tbuckley/cabot-search huggingface dataset:
Phase I trial of the PARP inhibitor veliparib (V) in combination with carboplatin (C) in metastatic breast cancer (MBC).
Authors: Robert Wesolowski, Meng Zhao, Susan Michelle Geyer, Maryam B. Lustberg, Ewa Mrozek, Rachel M. Layman, Erin Macrae Macrae, Jun Zhang, Nathan Hall, Katharina Schregel, Susan Ottman, Andrea Camp, Jeffrey J. Chalmers, Eleni Andreopoulou, Miguel Angel Villalona-Calero, Charles L. Shapiro, Michael V. Knopp, Michael R. Grever, Bhuvaneswari Ramaswamy
Journal: Journal of Clinical Oncology (2014)

1074 Background: Poly(ADP-ribose) polymerase (PARPi) inhibitors have shown activity in BRCA mutant and triple negative breast cancers (TNBC). The ideal dose and schedule of C and oral PARPi V is not known. We used sequential fluoro-3'-deoxythymidine (FLT) PET imaging and correlated tumor uptake to C with varying doses/schedules of V. Methods: To identify the recommended phase 2 dose (RP2D) of V when combined with C in patients (pts) with MBC with either TNBC or HER2 negative/estrogen receptor positive tumors with defective Fanconi Anemia (FA) pathway (i.e. no FANCD2 foci in nuclei of proliferating tumor cells via FA Triple Stain Immunofluroscence test), we used a standard 3+3 phase I design. Escalating doses of V were evaluated on a 7, 14, or 21-day schedules (table). Response was based on RECIST criteria using FDG PET/CT scans. FLT PET was done at baseline, cycle 1 day 7 and 14 or 21 and after cycle 3. Lesions were track-matched with FDG PET/CT and semi-quantitatively assessed using 2D ROI placement in a matched, blinded fashion. Results: 44 pts with a median of 2 prior lines of chemotherapy (range 0-3), received a median of 5 cycles (range 1-36); 39 had TNBC. The table shows observed DLTs. Of 43 evaluable pts, 18.6% had a PR; 48.8% had SD. Of 16 pts with BRCA 1/2 mutation or defect in FA pathway, 25% had a PR and 62.5 % had SD. The change in SUV on FLT PET between baseline and follow up scans did not depend on dose or schedule of V (N=24). Pts with PR had significant drop in max SUV of target lesions between baseline and day 14 or 21 FLT PET compared to non-responders (p=0.046 - Wilcoxon Rank Sum test). Conclusions: Combination of V and C is active in MBC. Thrombocytopenia was the major toxicity observed. The RP2D is C: AUC 5 and V: 250 mg bid on days 1-21. We observed that early drop in SUV values on FLT PET was predictive of response. The study is supported by U01 CA076576. Clinical trial information: NCT01251874. Dose level C dose (AUC) V dose/schedule N DLT 1 6 50 mg BID (D1-7) 7 G4 thrombocytopenia (N=2) G4 neutropenia (N=1) 1A 5 50 mg BID (D1-7) 3 None 2 5 50 mg BID (D1-14) 6 Gr 4 thrombocytopenia (N=1) 3 5 100 mg BID (D1-14) 3 None 4 5 150 mg BID (D1-14) 6 G3 akathisia (N=1) 5 5 200 mg BID (D1-14) 6 G4 thrombocytopenia (N=1) 6 5 200 mg BID (D1-21) 7 G4 thrombocytopenia (N=1) 7 5 250 mg BID (D1-21) 6 None
Compositions Including Synthetic and Natural Blends for Integration and Structural Integrity: Engineered for Different Vascular Graft Applications
Authors: Mozhgan Shojaee, Chris A. Bashur
Journal: Advanced Healthcare Materials (2017)

