tbuckley/cabot-search huggingface dataset:
Thymoma: A population-based study of the management and outcomes for the province of British Columbia.
Authors: C. J. Mariano, D. Ionescu, W. Y. Cheung, R. Ali, J. J. Laskin, H. Carolan, K. Evans, N. Murray
Journal: Journal of Clinical Oncology (2011)

7023 Background: The optimal approach to the management of thymoma and thymic carcinomas is unclear, particularly for advanced stage disease. Our primary study aim was to analyze treatment practices and outcomes in a population-based cohort of thymoma patients. Methods: All patients (pts) with a pathological diagnosis of thymoma or thymic carcinoma and referred to the British Columbia Cancer Agency (BCCA) between 1994 and 2009 were reviewed. Kaplan-Meier curves and Cox proportional hazard models were used to correlate histology, stage, and treatment with outcomes. Pathology review using WHO classification is currently underway. Results: 190 pts were identified of which 171 (90%) were referred to BCCA and eligible for analyses. Median was 60 years; 50% of pts were male. 26% had paraneoplastic phenomena; including 21% with myasthenia gravis.Pts with thymic carcinoma (n=23) and thymoma (n=148) had 5-year overall survival (OS) rates of 38% and 81%, respectively. Survival by stage is detailed in the table. Pts with stage I disease were treated primarily with surgery. Selected stage II pts received adjuvant radiation therapy, which conferred a significant improvement in progression free survival (98 vs. 62 months, p<0.01), but no OS benefit. There were practice variations in management of pts with advanced stage disease (n=71). A multimodality approach that included surgery, radiation, and chemotherapy correlated with better outcomes. Tri-modality treatment for thymoma achieved a 5-year OS of 85%; however, pts with advanced thymic carcinoma had poor outcomes despite aggressive treatment. In multivariate analyses histology (thymoma vs. thymic carcinoma) and surgery were significant predictors of OS. Conclusions: This study is the first population-based series to detail treatment and outcomes for thymoma. Outcomes compare favorably to series from single institutions. Pts with locally advanced disease for whom initial surgical resectibility is uncertain should be triaged to a multidisciplinary team for consideration of multimodality treatment. Five-year overall survival and progression-free survival. Stage 5 yr OS 5 yr PFS I (n=13) 91% 91% II (n=84) 86% 83% III (n=42) 70% 49% IV (n=32) 46% 13%
Molecular changes in the primary breast cancer versus the relapsed/metastatic lesion from a large population-based database and tissue microarray series
Authors: R. MacFarlane, C. Speers, H. Masoudi, S. Chia
Journal: Journal of Clinical Oncology (2008)

1000 Background: Relapsed/metastatic breast cancers are presumed to have the same predictive factors as the initial primary tumour. As such, the majority of patients do not have additional biopsies performed at the time of relapse. Recent small studies have suggested that a significant proportion of relapsed lesions may have a change in the hormone receptor and/or HER2 receptor status from the original tumour. We sought to compare the hormonal and HER2 receptor status of relapsed/metastatic breast cancer tumours with those of the original tumour from a large population-based database and tissue microarray (TMA) cohort. Methods: Using the BCCA Breast Cancer Outcomes Unit Database from 1986–1992, patients with biopsy proven relapses were identified. These identified patients were linked to a current large TMA series (n=4,444) of primary breast cancers. Charts were reviewed, and available tissue blocks of the relapsed/metastatic cancer were requested and collected. An additional TMA was created of the relapsed/metastatic tumours. IHC was performed for ER (LabVision SP 1 antibody), PR (Ventana 1E2 antibody) and HER2 (LabVision SP 3 antibody) on both the primary and relapsed tumours. The pathologist was blinded to knowledge of the primary tumour receptor status. Results: 281 cases were linked between the BCOU database and the TMA series. Of the 281 cases, 184 tissue blocks were received, and 160 had adequate tumour for analyses. Of the 160 blocks, 115 (72%) had no changes in either the ER/ PR or HER2 status. Of the 45 (28%) tumours that did have changes in the receptor status, 11 (7%) were local recurrence, 34 (21%) were regional or distant relapses. Among the 34 regional/distant relapses 11 went from ER/PR(+) to ER/PR(-), 14 went from ER/PR(-) to ER/PR(+), 3 went from HER2(-) to HER2(+), and 6 went from HER2(+) to HER2(-). Conclusions: This is one of the largest known studies assessing for changes in molecular phenotype between the primary and relapsed breast cancer. A significant proportion (21%) of relapsed tumours had changes in either ER/PR or HER2 receptor status. This study suggests that biopsies of relapsed/metastatic breast cancers should be performed routinely. No significant financial relationships to disclose.
Efficacy and tolerability of ABVD and Stanford V for elderly advanced-stage Hodgkin lymphoma (HL): Analysis from the phase III randomized U.S. Intergroup Trial E2496.
Authors: A. M. Evens, F. Hong, L. I. Gordon, R. I. Fisher, N. Bartlett, J. M. Connors, H. Wagner, M. K. Gospodarowicz, B. D. Cheson, R. Advani, B. S. Kahl, R. T. Hoppe, S. J. Horning
Journal: Journal of Clinical Oncology (2011)

