n=58), brain only was the site of progression in 26 patients (45%): 12/30 (40%) in patients treated with BEP and 14/28 (50%) in those treated with dose-dense chemotherapy. Conclusions: Brain metastases develop often, early, and frequently as the only site of relapse in the course of poor-prognosis GCT. This raises the question of early detection and treatment of brain metastases in these patients, for example by integrating a systematic brain MRI after 2-3 months of chemotherapy.
Off-shift Administration operations improvement collaborative.
Authors: Angela Hayes-Rodgers, Altrivice D. Revis
Journal: Journal of Clinical Oncology (2012)

144 Background: Off-Shift Administration (OSA) supports the senior leadership by overseeing clinical operations for both inpatient and outpatient areas at MD Anderson. Our team is responsible for resolving and/or managing issues that could impede patient care, particularly when unsuccessful at the departmental level. This project focuses on streamlining inpatient discharge activities. Data reports from December 2010 to February 2011 revealed that OSA received 1,923 assistance requests institution-wide of which 13% were case management related. A taskforce familiar with patient care and case management processes ultimately resolved to decrease the number of calls made to Off-Shift Administration requesting case management services by 50% by June 2011. Methods: The pilot period began March 1, 2011 and ended May 31, 2011. The earliest intervention was to re-route after hours case management requests directly to the case manager on-call. In the new process, the RN paged the case manager on-call directly who would then escalate calls to OSA as deemed necessary for internal support. A staff education plan complemented the intervention. The education plan entailed in-services with nursing staff, discharge planning teams and nurse leaders for each unit. Education by way of posters was delivered on select units. Piloted areas were also surveyed to assess their knowledge of case management processes and wait time experiences. Results: Outcomes were favorable. OSA experienced an 80% reduction in call volume from the piloted areas. Survey results showed educational efforts yielded a positive practice change and increased awareness of case management protocol. Survey results also revealed a 20-minute reduction in wait time for case management assistance. Certainly, of greatest benefit were the reduced wait times and more expedient patient care and customer service for staff. Conclusions: The project was successful and knowledge gained was be used to implement permanently and within all patient care settings. This project also serves as a useful paradigm of Clinical Operations’ improved ability to distinguish operational trends requiring attention, thereby increasing operational efficiency and customer satisfaction.
Clinicopathologic features of patients with KRAS wild-type pancreatic adenocarcinoma.
Authors: Mohamed E. Salem, Marwan R. Al-hajeili, Gregory Dyson, Natalja Stanski, Tania Jain, Hemchandra Mahaseth, Minsig Choi, Anthony Frank Shields, Philip Agop Philip
Journal: Journal of Clinical Oncology (2014)

192 Background: Pancreatic adenocarcinoma (PC) has the highest frequency of KRAS gene mutations among human cancers. A better understanding of disease biology may help improve targeted therapies for this disease. There is limited data about clinical, pathological features and treatment outcomes in patients (Pts) with wild type KRAS tumors (KRAS wt ). Methods: Retrospective review of 71 pts with histologically confirmed PC between 2009 and 2012 was undertaken. The KRAS codon 12 and 13 and BRAF codon 600 mutations were assessed in diagnostic tumor tissues (TrimGen Mutector II Shifted Termination Assay). Differences were evaluated with t-test and Fisher exact test. Results: KRAS mutations were identified in 50 tumors (70%), while 21 tumors (30%) had KRAS wt genotype. Almost all (96%) mutations occurred at codon 12, there were no mutations in codon 13, and none of the KRAS wt tumors harbored BRAF mutations. Pts with KRAS wt tumors were mostly white (76%), females (57%), and did not have diabetes mellitus (80%). At diagnosis, pts with KRAS wt tumors had a tendency to present at younger age (median age of 60 vs. 66 y; P = 0.1) and with lower CA19-9 values (median CA19-9: 392 vs. 3371 U/mL; P=0.042). Head of the pancreas was the primary site of disease in the majority of pts with KRAS wt tumors (58%), while body or tail was the primary site of disease in the majority of pts with KRAS mutant tumors (53%). There was no difference in the histologic differentiation. Although the majority of pts with KRAS wt (55%) and mutant tumors (57%) presented with distant metastases or locally advanced disease (40% and 39%; respectively), liver involvement was seen in only 55% of pts with KRAS wt tumors vs 92% in the pts with mutant tumors (p=0.016). In univariable analysis, age was an independent predictor of overall survival (HR 1.14, p=0.037) in pts with KRAS wt tumors, while level of bilirubin at presentation was a predictor of overall survival (HR 1.86 (0.77, 4.53); P &lt;0.0001) in pts with KRAS wt tumors who had distant metastasis. Conclusions: The frequency of pts with PC who had KRAS wt tumors was higher than previously described. Pts with KRAS wt tumors may have a disease that is biologically different than those with mutated KRAS. Further prospective characterization is warranted.
TMS1 as a potential therapeutic target of pancreatic cancer.
Authors: H. Miller, K. Ramachandran, E. Gordian, C. S. Rocha Lima, R. Singal
Journal: Journal of Clinical Oncology (2010)