Tissue engineering approaches for small‐diameter arteries require a scaffold that simultaneously maintains patency by preventing thrombosis and intimal hyperplasia, maintains its structural integrity after grafting, and allows integration. While synthetic and extracellular matrix‐derived materials can provide some of these properties individually, developing a scaffold that provides the balanced properties needed for vascular graft survival in the clinic has been particularly challenging. After 30 years of research, there are now several scaffolds currently in clinical trials. However, these products are either being investigated for large‐diameter applications or they require pre‐seeding of endothelial cells. This progress report identifies important challenges unique to engineering vascular grafts for high pressure arteries less than 4 mm in diameter (e.g., coronary artery), and discusses limitations with the current usage of the term “small‐diameter.” Next, the composition and processing techniques used for generating tissue engineered vascular grafts (TEVGs) are discussed, with a focus on the benefits of blended materials. Other scaffolds for non‐tissue engineering approaches and stents are also briefly mentioned for comparison. Overall, this progress report discusses the importance of defining the most critical challenges for small diameter TEVGs, developing new scaffolds to provide these properties, and determining acceptable benchmarks for scaffold responses in the body.
Abstract A32: The role of the ribosome in GCN2's ability to sense amino acid deprivation and initiate the integrated stress response
Authors: Alison J. Inglis, Sichen Shao, Glenn R. Masson, Olga Perisic, Ramanujan S. Hegde, Roger L. Williams
Journal: Cancer Research (2017)

Abstract The ability to replicate without limit is one of the traditional hallmarks of cancer. It is therefore evident that the majority of tumor cells are operating in environments with limited nutrients. This means that tumor cells are disproportionately reliant on their stress response pathways in comparison to healthy cells. One such stress response pathway is a component of the integrated stress response pathway that responds to deprivation of amino acids. GCN2 is a serine/threonine protein kinase that is activated in response to a drop in the intracellular concentration of amino acids. Upon activation, GCN2 phosphorylates the translational initiation factor eIF2, inhibiting its activity in the translational cycle. This leads to a global inhibition of translation, whilst paradoxically upregulating the expression of certain genes involved in stress responses. It has been shown that knocking out GCN2 leads to a significant reduction in the growth of tumors in mice, suggesting that GCN2 could be a useful therapeutic target. We have expressed and purified human GCN2 and found it to be a dimer, as has been observed for yeast GCN2. We have shown in vitro that GCN2 becomes autophosphorylated, and it catalyses phosphorylation of a putative binding partner GCN1 as well as eIF2. We have found that human GCN2 forms a stable complex with 80S ribosomes, and mammalian 80S ribosomes significantly increase GCN2 kinase activity in vitro, consistent with a previous report that an increase in ribosomal stalling leads to a rise in eIF2 phosphorylation in vivo. We are attempting to determine the structure of GCN2 bound to ribosomes in order to understand the detailed interactions and the molecular mechanisms that lead to GCN2 activation. Citation Format: Alison J. Inglis, Sichen Shao, Glenn R. Masson, Olga Perisic, Ramanujan S. Hegde, Roger L. Williams. The role of the ribosome in GCN2's ability to sense amino acid deprivation and initiate the integrated stress response. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A32.
Relationship of anti-proliferative activity of TAS-108, a steroid anti-estrogen, and high expression of ERα in MCF7 cells.
Authors: Ye-Whang Cheong, Young Choi Kim, Tae-Hoon Kim
Journal: Journal of Clinical Oncology (2013)