8035 Background: There remains a lack of prospective data studying ABVD or Stanford V in the modern era in advanced-stage elderly HL (≥60 years). Methods: We analyzed outcomes and tolerability of elderly pts with advanced-stage HL treated in E2496. Pts were randomizedto ABVD chemotherapy (CT) x 6–8cycles + radiotherapy (RT) for bulky disease or StanfordV (12 CT weeks + RT 36 Gy for sites > 5 cm). Primary endpoint was FFS, defined as time to either progression/relapse or death.Fisher’s exact test was used for data comparisons; stratified log-rank test was used for FFS and overall survival (OS). Results: Of 812 eligible pts, 43 were ≥ 60 years of age (n=23 ABVD, n=20 Stanford V). Pt characteristics between CT arms were balanced; data for the 43 elderly pts included: median age 65 (60-83); stage: II 7%, III 69%, IV 23%; B symptoms 47%; and IPS ≥ 4 16%. Several differences were noted comparing pts ≥ 60 vs < 60 years: mixed cellularity (35% vs 13%, respectively, p=0.0004) and ECOG PS 0 (35% vs 58%, respectively, p=0.004). CT was tolerated well; besides neutropenia, there were 11 total grade 4 toxicities (3 dyspnea, 2 each motor/sensory neuropathy, and 1 each of hypoxia, constipation, infection, myalgia). The treatment-related mortality rate was 5% (1 pulmonary [ABVD], 1 infection [Stanford V]). Among elderly pts, overall response rate (ORR), complete response (CR), FFS, and OS did not differ between CT arms. Therefore, treatment arms were pooled and stratified for an exploratory analysis comparing outcomes in pts ≥ 60 vs <60 years. The ORR (70% vs 78%, p=0.19) or CR (65% vs 71%, p=0.49) did not differ; however, FFS and OS were significantly inferior for elderly pts (Table). Conclusions: ABVD and Stanford V had comparable efficacy and tolerability for elderly advanced-stage HL. When comparing elderly vs non-elderly pts, we observed similar ORR and CR rates, but inferior survival. These observations suggest in part a potential difference in disease biology, underscoring the continued need for novel therapeutic approaches for elderly HL. Elderly Non-elderly All (n=43) All (n=769) Survival % % Log-rank p 3-year FFS 55 76 0.0014 5-year FFS 46 74 3-year OS 69 93 <0.0001 5-year OS 56 90
A survey of phase I study designs of cellular, gene therapy and antigenic products for cancer at the US Food &amp; Drug Administration
Authors: R. Fiorentino, A. El-Khoueiry, S. Hirschfeld
Journal: Journal of Clinical Oncology (2005)

6035 Background: Phase 1 studies often use dose-escalation designs to detect dose-limited toxicity (DLT). This paradigm may not apply to products that act through complex biological mechanisms. Biologic activity or immunologic endpoints may represent an alternative endpoint for dose determination in studies of cellular, gene therapy and antigenic products. In this study, we survey the choice of the dose-determining endpoint and summarize the use of bioassays in investigational new drug applications (INDs) for cell and gene therapy products for cancer submitted to CBER. Methods: All phase 1 oncology INDs submitted in 2004 were analyzed. Data collected included the product being studied (gene therapy, cellular, antigen), primary endpoint, the dose-determining endpoints, including toxicity, clinical (tumor response), immunologic (in vitro immunoassays), or correlative (in vitro assays of tumor tissue) activity along with types of bioassay employed. Results: The 44 studies evaluated included cellular therapies (59%), gene therapies (34%), and immunogenic peptides (18%). Only three (7%) employed immunologic activity as a dose-determining (or primary) endpoint, with the majority utilizing DLT (75%). Frequencies of the bioassays utilized are summarized in the table below. Dose determining endpoint selection did not vary with product type. Conclusions: DLT may be critical to determine for some products. Our survey suggests biologic activity is not commonly used to determine doses for subsequent clinical studies of cellular, gene therapy, and antigenic products for cancer. The multiplicity of bioassays used in phase 1 studies makes interpretation and comparison of their utility challenging. Systematic evaluation of parameters that characterize biologic activity could lead to better understanding of dosing and potential clinical effects of these new therapies. No significant financial relationships to disclose.
Patterns of referral to palliative care in clinical practice in patients with stage IV non-small cell lung cancer.
Authors: Safiya Karim, Shahid Ahmed
Journal: Journal of Clinical Oncology (2013)