e14614 Background: Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States, with an estimated 42,470 new cases and 35,240 deaths in 2009. Advanced pancreatic cancer responds poorly to chemotherapy. Epigenetic silencing of pro-apoptotic genes contributes to chemoresistance. Target of Methylation induced Silencing 1 (TMS1) is a pro-apoptotic gene frequently silenced by methylation in other cancers. In this study we examined whether epigenetic silencing of TMS1 contributes to resistance to chemotherapy in pancreatic cancer. Methods: Methylation status of the TMS1 promoter region in 3 pancreatic cancer cell lines (MiaPaCa-2, ASPC1 and PANC1) was examined by methylation-specific PCR (MS-PCR). Gene expression was analyzed by quantitative reverse transcriptase PCR (RT-PCR). Cell viability after drug treatment was measured with Cell Titer Blue. MiaPaCa-2 cells were transfected with pCMV6-XL5/TMS1 plasmid and effect of gene expression on sensitivity to gemcitabine and docetaxel was determined by cell viability assays. Results: The promoter region of TMS1 was found to be completely methylated in MiaPaCa-2 cells and unmethylated in ASPC1 and PANC1 cells. Promoter methylation of TMS1 correlated inversely with gene expression levels in these cell lines. Treatment of MiaPaca-2 cells with a DNA methyl transferase (DNMT) inhibitor, 5-azacytidine, resulted in demethylation of TMS1 promoter and gene re-expression. Pretreatment with 5-azacytidine and recombinant expression of TMS1 in MiaPaca-2 cells resulted in increased sensitivity to gemcitabine and docetaxel chemotherapy. Conclusions: TMS1 is inactivated through promoter methylation in MiaPaCa-2 cells and up-regulation of TMS1 in these cells enhanced sensitivity to gemicitabine and docetaxel chemotherapy. No significant financial relationships to disclose.
Age barrier in clinical trials: Are we truly moving forward?
Authors: Olubukola Ayodele, Aiste Linkeviciute-Koneko, Miriam O'Connor, Paula Calvert, Anne M. Horgan
Journal: Journal of Clinical Oncology (2016)