e11566 Background: TAS-108 is an anti-estrogen that binds to both ERα and ERβ and has potent anti-proliferative activity in vitro and in vivo assay. Recently, the phase II clinical study of TAS-108 showed that it has competitive clinical benefic with lower level of adverse effects. However, the effect of TAS-108 on molecular mechanism, including ER dimerization, remains largely uninvestigated. Methods: The plasmids containing ERα or ERβ fused with N- and C-terminal fragments of firefly luciferase were constructed for split luciferase complementation assays. The resulting plasmids were transfected in HEK293 cells for 24 hr and TAS-108 was added to the media for 6 hr. For RT-qPCR of AREG and TFF1 and proliferation assay, ERβ was transfected in MCF7 cells for 24hr. The proliferation level was determined by measuring the fluorescent level induced by Prestoblue reagent. Results: Using split luciferase complementation assay, we determined that TAS-108 induced ERα/β heterodimerization about 100-fold more potently than ERα/α homodimerization. Increasing the ERβ level by transfection in MCF7 cells (MCF7-ERβ), potency of TAS-108 was increased significantly; 30nM TAS-108 was suitable to block the E2 mediated increase of AREG and TFF1 expression and significantly decrease proliferation of MCF7-ERβ. Conclusions: Taken together, these data suggest that TAS-108 has a higher affinity for ERα/β heterodimerization than ERα/α homodimerization and TAS-108 shows more effective anti-proliferative activity by blocking the expression of E2-induced proliferative genes when coupled with increased levels of ERβ. These findings also underscore the molecular role of ERβ in the biology and suggest the possibility of the compound inducing ERα/β heterodimerization as anti-breast cancer drugs.
GPs are warned of costs of missing “red flags” for spinal condition
Authors: Ingrid Torjesen
Journal: BMJ (2017)

The Medical Defence Union (MDU) has warned GPs, particularly those working out of hours, about the importance of diagnosing cauda equina syndrome promptly to avoid long term disability in patients.1

The MDU has paid out £8m (€9.2m; $9.9m) in compensation and £4.5m in claimants’ legal costs to settle claims for alleged failure to diagnose cauda equina syndrome over the past 11 years. The condition causes compression to nerve roots below the end of the spinal cord, leading to long term disability, and is most commonly the result of a slipped disc, although it can be caused by an infection or tumour.

An article in the MDU …
Extent of transmission captured by contact tracing in a tuberculosis high endemic setting
Authors: Karen Bjorn-Mortensen, Troels Lillebaek, Anders Koch, Bolette Soborg, Karin Ladefoged, Hans Christian Florian Sørensen, Thomas Andreas Kohl, Stefan Niemann, Aase Bengaard Andersen
Journal: European Respiratory Journal (2017)

We have previously documented a high incidence of tuberculosis (TB) (>1000 per 100 000 inhabitants) and considerable Mycobacterium tuberculosis transmission in East Greenland despite population-wide screenings implemented by the Greenland health authorities [1–5]. In Greenland, all contacts of TB patients are routinely screened for M. tuberculosis infection and TB. Individuals with newly acquired M. tuberculosis infection are offered 6 months of preventive isoniazid treatment. Despite the considerable resources spent on clinical examinations and preventive treatment over the years, TB incidence rates have remained high in East Greenland [1]. In a TB endemic setting >50% of culture-positive TB cases were likely infected via community acquired transmission <http://ow.ly/Rqjd307cf6o> The authors thank the hospital staff in Tasiilaq for identifying and treating TB patients, the National Board of Health for support and access to data, and laboratory staff at the IRLM and Forschungszentrum Borstel for DNA extraction, library preparation and WGS. All authors contributed to the conception and design of the study, the analyses of data and writing of the article.
Breaking the bad news: Experiences of contingency in advanced cancer patients.
Authors: Egbert J. van Dalen, Michael Scherer-Rath, Chris A.M. Hermans, Hanneke W.M. Van Laarhoven
Journal: Journal of Clinical Oncology (2012)