39 Background: Recent evidence has shown that patients with stage IV NSCLC benefit from early referral to palliative care (PC). In August 2010, a landmark randomized control trial revealed that patients with advanced NSCLC, who received early PC, had better quality of life, mood and survival (NEJM 2010; 363:733-42). Our study aimed to determine pattern of PC referral in clinical practice, in patients with stage IV NSCLC before and after the publication of the trial, and to assess factors correlated with PC referral. Methods: The study population was comprised of a cohort of patients with stage IV NSCLC, diagnosed between 2009 and 2011, and referred to the Saskatoon Cancer Center. Logistic regression models were used to assess factors correlated with PC referral. Kaplan Meier method was used to estimate survival. Cox regression analyses were used to determine factors correlated with survival. Results: 215 patients with median age of 68 yrs (range: 40-92) and M:F of 108:107 were identified. 101 (47%) patients had comorbid illness, 100 (47%) had ECOG performance status &lt;2, 136 (63%) were married/common law and 161 (75%) had symptomatic disease. 126/251 (58%) were referred to PC. 70/118 (59%) diagnosed before Sep 2010 were referred to PC compared with 56/97 (58%) diagnosed after Sep 2010 (p=NS). The median time to PC referral from date of diagnosis was 51 days (inter-quartile range: 19-155). 33% patients were referred within 4 wks of diagnosis. Symptomatic disease (odd ratio [OR]=3.7, 95% CI =1.8-7.5), bone metastasis (OR = 3.0, 95% CI = 1.6-5.6), and brain metastasis (OR=2.2, 95% CI =1.1-4.5) were correlated with referral to PC. Median survival of whole cohort was 4 months (95% CI: 3.1-4.8). 2 nd or 3 rd line therapy (Hazard ratio [HR]= 0.54, 95% CI:0.34-0.87), non-smoking status (HR= 0.58, 95% CI:0.38-0.87), chemotherapy (HR 0.64, 95% CI:0.46-0.89), and lack of symptoms (HR=0.68, 95%CI:0.48-0.96) were correlated with better survival. Conclusions: Our study shows that publication of the landmark trial did not influence the pattern of referral to PC at our center. Symptomatic patients and those with metastasis to brain or bone were more often referred to PC. No survival benefit was seen in patients who were referred to PC.
Beyond the pilot: Navigating through 8 years of palliative radiotherapy integrated symptom management (PRISM).
Authors: Fleur Huang, Bronwen LeGuerrier, Diane Severin, Shannon Eberle, Karen P Chu, Lori Gagnon, Alysa Fairchild
Journal: Journal of Clinical Oncology (2015)

156 Background: Patients with incurable cancer often have problematic symptoms and functional impairment despite active cancer care. Opportunities to assess and address these unmet needs exist at every care point. Methods: In 2007, we piloted a holistic model of care in an outpatient Palliative Radiation Oncology clinic. Twin goals (timely access to radiotherapy (RT) and multidisciplinary (MDT) symptom assessment/management) were met: a one-stop-shop to see a radiation oncologist (RO), nurse (RN), radiation therapist (MRT(T)) and pharmacist, with Social Work, Nutrition and Rehabilitation as needed. The model has since evolved, adapting to shifting system-level barriers, with continued attention to patient-reported outcomes. We discuss our team’s 8-year effort to integrate symptom management and palliative RT in a tertiary cancer center. Results: Despite challenges (patient-, provider-, facility-, service- or logistics-related), our target RT population grew from initially only those with bone metastases (served by 1 RO once weekly), to include brain or chest disease (seeing any local RO, any day). Priorities were complex, even at odds, to cater to broadly defined stakeholders: access to RT, systematic basic supportive care (BSC), operational efficiency, care transitions. From strong interdisciplinary focus and task-shifting emerged a critical patient navigation piece. Informal, then formal quality improvement work recast key functions by person/time/place, recently streamlining (e.g. intake/triage/referral pathways) and upgrading (e.g. shared RN/MRT(T) navigator role). Interfaces are layered, broad now between BSC (e.g. horizontal pre-/post-visit telephone symptom screening and goal-setting) and RT processes (e.g. more consistently vertical, less disruptive to technical workflows), enabling scale-up and alignment by design with quality dimensions. Operational and patient outcome metrics remain under periodic review. Conclusions: Integrating MDT BSC with outpatient palliative RT is feasible and scalable, when incrementally tailored to context. Further work, to formally assess patient satisfaction and downstream care needs, will inform PRISM as our local standard.
<i>TOP1</i> gene copy number in stage III colorectal cancer (CRC) samples: Association to prognosis.
Authors: Sune Boris Nygaard, Maria Unni Rømer, Ib Jarle Christensen, Signe Lykke Nielsen, David Hersi Smith, Kirsten Vang Nielsen, Sven Müller, Ben Vainer, Hans J. Nielsen, Nils Brünner
Journal: Journal of Clinical Oncology (2012)

