tbuckley/cabot-search huggingface dataset:
Phase II study of sunitinib (SU) in Japanese patients with unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumor (NET).
Authors: Takuji Okusaka, Tetsuhide Ito, Toshirou Nishida, Hisato Igarashi, Nobumasa Mizuno, Kazuo Hara, Chigusa Morizane, Shunsuke Kondo, Satoshi Hashigaki, Nobuyuki Kimura, Kyoko Okano, Junichi Tanuma, Mami Murakami, Akira Sawaki, Kenji Yamao, Masayuki Imamura
Journal: Journal of Clinical Oncology (2012)

381 Background: SU is an oral, multitargeted, antiangiogenic, tyrosine kinase inhibitor effective in patients (pts) with unresectable, well-differentiated pancreatic NET. This open-label, phase II study examined whether SU is also effective in Japanese pts with this disease. Methods: Japanese pts received SU 37.5 mg/day on a continuous daily dosing (CDD) schedule (28-day cycle). The primary endpoint was clinical benefit rate (CBR; complete response [CR] + partial response [PR] + stable disease [SD] ≥24 weeks). Secondary endpoints included: objective response rate (ORR; CR + PR), 6-mos progression-free survival (PFS) probability, safety and pharmacokinetics. Tumor assessments were performed at baseline and 8-wk intervals by CT or MRI (RECIST). Results: Twelve patients were enrolled and received treatment (tx; median age 54 yrs, range 34–79); 9 were ongoing at data cut-off (July 1, 2011). CBR was 75.0% (95% CI 42.8, 94.5), comprising 5 PRs and 4 pts with SD ≥24 weeks. ORR was 41.7% (95% CI 15.2, 72.3). 6-mos PFS probability was 91.7% (95% CI 53.9, 98.8). One PR occurred in a pt with gastrinoma, in whom gastrin levels decreased by 93% and tumor bulk decreased by 45%. All-causality, any-grade (G) AEs included diarrhea (n=9, 75%), HFS and hypertension (both n=8, 67%). Neutropenia was the most common G3 AE (n=5, 42%, all tx-related). Three pts (25%) experienced G4 AEs (herpes encephalitis, convulsion, loss of consciousness [n=1] and lipase increased [n=2], all tx-related).Two pts (17%) experienced serious AEs: convulsion and loss of consciousness (n=1, tx-related), and acute cholecystitis (n=1, unrelated to tx). There were no deaths on study; one death due to disease progression occurred 3 mos after study withdrawal. On day 15 (cycle 1), mean trough plasma concentrations (n=10) for SU, its metabolite, and SU + metabolite were 53.9, 23.7 and 77.5 ng/mL, respectively. SU on a CDD schedule resulted in sustained drug concentrations without accumulation across cycles. Conclusions: SU 37.5 mg/day on a CDD schedule demonstrated antitumor activity in Japanese pts with unresectable, well-differentiated pancreatic NET. Common AEs were consistent with the known safety profile of SU.
Phase I and IIa studies of simtuzumab alone and in combination with FOLFIRI in patients with advanced solid tumors.
Authors: Patricia LoRusso, J. Randolph Hecht, Dung Luong Thai, Michael J. Hawkins, Hua Dong, Anthony W. Tolcher
Journal: Journal of Clinical Oncology (2014)