208 Background: Older patients are underrepresented in clinical trials. This may in part be explained by the fact that, historically, there has often been an upper age limit for inclusion in studies. This is despite data that suggests that older patients are as likely as their younger counterparts to enroll in clinical trials if offered. Methods: All prospective, interventional phase III studies in GI malignancies registered with clinicaltrials.gov were identified. Currently opened and recruiting studies were included. Results: A total of 365 eligible trials were identified. One hundred and fifty (41%) were colorectal, 67 (18%) liver and 62 (16%) were pancreatic malignancies. Other malignancies were gastroesophageal, hepatobiliary and neuroendocrine tumours. A total of 172 (47%) studies had an upper age limit for inclusion. The most common tumor sites to have older age as an exclusion factor were - hepatobiliary (n = 10; 66%), liver (n = 39; 58%) and gastroesophageal (n = 31; 51%). The median age of exclusion was 75 years (range: 60-95). Chinese studies, which represented 30% (n = 111) of the total studies included, had the greatest proportion with an upper age limit (85%). The United States had the least, with only 3% of studies having an exclusion age. Conclusions: Significant progress had been made in recent years with many clinical trial protocols not having an upper age limit for inclusion. Study design and restrictive eligibity criteria need to be assessed and modified to ensure older patients are well represented in future clinical trials.
Efficacy of radiation therapy on epileptic seizures of grade 2 and 3 gliomas: A retrospective study.
Authors: R. Ruda, E. Trevisan, U. Magliola, C. Mantovani, U. Ricardi, R. Soffietti
Journal: Journal of Clinical Oncology (2011)

2074 Background: Epilepsy may be the unique symptom in patients with slowly growing gliomas, is often pharmakoresistant, and negatively impacts the quality of life. Total surgical resection and, recently, chemotherapy have been reported to allow the control of seizures, whereas the role of radiation therapy is unclear. The aim of this study was to investigate the efficacy of radiotherapy in controlling the epileptic seizures in slowly growing gliomas. Methods: We retrospectively analyzed, utilizing the neuro-oncological database of the University Hospital of Turin, 40 patients with hemispheric grade 2 and 3 gliomas ( according to WHO classification), either newly diagnosed or recurrent, who had an active epilepsy before receiving radiation therapy between 1989 and 2009. Seizure decrease following radiotherapy was considered as significant when >= 50% reduction in seizure frequency from baseline was observed, being steroids stable and concomitant antiepileptic drugs unchanged or reduced. Response on MRI was evaluated based on changes of the tumor area in T2 – FLAIR sequences. Results: Overall, seizure frequency was significantly decreased in 24/40 (60%) and 29/40 (72.5%) patients at 1 and 3 months following radiotherapy respectively. In most patients seizure reduction began during radiation therapy. Eleven out of 40 patients (27.5%) began seizure-free. We did not find any correlation between seizure response and response of tumor on MRI: at 3 months following the radiotherapy, among patients with a significant seizure reduction, half had a partial response (>= 50% decrease on MRI) and half no change. Factors, such as histological type, grade of malignancy, tumor location, contrast enhancement on MRI and type of original surgery, did not influence the seizure response to radiotherapy. Conclusions: Epileptic seizures of patients with grade 2 and 3 gliomas can benefit from radiation therapy. Future studies must better clarify factors associated with this efficacy and the underlying mechanisms. Epilepsy control must be a secondary end-point in clinical trials involving grade 2 and 3 gliomas.
Development of a comprehensive set of colorectal cancer care quality metrics.
Authors: Laurence E. McCahill, Jamie Kokko, Chris Werkemma, Pierson Ebrom, Sarat Khandavalli
Journal: Journal of Clinical Oncology (2012)

