tbuckley/cabot-search huggingface dataset:
Dual blockade of epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) signaling in metastatic pancreatic cancer: Phase I/randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG-0727).
Authors: Philip Agop Philip, Bryan H. Goldman, Ramesh K. Ramanathan, Heinz-Josef Lenz, Andrew M. Lowy, Robert P. Whitehead, Syma Iqbal, Rakesh Gaur, Jacqueline K. Benedetti, C. D. Blanke
Journal: Journal of Clinical Oncology (2012)

4019 Background: Targeting a single pathway in pancreatic adenocarcinoma (PAC) is unlikely to impact its natural history. EGFR targeting with erlotinib added to gemcitabine (G) marginally improved the outcome of patients with advanced disease. We tested the hypothesis that if the EGFR and IGF-1R pathways are simultaneously blocked then progression free survival (PFS) would be significantly improved by abrogating reciprocal signaling that leads to resistance to either drug. Methods: This was a phase I/randomized phase II (RP2) study testing the anti-IGF-1R monoclonal antibody cixutumumab combined with erlotinib and G in patients with metastatic PAC. The control arm was erlotinib plus G. The primary endpoint of the RP2 portion of the study was PFS. Eligibility included patients with untreated metastatic disease, performance status 0/1, fasting blood glucose less than institutional upper limit of normal, and willingness to provide tissue and blood specimens for correlative studies. Results: In phase I portion (n=10) safety of cixutumumab 6 mg/kg IV/wk, erlotinib 100 mg/day orally and G 1000 mg/m 2 IV D 1, 8, and 15 of a 28-day cycle was established. In the RP2 portion (n=124) 114 eligible patients (median age 63) were included. On the cixutumumab arm, 59% of patients were female vs. 40% on control arm. Median PFS and overall survival were 3.7 and 6.7 months, respectively, in both arms of the study. Major grade 3 and 4 toxicities were (cixutumumab/control) elevation of transaminases (12%/6%), fatigue (16%/12%), gastrointestinal (35%/28%), neutropenia (21%/10%), and thrombocytopenia (16%/7%). Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 kin toxicity was similar in both arms of the study (&lt; 5%). Five treatment-related deaths were reported: 2 cardiac on each arm, 1 pulmonary on cixutumumab. Conclusions: IGF-1R inhibitor cixutumumab did not improve the progression free or overall survival of patients with metastatic PAC treated with erlotinib and G in a molecularly unselected population.
Evaluation of the effect of care at NCI comprehensive cancer centers (NCICCCs) on disparities in outcome within adolescents and young adults (AYAs) with cancer.
Authors: Julie Anna Wolfson, Can-Lan Sun, Heeyoung Kim, Tongjun Kang, Smita Bhatia
Journal: Journal of Clinical Oncology (2012)

9512 Background: AYAs (15-39y at diagnosis) with cancer have not seen the survival improvement evidenced by younger and older age groups with similar diagnoses, leaving an AYA Gap. While treatment on pediatric protocols is associated with superior survival in 15-21 year-olds, the impact of site of care on survival for vulnerable AYA subpopulations (age at diagnosis or race/ ethnicity) between 22-and 39y at diagnosis remains unstudied. Methods: We constructed a cohort of 10,727 patients newly diagnosed between the ages of 22- and 39y with lymphoma, leukemia, brain tumors, melanoma, thyroid and GU cancers, and reported to the LA County cancer registry between 1998 and 2008. Multivariable Cox regression analysis was conducted, and included race/ethnicity, age at diagnosis, SES, insurance status, primary cancer diagnosis and diagnosis year in the model; the analysis was stratified by site of care (NCICCC vs. non-NCICCC). Results: A total of 928 (9%) patients received treatment at the 3 NCICCCs (City of Hope, Jonsson Cancer Center and Norris Cancer Center) in LA County, and 9,799 received care elsewhere. Five-year overall survival (5y OS) was significantly worse for patients treated at non-NCICCC (87%) when compared with those treated at NCICCC (84%, p=0.02). In addition, 5y OS was worse for African Americans (71%) vs. non-Hispanic whites (89%, p&lt;0.0001) and for older patients (31-39yo: 84%, vs. 22-30yo: 86%, p=0.0004). Multivariable analysis adjusting for SES, insurance status, diagnosis and diagnosis year revealed that African Americans (HR=1.4, p=0.0002) and older AYAs (31-39y: HR=1.24, p&lt;0.0001) were at an increased risk of death. Among patients treated at NCICCC, the difference in risk of death due to race (African Americans: HR=0.8, p=0.7) and age (31-39yo: HR=1.1, p=0.6) was abrogated. On the other hand, among patients treated at non-NCICCC, these differences in outcome persisted (African Americans: HR=1.45, p =0.0002; 31-39yo: HR=1.25, p&lt;.0001). Conclusions: Population-based data reveal that receipt of care at an NCICCC abrogates the effects of race and older age on mortality in AYAs with cancer. Barriers to accessing care at NCICCCs are being explored.
An audit of outcome of pancreatic cancer in a UK region: Does chemoradiation add to systemic chemotherapy for locally advanced disease
Authors: E. Hudson, S. Mukherjee, S. Reza, M. Thomas, T. Crosby, T. Maughan
Journal: Journal of Clinical Oncology (2007)