554 Background: Simtuzumab (SIM) is a monoclonal antibody that inhibits lysyl oxidase like molecule 2 (LOXL2), an extracellular matrix enzyme involved in tumor growth and metastasis. Methods: A phase I dose escalation study evaluated the safety and pharmacokinetics (PK) in patients (pts) with advanced solid tumors. Dose escalation occurred at doses up to 20 mg/kg of SIM every 2 weeks by IV infusion followed by a dose expansion of 20 pts at 10 mg/kg of SIM every 2 weeks. PK was evaluated following the first and fourth doses. In a separate Phase IIa study, 11 pts with KRAS mutant colorectal cancer (CRC) were given SIM at 700 mg IV combined with FOLFIRI every 2 weeks in the 2nd line setting. All pts continued until disease progression or unacceptable toxicity. CT or MRI was performed every 8 weeks. Results: In the phase I study, 12 pts (3 per cohort) received SIM at doses of 1, 3, 10 and 20 mg/kg. Tumor types included CRC (5), pancreatic neuroendocrine (PNE, 1), and other tumors (1 each). In the dose expansion, 20 CRC pts (11 KRAS mutant and 9 KRAS wild-type) received SIM at 10 mg/kg. Treatment-emergent AEs (TEAEs) included fatigue and constipation. No DLTs or drug-related SAEs were observed. The mean terminal T 1/2 was ~20 days, and exposure was dose proportional between 1 and 20 mg/kg. Decreased tumor size (-56% for PNE and -17%, -8%, -5%, -5%, and -4% for CRC) as measured by the sum of the linear diameter of the target lesions was observed in 6 pts following treatment with SIM alone. In the Phase IIa trial of SIM/FOLFIRI, the most common TEAEs were diarrhea, fatigue, and nausea. Median PFS was 7.8 months. Conclusions: SIM was well tolerated as a single agent and when combined with FOLFIRI and showed promising efficacy in pts with CRC. A randomized, double-blind, placebo controlled phase II study in KRAS mutant CRC pts is ongoing. Clinical trial information: NCT01323933.
Evolving patterns of metastatic disease in castration-resistant prostate cancer (CRPC) reported in clinical trials from 1990 to 2011.
Authors: Stephanie Doctor, Che-Kai Tsao, James H. Godbold, Matt D. Galsky, William K. Oh
Journal: Journal of Clinical Oncology (2013)

5015 Background: Bone remains the most common site of metastasis in CRPC. With new therapies extending survival in metastatic CRPC (mCRPC), we hypothesized that the incidence of non-osseous metastases is increasing over time. In this study, we evaluated the pattern of metastatic disease in mCRPC as reported in baseline characteristics of prospective clinical trials over 2 decades. Methods: We identified all therapeutic studies in patients with mCRPC in Pubmed and ASCO abstracts from 1990-2011. Inclusion criteria included phase 2 or 3 clinical trials in mCRPC with available baseline demographic data and no exclusion of specific site of metastatic disease (except brain). ASCO abstracts were limited to presentations in which data were available online. For each study, demographic data and study-reported sites of non-osseous metastatic disease were recorded (lymph node, visceral, soft tissue, liver). For each type of metastasis, weighted least squares linear regression models were used to evaluate temporal trends. Results: We identified a total of 290 eligible studies (270 phase II and 20 phase III) involving 19,110 patients. Of these, 127 studies reported data on non-osseous metastases and prior chemotherapy. There was a significant trend over time (p=0.001) of increasing proportions of patients with non-osseous metastasis in both chemotherapy- naïve and treated groups (1.4% per year increase). Increased lymph node, visceral, and soft tissue metastases were seen over the study period. However, the proportion of patients with liver metastasis remained relatively stable Conclusions: In this study, we noted an increasing trend of non-osseous metastatic disease in patients with mCRPC over 20 years. This included lymph node, visceral and soft tissue metastatic disease, and this trend was observed in both chemotherapy-naïve and treated patients. Longer survival and new therapies may be changing the clinical presentation of patients with mCRPC.
Mutation prevalence in a large series of patients with Lynch Syndrome
Authors: M. Martin, L. Burbidge, C. Frye, B. Roa, R. Wenstrup
Journal: Journal of Clinical Oncology (2008)

11097 Background: Deleterious mutations in MLH1, MSH2 and MSH6 are known to cause Lynch Syndrome (HNPCC). The aim of this study was to determine the percentage of deleterious mutations represented by each of these genes in a series of patients referred for genetic testing for Lynch Syndrome. Methods: Full sequencing and Southern blot analysis of MLH1 and MSH2 is offered as a grouped test with full sequencing of MSH6 offered as a reflex test to patients negative for MLH1 and MSH2. We identified a group of patients who had testing for all three genes ordered at Myriad Genetic Laboratories and determined the percentage of Lynch syndrome causative mutations represented by each gene. In addition, we determined the types of mutations identified and stratified them by gene. Results: A total of 994 patients had testing for MLH1, MSH2, and MSH6 ordered and 157 patients were found to carry a deleterious mutation for an overall 15.8% positive rate. Of these patients 71 had mutations in the MLH1 gene, representing 45.2% of mutation positive patients. For the MSH2 gene, 64 patients were identified with a deleterious mutation, accounting for 40.8% of mutation positive patients. MSH6 gene sequencing was performed on a total of 859 patients (only patients negative for MLH1 and MSH2), identifying 22 patients with deleterious mutations and representing 14.0% of all deleterious mutations. The table below presents data on the number and distribution of mutation types observed overall and stratified by gene. Conclusions: MLH1, MSH2 and MSH6 each represent a substantial percentage of Lynch syndrome causative mutations and testing for all three genes should be considered to rule out the syndrome in patients with personal and family histories suggestive of the disease. Mutation Type by Gene Total # MLH1 Positive MSH2 Positive MSH6 Positive Frame Shift 44 18 10 16 Splice 35 23 10 2 Missense 7 4 3 0 Nonsense 25 10 10 5 Synonymous 3 3 0 0 Large Rearrangements 44 13 31 NA Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Myriad Genetic Laboratories Myriad Genetic Laboratories
A single-center experience of modified FOLFOX-6 in locally advanced and metastatic pancreatic adenocarcinomas.
Authors: Bradley Thomas Sumrall, Chang O Son, Jyotsna Fuloria, Suma Satti
Journal: Journal of Clinical Oncology (2013)