475 Background: TOP1 inhibitor treatment is frequently being used in combination therapy of metastatic CRC. This study aims to reveal whether TOP1 gene copy number associates with patient prognosis, since such a relationship may have significant implications for future studies aiming at validating the predictive value of TOP1 gene copy number. Methods: The study included TOP1 and CEN-20 FISH analyses (DAKO A/S Denmark) on FFPE tissue sections from 154 stage III CRC patients who did not receive adjuvant chemotherapy. TOP1 gene copy number, CEN-20 copy number and the TOP1/CEN-20 ratios were analyzed and correlated to overall survival (OS), to time to recurrence (TTR) of patients with CRC and to local recurrence (LR) in patients with rectal cancer (RC). Results: TOP1 copy number counts and the TOP1/CEN-20 ratios, age, gender and primary tumor location were separately added into a multivariate analysis as continuous variables. For OS and LR, TOP1 copy number was significant and the ratio was borderline significant with higher copy number associated with longer OS or longer time to LR. When the patients were dichotomized using the TOP1 median copy number, we found that patients with high TOP1 copy number in their tumor cells had a significant longer OS (HR: 0.68; 95% CI: 0.47-0.98; p = 0.04) compared to patients with low TOP1 copy number. Using the median TOP1/CEN-20 ratio to dichotomize, no significant differences were observed between patients with levels above or below the median ratio number for OS (HR: 0.76; 95% CI: 0.53-1.10; p = 0.14). TOP1 copy number divided the RC patients into two groups with a trend towards a significant difference in time to LR (HR: 0.56; 95% CI: 0.27-1.16; p = 0.11) with higher copy number. If the median ratio was used, a significant association with longer time to LR (HR: 0.43; 95% CI: 0.20-0.92; p = 0.03) was found. No significant associations between TOP1 copy number or ratio and TTR were observed. Conclusions: Increased TOP1 copy number is associated with longer OS in CRC patients and fewer LR in RC patients. Thus, future studies analyzing the association between TOP1 copy number and response to therapy in CRC patients should be planned in such a way that a prognostic and a predictive value of TOP1 can be separated.
Correlation between adverse event reports of hypothyroidism and clinical response in patients treated with vascular endothelial growth factor receptor inhibitors (VEGFR-I).
Authors: G. Speranza, L. Rubinstein, S. P. Ivy, P. J. Harris
Journal: Journal of Clinical Oncology (2011)

2602 Background: Although VEGFR-I associated treatment-emergent hypothyroidism has been recognized for years, a possible correlation with response has not been made. We describe our findings supporting such an association. Methods: We examined our database of NCI-sponsored single agent clinical trials of cediranib, sunitinib, pazopanib and sorafenib. Patients with an adverse event report of “low thyroid function” or “hypothyroidism” and patients without reported hypothyroidism were separated into two groups; the response rate (RR) for each group was determined. Statistical analysis, using a 2-sided Fisher’s Exact Test, was performed to determine if response correlated with hypothyroidism. Results: 168/504 (33.3%) of cediranib-treated patients were reported to have hypothyroidism; these had a RR of 25.0% while the remainder had a RR of 8.6%, p < 0.001. 22/220 (10%) of suntinib-treated patients were reported to have hypothyroidism. These had a RR of 22.7%; while the remainder had a RR of 12.1%, p = 0.15. 10/115 (8.7%) of pazopanib-treated patients were reported to have hypothyroidism; the number of patients was too small to determine a possible relationship. There were also too few sorafenib-treated patients in our data base to demonstrate a relationship. Conclusions: We found a significant positive correlation between treatment-emergent hypothyroidism and response to cediranib. We also found a positive correlation for sunitinib; although not statistically significant, the trend was consistent with a previously-described association with PFS. Our results must be interpreted with caution and within the limitations of our database. Hypothyroidism may have been under-reported. It is beyond the scope of this abstract to hypothesize about the mechanism of action of this observation. Prospective trials are needed to confirm our findings.
Physician treatment selection in the prospective Metastatic Renal Cell Cancer (MaRCC) Registry.
Authors: Christos Kyriakopoulos, Michael Roger Harrison, Nrupen Anjan Bhavsar, Steven Paul Wolf, Brian Addis Costello, Walter Michael Stadler, Hans J. Hammers, Ulka N. Vaishampayan, Leonard Joseph Appleman, Patricia A. Creel, Greg P. Samsa, Eric M. Richardson, Kathleen A. Johnson, Azah Borham, Daniel J. George
Journal: Journal of Clinical Oncology (2016)