15021 Background: The benefit of adding radiotherapy to chemotherapy (CT) in patients with locally advanced non-metastatic pancreatic cancer (LANPC) is uncertain with chemoradiation (CRT) being the treatment of choice in the USA and CT alone more common in the UK. To establish the outcome of LANPC treated with CT alone we undertook a review of outcomes of all patients with LANPC referred to a single UK Cancer Network (South East Wales, population 1.5 million) over a 4 year period. Methods: Case notes, radiology and histology reports of patients with LANPC referred to Velindre Cancer Centre between 1.1.2002 and 31.12.2005 were reviewed. Patient and tumour characteristics, treatment type and duration, response to treatment and overall survival were collected. The primary end-point of the study was overall survival. Log-rank was used to compare survival between groups, and Cox regression analysis model was used to evaluate whether age, sex, tumour site and treatment response correlated with overall survival. Results: 357 patients were identified with pancreatic cancer. 116/357 (32.5%) patients had LANPC of which 74/116 (64%) were fit for active treatment. Treatment included primary gemcitabine based CT (n= 68) and CRT (n=6). For patients receiving primary CT median duration of treatment was 3.2 months. The median survival of all patients with LANPC was 7.7 months (95% CI 6.7–8.7). Survival for patients receiving primary CT, CRT and no treatment were 10 (8.5–11.3) months, 10.3 (0–20.7) months and 4.6 (3.8–5.4) months respectively. Survival of 4 patients who received neoadjuvant CT prior to CRT was 12.9 (6.8–19) months. 32 patients (47%) progressed on CT. OS of patients with non-progressive disease was significantly better than those who progressed (12.1 v 6.7 months, p=0.039). Conclusions: In this UK Network, only a small proportion of patients are eligible for active treatment. The outcome of patients treated with CT alone is comparable to published series of CRT. There is an urgent need for a randomised trial to define the additional role of CRT over and above Gemcitabine-based chemotherapy and such trials should include a neo-adjuvant ‘chemotherapy-only’ phase to select out patients most likely to benefit from multi-modality treatment. No significant financial relationships to disclose.
Risk of disease recurrence and mortality in gastrointestinal stromal tumor (GIST) patients receiving short-term versus long-term imatinib adjuvant therapy: A chart review analysis.
Authors: Anthony Paul Conley, Annie Guerin, Medha Sasane, Genevieve Gauthier, Frances Schwiep, Christopher Hunt Keir, Eric Q. Wu
Journal: Journal of Clinical Oncology (2012)