303 Background: Pancreatic adenocarcinoma has historically been as a disease with a poor prognosis with a 5 year survival rate of about 6%. The recently published ACCORD 11 trial demonstrated an improved overall survival utilizing FOLFIRINOX versus gemcitabine which has been the standard of care. However, FOLFIRINOX was associated with a significantly higher incidence of both hematologic and nonhematologic toxicities at the expense of increased toxicity. At our institution, FOLFIRINOX has been found to have a very similar toxicity profile with a significant impact on quality of life. For that reason, many patients at our institution have been treated with mFOLFOX6 with better tolerability instead of FOLFIRINOX in the palliative setting. Methods: We performed a retrospective chart review to analyze overall survival in patients withof unresectable pancreatic cancer (locally advanced and metastatic). Institutional tumor registry database was used to identify patients with unresectable pancreatic adenocarcinoma from January 2009 to March 2012. Medical records were reviewed to identify patients who were treated with at least 1 cycle of modified FOLFOX-6 as a line of treatment during their disease course. Overall survival was calculated for this cohort of patients. Results: 26 patients (15 male, 11 female) with unresectable pancreatic adenocarcinoma were identified. Mean age was 65.3 years. 19 patients had metastatic disease whereas 7 patients had locally advanced disease at diagnoses. Modified FOLFOX6 as a 1 st line, 2 nd line and 3 rd line therapy was given in 17, 6 and 3 patients respectively. The median overall survival was 9 month while the mean survival was 10.6 months. 7 patients were treated with FOLFIRI as 2 nd or 3 rd line treatment. Nine patients are still alive. Conclusions: Modified FOLFOX-6 is an acceptable treatment for metastatic and locally advanced pancreatic adenocarcinoma. Even though our sample size is small, overall survival is comparable to that of FOLFIRINOX. A multi-institutional, randomized trial evaluating sequencing of mFOLFOX6 and FOLFIRI and comparing it with FOLFIRINOX would be useful.
A Perspective on the Role of Computational Models in Immunology
Authors: Arup K. Chakraborty
Journal: Annual Review of Immunology (2017)

This is an exciting time for immunology because the future promises to be replete with exciting new discoveries that can be translated to improve health and treat disease in novel ways. Immunologists are attempting to answer increasingly complex questions concerning phenomena that range from the genetic, molecular, and cellular scales to that of organs, whole animals or humans, and populations of humans and pathogens. An important goal is to understand how the many different components involved interact with each other within and across these scales for immune responses to emerge, and how aberrant regulation of these processes causes disease. To aid this quest, large amounts of data can be collected using high-throughput instrumentation. The nonlinear, cooperative, and stochastic character of the interactions between components of the immune system as well as the overwhelming amounts of data can make it difficult to intuit patterns in the data or a mechanistic understanding of the phenomena being studied. Computational models are increasingly important in confronting and overcoming these challenges. I first describe an iterative paradigm of research that integrates laboratory experiments, clinical data, computational inference, and mechanistic computational models. I then illustrate this paradigm with a few examples from the recent literature that make vivid the power of bringing together diverse types of computational models with experimental and clinical studies to fruitfully interrogate the immune system.
Glioblastoma in the elderly: Radiation, chemoradiation, and supportive care
Authors: R. J. Kimple, S. Grabowski, M. Papez, F. Collichio, M. G. Ewend, D. E. Morris
Journal: Journal of Clinical Oncology (2008)