670 Background: Institute of Medicine report calls for improved quality of cancer care. Numerous entities have sought measures of health care quality, but there is limited consensus regarding metrics for quality of colorectal cancer (CRC) care. Current measures are very limited; there exist no comprehensive metrics for quality of CRC care across the continuum of care. We sought to identify robust quality metrics, including measures related to pathology, coordination of cancer care, surgery, radiation, chemotherapy and surveillance, in order to identify gaps in quality of CRC care. Methods: National guidelines (NCCN and ASCO), National Quality Forum, and select peer reviewed publications were reviewed to develop evidence based metrics to assess quality of CRC care from diagnosis to post treatment surveillance and survivorship. A core group of health care providers, including a surgical oncologist, a pathologist and a Cancer nurse practitioner developed the metrics based on literature review. Measures were reviewed by key physician stakeholders including Radiation Oncology, Medical Oncology, General surgery, and Gastroenterology to obtain support for the quality initiative at our institution. Results: Twenty-three quality metrics were developed including 6 metrics related to access and process, 6 related to pathology, 7 related to multidisciplinary care and 4 measures related to surveillance and survivorship. Novel metrics included documentation of a three generational cancer family history, documentation of preoperative CT imaging of chest/abdomen/pelvis, MSI and KRAS testing in specific populations, appropriate pre-operative radiation oncologist evaluation for rectal cancer, multidisciplinary team planning prior to treatment initiation for rectal cancer and patients with newly identified liver metastases, appropriate referral for genetic counseling and surveillance annual CT scans for 3 years post treatment. Conclusions: These novel and comprehensive metrics allow for detailed review of the quality of CRC care received by patients at our institution. Individual patient data are currently being abstracted to assess the utility and logistics of implementing these quality metrics at a community cancer center.
Transplantation of Human Aldehyde Dehydrogenase Expressing Cells Leads to Widespread Tissue Distribution of Donor Cells in the Novel NOD/SCID/MPSVII Xenotransplantation Model.
Authors: David A. Hess, Timothy P. Craft, Louisa Wirthlin, Phillip E. Herrbrich, A. Alex Hofling, Mark S. Sands, Jan A. Nolta
Journal: Blood (2004)
Chemoradiation for nasopharyngeal carcinoma (NPC) with pilot hypoxia imaging with F18 misonidazole PET scanning.
Authors: A. D. Colevas, A. Quon, A. McMillan, Q. Le
Journal: Journal of Clinical Oncology (2011)

5556 Background: NPC is traditionally treated with chemoradiation followed by chemotherapy. Ongoing trials are exploring neoadjuvant chemotherapy in NPC. Hypoxic head and neck cancers are known to be less sensitive to radiation. It is unknown if reversal of hypoxia prior to radiation results in better tumor control with radiation or if hypoxia is merely a marker of inherent radiation resistance. Data in other cancer settings suggest that both chemotherapy and bevacizumab might reduce tumor hypoxia. F-18 misonidazole (FMISO) is a hypoxia detection agent based upon misonidazole’s covalent binding to cellular macromolecules when reduced. Tumor/blood pool ratios of FMISO can be used to assess for relative tumoral hypoxia. Methods: Patients with locoregionally advanced or oligometastatic NPC were enrolled on an IRB approved clinical trial of a single dose of bevacizumab, followed by 3 cycles of therapy with concurrent cisplatin, docetaxel, 5-fluorouracil and bevacizumab (TPFB), followed by chemoradiation with cisplatin and bevacizumab. Hypoxia imaging was attempted using FMISO PET scans at baseline, following the single dose of bevacizumab and after the completion of TPFB in order to assess the feasibility of detecting baseline tumor hypoxia and changes in tumor hypoxia. The primary endpoint of the trial was progression free survival with early stopping rules for safety and feasibility concerning FMISO PET imaging. Results: Five patients have completed treatment and hypoxia imaging as of 1.31.11. Two achieved a CR and 3 a PR to TPFB, and all patients achieved a CR after completing chemoradiation. All patients remain alive without evidence of disease. Treatment was completed as planned without delay in all patients without SAEs. There were no clinically significant bleeding episodes. Baseline tumor/blood pool ratios of FMISO by PET imaging ranged from 1.2 to 2.2 without significant change in the ratios following bevacizumab and TPFB administration, despite large volume reduction in tumor mass. Conclusions: Details concerning FMISO imaging and implications for in vivo hypoxia imaging during cancer treatment will be presented. Further clinical testing of hypoxia detecting agents is warranted.
Enhanced anti-tumor effect of trastuzumab combined with less cardiotoxic anthracycline, amrubicin, in a HER2-positive human cancer xenograft in athymic mice
Authors: Y. Tokuda, S. Umemura, Y. Saito, Y. Suzuki
Journal: Journal of Clinical Oncology (2008)