e20511 Background: The benefits of long-term (36 months) use of adjuvant imatinib (IM) in high risk GIST patients (pts) have been demonstrated in a recent multicenter, prospective clinical trial that compared efficacy and safety of 3 years vs 1 year IM treatment. However, in clinical practice, there is no consensus on the optimal IM treatment duration after surgery. The objective of this retrospective observational study was to compare the risk of recurrence and survival among primary resectable Kit positive GIST pts treated with adjuvant IM for a short vs an extended period of time in a real-world setting. Methods: Information on adult pts with primary resectable Kit positive GIST initiating imatinib ≤84 days after surgery was collected from 248 U.S. oncologists using an online data collection form. Detailed pt information following first GIST diagnosis, including demographic, GIST-related characteristics (e.g., risk profile), comorbidity profile, IM treatment characteristics, disease recurrence and mortality was collected for pts with short-term (6-12 months) and long-term IM use (≥24 months). Disease recurrence and mortality rates were estimated from the 1 st surgery date to the 1 st evidence of recurrence, mortality, or end of observation period. Multivariate Cox proportional hazard models were used to compare recurrence and mortality rates between short vs long term IM use pts. Results: Among the 246 short-term and 395 long-term IM pts, the median follow up was 884 and 963 days, respectively. The average age was similar [59.0 (10.4) vs 58.1 (9.5); p=.23] but short-term pts had less males [57.7% vs 69.6% (p&lt;.01)] and a lower Miettinen risk score [0.3 vs 0.4, p&lt; .01)] than long-term pts. Disease recurrence [7.3 vs 1.8%, (p&lt; .01)] and mortality rates [6.9% vs 2.3%, (p &lt; .01)] were also higher in short- vs long-term pts. The adjusted risk of recurrence was 4.77 times [95% CI: 1.98 – 11.48, (p&lt;.01)] higher and mortality risk was 3.44 times [CI: 1.53 – 7.75, (p&lt;.01)] higher in short- vs long-term pts. Conclusions: Use of IM over an extended period of time is associated with a reduction in long-term risk of disease recurrence and mortality.
Perilesional edema in brain metastases: potential causes and implications for treatment with immune therapy
Authors: Thuy T. Tran, Amit Mahajan, Veronica L. Chiang, Sarah B. Goldberg, Don X. Nguyen, Lucia B. Jilaveanu, Harriet M. Kluger
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Little is known about tumor-associated vasogenic edema in brain metastasis, yet it causes significant morbidity and mortality. Our purpose was to characterize edema in patients treated with anti-PD-1 and to study potential causes of vessel leakage in humans and in pre-clinical models. <h3>Methods</h3> We analyzed tumor and edema volume in 18 non-small cell lung (NSCLC) and 18 melanoma patients with untreated brain metastases treated with pembrolizumab on a phase II clinical trial. Melanoma brain metastases were stained with anti-CD34 to assess vessel density and its association with edema. We employed an in vitro model of the blood-brain barrier using short-term cultures from melanoma brain and extracranial metastases to determine tight junction resistance as a measure of vessel leakiness. <h3>Results</h3> Edema volumes are similar in NSCLC and melanoma brain metastases. While larger tumors tended to have more edema, the correlation was weak (<i>R</i><sup>2</sup> = 0.30). Patients responding to pembrolizumab had concurrent shrinkage of edema volume and vice versa (<i>R</i><sup>2</sup> = 0.81). Vessel density was independent of the degree of edema (<i>R</i><sup>2</sup> = 0.037). Melanoma brain metastasis cells in culture caused loss of tight junction resistance in an in vitro blood-brain barrier model system in some cases, whereas extracerebral cell cultures did not. <h3>Conclusions</h3> Edema itself should not preclude using anti-PD-1 with caution, as sensitive tumors have resultant decreases in edema, and anti-PD-1 itself does not exacerbate edema in sensitive tumors. Additional factors aside from tumor mass effect and vessel density cause perilesional edema. Melanoma cells themselves can cause decline in tight junction resistance in a system void of immune cells, suggesting they secrete factors that cause leakiness, which might be harnessed for pharmacologic targeting in patients with significant perilesional edema.
Plasma folate, vitamin B6, vitamin B12 and risk of breast cancer in women
Authors: Jennifer-Hsiang-Ling Lin, I-Min Lee, Nancy Cook, Jacob Selhub, JoAnn Manson, Julie Buring, Shumin Zhang
Journal: Cancer Research (2007)