20738 Background: Elderly patients with glioblastoma (GBM) have poor outcomes. Short course radiation improves median survival over best supportive care (10 vs 4 months). Standard care for patients <70 years old includes radiation and concurrent temozolomide followed by adjuvant temozolomide (i.e., the “Stupp regimen”). Since 2002 we have offered this regimen as an alternative to select elderly patients with GBM. However, there is no data limited to the over 70 population using this approach. We undertook this IRB approved chart review to describe our outcomes with this approach. Methods: We reviewed the records of all patients over age 70 diagnosed with GBM since 2002 at the University of North Carolina to determine treatment received, performance status, age at diagnosis, and RPA class. Median survival was calculated according to the Kaplan-Meier method. Results: We identified 26 patients with a median survival of 20.6 weeks. One patient was excluded due to incomplete follow-up. Thirteen patients received best supportive care with a median survival of 8.6 weeks. Eight patients were treated with the Stupp regimen, 3 patients with short course radiation, and 2 with high dose radiation without chemotherapy; median survival was 38.0, 32.3, and 23.1 weeks, respectively. Median survival for patients classified as RPA class V and VI (36.9 vs 10.3 weeks) was consistent with that previously reported by the RTOG. Patients aged 70–80 fared better than those > 80 (22.1 vs 11.0 weeks, respectively). Increased performance status correlated with improved survival (Pearson r = 0.57, p=0.0024). Conclusions: Offering aggressive treatment with the Stupp regimen to good performance status elderly patients with GBM is a reasonable approach. In our experience, concurrent therapy with temozolomide and radiation is well tolerated with an overall survival slightly better than short course radiation alone. In our opinion, a frank discussion with good performance status elderly patients and their families regarding treatment options can include chemoradiation. Median survival by treatment, performance status, and age (weeks, n) All patients PS <70 PS ≥70 Age 70–80 Age >80 Hospice/supportive care 8.6 (13) 8.4 (11) 9.6 (2) 8.4 (8) 10.3 (5) Short course RT (4000 cGy) 32.3 (3) 34.5 (2) 32.3 (1) 34.5 (2) 32.3 (1) Long course RT (6000 cGy) 23.1 (2) (0) 23.1 (2) 23.1 (2) (0) Concurrent radiation (6120 cGy) and temozolomide 38.0 (8) 42.4 (2) 38 (6) 36.9 (7) 38 (1) No significant financial relationships to disclose.
The natural history of bone metastases in castrate-resistant prostate cancer.
Authors: Robert James Pell, Stephen John Harland
Journal: Journal of Clinical Oncology (2014)

239 Background: Previous authorities have commented on the lack of data regarding overall prevalence of Skeletal-Related Events (SREs) in Castrate Resistant Prostate Cancer (CRPC) in patients who have not received therapy for SRE prevention. We describe a cohort of 129 patients followed to death. Methods: 129 patients treated with palliative chemotherapy for CRPC at University College Hospital London between 01/01/2006 and 31/12/2010 had retrospective collection of data concerning date of prostate cancer diagnosis, date of CRPC, date of death, date of bone metastasis development, radiotherapy treatment, pathological fracture, bone surgery, and spinal cord compression up until 01/06/2013. Results: Median age at castrate resistant prostate cancer development was 70 years. Overall median time from prostate cancer diagnosis to establishment of castrate-resistant state was 33 months (range 5-223). Median time from castrate-resistant state to death was 23 months (0-99). Only 9/129 patients failed to develop bone metastases. A total of 162 palliative radiotherapy treatments were given to 74 patients. Only 10 radiotherapy treatments occurred prior to the development of castrate-resistant disease, the remaining 152 all occurred after castrate-resistance occurred. Symptomatic pathological fracture occurred 28 times in 22 (17%) patients. One or more surgical interventions for bone disease were carried out in 23 (18%) patients. 27 (21%) patients were treated for spinal cord compression. In total, 352 skeletal-related events occurred in 89 patients. Conclusions: Important skeletal-related events occurred in 69% of patients with mCRPC. It is possible that incomplete follow-up in clinical trials of agents such as bisphosphonates considerably under estimate the effect of the investigational agent. The frequency of pathological long bone fracture suggests current measures to detect prefracture and intervene are inadequate. [Table: see text]
Use of the Edmonton Symptom Assessment Scale in patients with advanced cancer referred to an embedded palliative care clinician.
Authors: Sarah D'Ambruoso, Anne M. Walling, Sara A. Hurvitz, Alexandra Drakaki, Jonathan Wade Goldman, Christopher Pietras, Frances Watts, Anne Coscarelli, Neil Wenger
Journal: Journal of Clinical Oncology (2016)