563 Background: Clinical trials mRCC pts are different from real world pts, resulting in bias in the literature. The MaRCC Registry is designed to survey questions not asked in tri als, such as why physicians make certain management decisions. This analysis describes reasons for physician treatment (tx) selection in the first 109 real world pts enrolled in a multicenter, prospective, observational registry. Methods: MaRCC Registry will enroll 500 pts from up to 60 US academic (ACAD) and community (COMM) sites with ~2 years of recruitment and ≥ 3 years of follow-up. Key inclusion criteria are age ≥ 18 years and diagnosis of mRCC with no prior systemic therapy (STx) for mRCC at study entry. Pts currently not on STx but who are being observed are permitted. Key endpoints include descriptive characteristics of txs, tx and patient outcomes, medication adherence, and health resource utilization. Results: At data cutoff, 105 pts have been accrued with known STx status; median age 64 (Q1-3 range, 56-70); 66% male; 75% ACAD; 87% clear cell histology; and 31% stage IV at diagnosis. Initial management decision was: 40% deferred systemic therapy (DSTx), 22% pazopanib, 18% clinical trial, 10% sunitinib, and 6% other. Among STx pts (N = 61), the most common categories for therapy choice as selected by providers were likelihood of clinical benefit (41%) followed by pt characteristics (30%). Within the clinical benefit category, the most common reason was OS/PFS (31%). Within the pt characteristic category the most common reasons included performance status/frailty (12%) or prognostic factors (12%). Common reasons for DSTx pts (N = 44) were active surveillance (AS) with disease present (39%), AS without disease present following a procedure (11%), or local therapy (7%). ACAD sites had higher percentages of pts with DSTx undergoing AS with disease present and local therapy. Conclusions: This is the first report describing factors driving physician decision making in management of mRCC. Management choices are not captured in other prospective or retrospective studies. Early experience suggests that clinical benefit and pt characteristics were common reasons for initial STx. Side effect profile rarely determined initial STx selection.
Tipifarnib prevents development of hypoxia-induced pulmonary hypertension
Authors: Lucie Duluc, Blerina Ahmetaj-Shala, Jane Mitchell, Vahitha B. Abdul-Salam, Abdul S. Mahomed, Lulwah Aldabbous, Eduardo Oliver, Lucio Iannone, Olivier D. Dubois, Elisabeth M. Storck, Edward W. Tate, Lan Zhao, Martin R. Wilkins, Beata Wojciak-Stothard
Journal: Cardiovascular Research (2017)

RhoB plays a key role in the pathogenesis of hypoxia-induced pulmonary hypertension. Farnesylated RhoB promotes growth responses in cancer cells and we investigated whether inhibition of protein farnesylation will have a protective effect.The analysis of lung tissues from rodent models and pulmonary hypertensive patients showed increased levels of protein farnesylation. Oral farnesyltransferase inhibitor tipifarnib prevented development of hypoxia-induced pulmonary hypertension in mice. Tipifarnib reduced hypoxia-induced vascular cell proliferation, increased endothelium-dependent vasodilatation and reduced vasoconstriction of intrapulmonary arteries without affecting cell viability. Protective effects of tipifarnib were associated with inhibition of Ras and RhoB, actin depolymerization and increased eNOS expression in vitro and in vivo. Farnesylated-only RhoB (F-RhoB) increased proliferative responses in cultured pulmonary vascular cells, mimicking the effects of hypoxia, while both geranylgeranylated-only RhoB (GG-RhoB), and tipifarnib had an inhibitory effect. Label-free proteomics linked F-RhoB with cell survival, activation of cell cycle and mitochondrial biogenesis. Hypoxia increased and tipifarnib reduced the levels of F-RhoB-regulated proteins in the lung, reinforcing the importance of RhoB as a signalling mediator. Unlike simvastatin, tipifarnib did not increase the expression levels of Rho proteins.Our study demonstrates the importance of protein farnesylation in pulmonary vascular remodelling and provides a rationale for selective targeting of this pathway in pulmonary hypertension.