860  Background: B vitamins such as folate, vitamin B6 and vitamin B12 are coenzymes that are essential for DNA methylation and synthesis. Deficiency in these B vitamins may promote tumor carcinogenesis. Studies assessing blood levels of folate, vitamin B6 and vitamin B12 in risk of breast cancer are limited. Methods: We prospectively evaluated plasma levels of folate, Pyridoxal 5’-Phosphate (PLP, the principal active form of vitamin B6), and vitamin B12 in relation to breast cancer risk from 28,345 women in the Women’s Health Study (WHS) aged 45 years or older who provided blood samples and had no history of cancer and cardiovascular disease at baseline in 1993. We included, in the analysis, 850 incident cases of invasive breast cancer identified as of March 31, 2004 and 850 individually matched control subjects. Logistic regression controlling for matching factors as well as other risk factors for breast cancer was used to estimate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two sided. Results: Plasma levels of folate, PLP, and vitamin B12 were not significantly associated with overall risk of breast cancer. Women in the highest quintile group relative to those in the lowest quintile had multiviariate RRs of 1.41 (95% CI=0.99-2.00) for plasma folate (p for trend=0.22), 0.89 (95% CI=0.62-1.29) for plasma PLP (p for trend=0.46), and 1.27 (95% CI=0.90-1.78) for plasma vitamin B12 (p for trend=0.20). The overall associations were not modified by alcohol consumption, supplement use, and follow-up time before/after the fortification of folate in 1998. However, we found a significant inverse association between plasma PLP and breast cancer risk among postmenopausal women; the multivariate RR comparing the highest to the lowest quintile was 0.64 (95% CI=0.42-0.99; p for trend=0.04). We also observed a marginal inverse association between plasma levels of folate and PLP and breast cancer risk in current smokers; the multivariate RRs in the highest quintile group were 0.27 (95% CI=0.07-1.12) for plasma folate (p for trend=0.03), and 0.25 (95% CI=0.06-1.06) for plasma PLP (p for trend=0.06). Conclusions: Plasma levels of B vitamins including folate, vitamin B6, and vitamin B12 are not associated with overall risk of breast cancer. However, higher plasma levels of vitamin B6 may be related to reduced risk of developing postmenopausal breast cancer. The inverse association between plasma folate and vitamin B6 and breast cancer risk among current smokers needs to be confirmed in other large studies.
A first-in-human, phase I safety and pharmacokinetic study of genz-644282, a non-camptothecin topoisomerase I inhibitor, in patients with advanced solid tumors.
Authors: Hyo S. Han, Antoinette R. Tan, Glen J. Weiss, Daniel Sullivan, Jonathan R. Strosberg, Sara Collins, Rebecca Anne Moss, Jingyang Wu, Reginald Ewesuedo, Patricia LoRusso
Journal: Journal of Clinical Oncology (2012)

2534 Background: The approved topoisomerase I (TopI) inhibitors (irinotecan and topotecan) are camptothecin derivatives. The lactone ring structure of camptothecins negatively impacts their clinical potential.Genz-644282 is a novel non-camptothecin that induces TopI-DNA cleavage complexes at similar as well as unique genomic positions; that are more persistent. This study was designed using a pharmacokinetic-pharmacodynamic (PK-PD) model to predict the maximum tolerated dose (MTD). Methods: A PK-PD relationship of Genz-644282 to inhibit tumor growth was derived (Simeoni, Can Res 2004). Using an accelerated titration design, cohorts of 1, 3 or 6 patients received 3 weekly doses of Genz-644282 on a 28 day schedule starting with 0.5 mg/m 2 . After MTD on the 28 day schedule was exceeded, 21 day schedule was initiated. Results: 49 patients (N=44 data available: 26M :18F) were dosed. Tumor types were colorectal (15), breast (5), small cell lung (SCLC 3), non-small cell lung (4), others (17). As predicted from the PK-PD model 8 cohorts were evaluated on the 28 day schedule before defining the MTD. The MTD was 8 mg/m 2 and 9 mg/m 2 for the 28 day and 21 day schedules, respectively. Dose limiting toxicities that determined the MTD were: gr 4 thrombocytopenia (n=2); gr 2 thrombocytopenia (n=1) and gr 4 neutropenia (n=1) both of which resulted in ≥72h delays in initiating cycle 2. Treatment emergent adverse events (&gt;10%) were nausea (45%), fatigue (39%), anorexia (32%), anemia (27%), vomiting (23%), thrombocytopenia (18%), diarrhea (16%), dehydration (16%), hyperglycemia (16%), cough (16%), dyspnea (14%), depression (11%) and hyponatremia (11%). Efficacy data suggest 2 responders with SCLC (1 minor response;1 complete response), and 2 patients (breast, gastric) with stable disease (≥ 6 months). PK data show a Genz-644282 half-life of approximately 50 h, a linear dose-exposure relationship, and no accumulation in between doses. Conclusions: Genz-644282 is a non-camptothecin TopI inhibitor in phase I development with ongoing expansion phase. The emerging pk, efficacy and safety data are suggestive of a distinct clinical profile of Genz-644282 from the camptothecins.
18F-FDG PET/CT in Metastatic Extramammary Paget’s Disease
Authors: Alex Cheen Hoe Khoo, Kheng Wei Yeoh
Journal: Clinical Nuclear Medicine (2019)