96 Background: Physical and emotional symptoms are highly prevalent in patients with advanced cancers and contribute to overall distress level and decreased self-reported quality of life. Oncology organizations and accrediting bodies now routinely recommend universal distress screening among patients with advanced cancers. Palliative and supportive care clinicians play an important role in implementing symptom and distress screening in cancer centers. Methods: As part of an embedded palliative care nurse practitioner (PC-NP) intervention within a large ambulatory oncology clinic, patients with advanced breast, GU, GI and lung cancer were screened for physical and emotional symptoms using the Edmonton Symptom Assessment Scale (ESAS) and treated appropriately including referral to psychology-based supportive care clinic for moderate to severe anxiety and depression or clinician-identified need. We used pre-test post-test methods to see if symptoms improved after enrollment in an embedded palliative oncology program. Results: Sixty-eight patients were screened at initial visit and 41 had follow-up screening during the first 13 months of the program with a part-time PC-NP. Only the 41 patients who had both an initial and a follow-up visit were included in the analysis. Patients were assessed using the ESAS at initial visit and at a follow-up visit an average of 5.9 weeks later (RANGE 1.0-30.6), and significant reductions were found in self-reported pain (4.0 v. 3.0), shortness of breath (3.0 v. 2.1), lack of appetite (2.8 v. 2.1), and overall well-being (4.7 v 3.8) (p &lt; 0.05). Emotional symptoms (anxiety and depression) also decreased but were not statistically significant. Aggregate scores (emotional symptoms plus physical symptoms plus well-being) demonstrated a 6 point reduction in severity (26.2 baseline to 20.3 at follow-up, p = 0.17). Conclusions: These findings are suggestive of improvement in cancer-related symptoms and distress after enrollment in an embedded palliative oncology program. More rigorous study designs are needed to better understand the impact of the intervention on symptom management.
Current landscape of prostate cancer quality measures in the United States.
Authors: Scott C Flanders, Eleanor Fitall, Dayo Jagun, Kristi Mitchell, Peter St. John Francis, Hong Tang, Kyung Min Song
Journal: Journal of Clinical Oncology (2016)

273 Background: Prostate cancer (PCa) is the leading cancer for men in the United States (US) and identified by the Centers for Medicare &amp; Medicaid Services (CMS) as one of the top 20 high-impact Medicare conditions experienced by beneficiaries. Thus, there is increasing focus by stakeholders to measure and achieve high-value, quality care in PCa. However, quality measurement is particularly difficult in oncology. Our aim was to assess the current landscape of PCa quality measures (QMs) in the US. Methods: Published literature and online resources from the past 5 years were reviewed to identify PCa QMs and general oncology QMs relevant to PCa. PCa QMs were categorized using a “continuum of care” framework across 5 stages: 1) symptom assessment and screening; 2) diagnosis and risk stratification; 3) initial treatment; 4) monitoring and additional treatment; and 5) advanced- or late-stage care. Finally, PCa QMs were evaluated for their type (eg. process, outcomes), and use by CMS. Results: We identified 16 PCa-specific QMs and 20 general oncology QMs relevant to PCa. The majority of PCa QMs were developed by the American Medical Association–Physician Consortium for Performance Improvements (6 measures) and the Michigan Urological Surgery Improvement Collaborative (6 measures). There are 3 QMs for symptom assessment and screening, 5 QMs for diagnosis and risk stratification, 6 QMs for initial treatment, 2 QMs for monitoring and additional treatment, and 0 QMs for advanced- or late-stage care. Fourteen PCa QMs focus on process of care, but only 2 PCa QMs address outcomes. Nine PCa QMs are part of CMS quality improvement programs, 6 of which are reportable through the Michigan Urological Surgery Improvement Collaborative. Three new PCa QMs are under consideration by CMS. Conclusions: We found few PCa QMs that capture outcomes of patient experience or care, and no PCa-specific QMs available for advanced disease and late-stage care, demonstrating a need to better define quality in this setting. Opportunities to increase the focus on innovative, real-world data-generation strategies, such as PCa disease registries that collect clinical outcomes, patient preferences, and comorbidities, may inform stakeholder development and adoption of new QMs in the US.