14641 Background: Trastuzumab extends survival when combined with doxorubicin to patients with HER2- positive metastatic breast cancer. However, this combination is associated with cardiotoxicity. Clinical trials are ongoing to investigate combinations of trastuzumab with less cardiotoxic anthracyclines. Amrubicin is a third generation, totally synthetic anthracycline. In preclinical studies, amrubicin demonstrated a higher level of anti-tumor activity than conventional anthracyclines without showing any evidence of the cumulative cardiac toxicity. Therefore, we investigated the combination of amrubicin and trastuzumab in human tumor xenograft model with HER2-positive cancer. Methods: A tumor fragment of HER2-positive human gastric cancer xenograft 4–1ST (Tokuda Y et al., Br J Cancer 73:1362, 1996) was subcutaneously inoculated into female Balb/cA athymic nude mice. Mice were randomly divided into experimental groups when each tumor had reached a palpable size (100–300mm3). Mice bearing the tumors were treated with a single intravenous administration of trastuzumab (36mg/kg)(T), amrubicin (25mg/kg)(A), or trastuzumab plus amrubicin(T+A). Five weeks after tumor inoculation, tumor tissues were immunohistochemically analyzed for HER2, phosphorylated HER2, apoptosis, Ki-67, topoisomerase IIα, cycline E, p53, phosphorylated MAPK, phosphorylated topoisomerase IIα, DNA polymerase, and cycline B1 expressions. Results: Mean tumor weight (g) of T+A was significantly reduced to 0.233±0.27, compared with that of control (3.152±0.83)(p<0.0001), T (2.697±0.64)(p<0.0001), and A (0.870±0.31) (p=0.001). The immunohistochemical analyses showed significant reduction of cycline E expression in the T+A group, compared with other groups. These data suggested a therapeutic advantage in the administration of anti-HER2 receptor antibody, trastuzumab in combination with amrubicin. Conclusions: This promising combination warrants further clinical evaluation in the treatment of HER2-positive breast cancer. No significant financial relationships to disclose.
Accounting for improved outcomes in budget impact analyses: Adjuvant trastuzumab in HER2/neu-positive breast cancer
Authors: C. Skedgel, D. Rayson, T. Younis
Journal: Journal of Clinical Oncology (2008)

6573 Background: Adjuvant trastuzumab is associated with considerable acquisition costs, but it is important to consider net budget impact after accounting for improved outcomes. We estimated the net budget impact of adjuvant trastuzumab (aTZ) in early-stage HER2/neu-positive breast cancer from the perspective of the Canadian healthcare system. Methods: The budget impact analysis (BIA) built upon a cost-effectiveness model (Skedgel et al, ASCO 2007) that considered the costs of drug acquisition and delivery, cardiotoxicities and recurrent disease, as well as improved disease-free and overall survival outcomes derived from the HERA trial of aTZ vs. primary treatment alone, over a 5-year horizon. The BIA took a population-level approach based on estimated 2007 breast cancer incidence rates, population projections for 2007–2011 and estimated eligibility rates from our previous work (Drucker et al, ASCO 2006). All costs are reported in 2007 Canadian dollars (CDN$). Results: aTZ had an upfront cost of CDN$49,965 per patient, but reductions in cancer recurrence over the 5-year analysis horizon reduced the net cost to CDN$44,998 per patient. Net impact declined over the initial 5 years (2007- 2011) as savings due to recurrences avoided accrued (start-up phase) and the ratio of net to gross annual budget impact fell from 95% to 85%. The cumulative net impact over the initial 5-year period (2007–2011) was roughly 10% less than the gross impact based on acquisition costs alone. In the second 5-year period (2012–2016), net and gross budget impact increased with population growth and increasing incidence in an ageing population (‘steady-state’ phase). Net budget impact in 2007 was projected to be CDN$91.3 million. Budget impact was driven primarily by the aTZ eligibility rate (8.5% in the baseline analysis). Conclusions: Annual net budget impact declined over the start- up phase as upfront costs were offset in part by savings due to recurrences avoided. Net budget impact in the steady-state phase grew at the same rate as the gross impact, but started from a lower baseline. While the projected net budget impact of aTZ was substantial, this analysis demonstrates the importance of accounting for differences in outcomes when conducting BIA. No significant financial relationships to disclose.