Abstract Extramammary Paget's disease (EMPD) is a rare disease with an estimated prevalence of 0.1 to 2.4 per 1,000,000 person-years. Metastatic EMPD has a poor prognosis with a 5-year survival of approximately 7%. Local therapy is the only curative option with surgery being recommended for resectable disease. It is therefore crucial to be able to stage such patients appropriately. The utility of 18 F-FDG PET/CT for this disease is not well established. We share a case on how 18 F-FDG PET/CT was used to stage metastatic EMPD.
Can even experienced orthopaedic surgeons predict who will benefit from surgery when patients present with degenerative meniscal tears? A survey of 194 orthopaedic surgeons who made 3880 predictions
Authors: Victor A van de Graaf, Coen H Bloembergen, Nienke W Willigenburg, Julia C A Noorduyn, Daniel BF Saris, Ian A Harris, Rudolf W Poolman
Journal: British Journal of Sports Medicine (2019)

To examine the ability of surgeons to predict the outcome of treatment for meniscal tears by arthroscopic partial meniscectomy (APM) and exercise therapy in middle-aged patients.Electronic survey. Orthopaedic surgeon survey participants were presented 20 patient profiles. These profiles were derived from a randomised clinical trial comparing APM with exercise therapy in middle-aged patients with symptomatic non-obstructive meniscal tears. From each treatment group (APM and exercise therapy), we selected five patients with the best (responders) and five patients with the worst (non-responders) knee function after treatment. 1111 orthopaedic surgeons and residents in the Netherlands and Australia were invited to participate in the survey.For each of the 20 patient profiles, surgeons (unaware of treatment allocation) had to choose between APM and exercise therapy as preferred treatment and subsequently had to estimate the expected change in knee function for both treatments on a 5-point Likert Scale. Finally, surgeons were asked which patient characteristics affected their treatment choice.The primary outcome was the surgeons' percentage correct predictions. We also compared this percentage between experienced knee surgeons and other orthopaedic surgeons, and between treatment responders and non-responders.We received 194 (17%) complete responses for all 20 patient profiles, resulting in 3880 predictions. Overall, 50.0% (95% CI 39.6% to 60.4%) of the predictions were correct, which equals the proportion expected by chance. Experienced knee surgeons were not better in predicting outcome than other orthopaedic surgeons (50.4% vs 49.5%, respectively; p=0.29). The percentage correct predictions was lower for patient profiles of non-responders (34%; 95% CI 21.3% to 46.6%) compared with responders (66.0%; 95% CI 57.0% to 75.0%; p=0.01).In general, bucket handle tears, knee locking and failed non-operative treatment directed the surgeons' choice towards APM, while higher level of osteoarthritis, degenerative aetiology and the absence of locking complaints directed the surgeons' choice towards exercise therapy.Surgeons' criteria for deciding that surgery was indicated did not pass statistical examination. This was true regardless of a surgeon's experience. These results suggest that non-surgical management is appropriate as first-line therapy in middle-aged patients with symptomatic non-obstructive meniscal tears.ClinicalTrials.gov Identifier: NCT03462134.
Anti-proliferative targets of sulforaphane in ovarian cancer
Authors: Badithe T. Ashok, Devyani Chaudhuri
Journal: Cancer Research (2005)

1567  Epidemiological studies have shown that an increased consumption of fruits and vegetables reduces the risk of ovarian cancer. However, the literature does not contain many reports on the use of dietary components as chemopreventive agents for ovarian cancer. Sulforaphane (SFN) is derived from the breakdown of glucoraphanin and is found in large amounts in cruciferous vegetables, particularly broccoli. We observed a strong anti-cancer effect of SFN on human ovarian cancer cell line SKOV3 by cell viability assays and determined the IC50 to be 10 μM. The loss of viability was due to induction of apoptosis where we observed a four fold increase in apoptosis at 10 μM going upto 20 fold at 100 μM. The apoptotic effect that results in the loss of viability is preceded by a significant effect on the regulator of cell cycle transition molecules specifically cdk4. The steady state level of cdk4 decreased in dose dependent manner with complete abrogation at 20 μM. In an effort to identify further upstream targets of SFN we examined the effect of SFN on signal transduction pathways that may be of significance in ovarian cancer. We observed that both total Akt protein and the active phosphorylated levels of Akt were significantly inhibited in SFN treated SKOV3 cells. We conclude that the pro-survival Akt pathway is a target of the chemopreventive SFN that may lead to cell cycle inhibition and induction of apoptosis and propose use of SFN with other chemotherapeutic agents that target phosphorylation mediated signal transduction pathways in ovarian cancer.