e19560 Background: The diagnosis of advanced cancer implies a radical change in a patient’s future outlook. The way patients interpret this change can be understood in terms of emotion and contingency theory. Events which seem to come out of the blue and augur unforeseen consequences are difficult to interpret and attribute meaning to. They can cause so-called experiences of contingency, in which the subject is in a state of being lost and faces an uncertain future fraught with vague and threatening possibilities. The aim of this study is to understand this experience that can affect a person’s fundamental beliefs. Methods: Patients with advanced cancer, not amenable to curative treatment, with a Karnofsky performance score of ≥ 70 and good command of the Dutch language were asked for participation. Patients were interviewed once, at their homes. The tape-recorded and transcribed interviews were analyzed within the framework of grounded theory. Codes were arranged along the dimensions of probability of the event and emotional impact, which influence each other. Results: 56 patients with an average age of 62 years were included in the study. Breast cancer, colorectal cancer and renal cell cancer were the most common cancer types. The average time since the diagnosis of advanced cancer was two years. 32 % of the patients were able to interpret the bad news and react calmly. However, for 68 % of the patients the event had a high emotional impact and the limits of their interpretation framework were exceeded, as evidenced by the spontaneous and highly frequent use of metaphors pointing towards the collapse of their reality. They perceived their existence as being contingent. Receiving the bad news unexpectedly shook the very foundations of their lives for reasons related to loss of confidence in life. Conclusions: The experience of contingency can be understood in terms of shaken confidence and implies an existential confrontation with life as a power which cannot always be controlled. Confidence in life can be regained after acknowledging one’s boundaries, accepting the new future perspective and finding a new attitude towards life.
Low-dose oral cyclophosphamide-methotrexate maintenance (CMM) for receptor-negative early breast cancer (BC).
Authors: Marco Colleoni, Kathryn P. Gray, Shari I. Gelber, Istvan Lang, Beat J. K. Thurlimann, Lorenzo Gianni, Ehtesham A. Abdi, Karen N. Price, Richard D. Gelber, Giuseppe Viale, Alan S. Coates, Aron Goldhirsch
Journal: Journal of Clinical Oncology (2015)

1002 Background: IBCSG Trial 22-00 was designed to test the efficacy of the CMM regimen, hypothesized to have anti-angiogenic activity, administered following standard chemotherapy in patients (pts) whose tumors are hormone receptor negative. Methods: 1,086 women (ITT 1081) with hormone receptor-negative ( < 10% positive cells by IHC) early BC, any nodal and HER-2 status were randomized to CMM (C, cyclophosphamide 50 mg/day orally continuously and M, methotrexate 2.5 mg twice/day orally days 1 and 2 of every week for 1 year) vs no further treatment (no CMM). 814 (75%) had triple-negative (TN) BC and 350 (43%) of them had node positive (N+) disease. The primary end point was disease free survival (DFS), and 307 DFS events were required for 80% power. Results: At 82.6 months’ median follow-up, 271 DFS events had been observed. Overall, 71 (13%) of 527 pts randomized to CMM did not receive CMM therapy and only 177 (39%) of the 456 pts who started received 75% or more of the scheduled doses. Nevertheless, pts assigned to CMM had a reduced risk of a DFS event compared with no CMM, which was not statistically significant (p = 0.14; table). The magnitude of effect appeared to be greater for those with TNBC, especially for those with N+ disease. Multivariable allowance for baseline prognostic factors suggested a greater treatment effect within those with TN and N+ BC. A total of 64 pts, 13.5% of those receiving at least one dose of CMM, had a grade 3 or 4 treatment-related AE. Elevated SGPT was most frequently reported, followed by leukopenia. Conclusions: Adding CMM to adjuvant chemotherapy showed a non-significant 16% reduction in risk of a DFS event in the overall population of hormone receptor-negative early BC. Women with TN disease at higher risk of recurrence, for whom no maintenance regimen is currently available, had a greater benefit. Clinical trial information: NCT00022516. Group Treatment No. of Patients DFS events 5-year DFS % Univariate HR (95% CI) Multivariable HR (95% CI) All pts CMM 542 124 78.1% 0.84 (0.66, 1.06) 0.82 (0.65,1.05) No CMM 539 147 74.7% TN CMM 408 89 78.7% 0.80 (0.60, 1.06) 0.79 (0.60,1.04) No CMM 406 110 74.6% TN & N+ CMM 175 48 71.9% 0.71 (0.49, 1.03) 0.68 (0.47, 0.99) No CMM 175 64 64.2%
A randomized control trial (RCT) of an online, symptom self-management curriculum (Reimagine) among breast cancer survivors.
Authors: Sophia Kustas Smith, Kristin MacDermott, Sathya Amarasekara
Journal: Journal of Clinical Oncology (2017)

182 Background: Chronic pain, depression, and fatigue are common effects resulting from the cancer experience (e.g., disease, treatment); new interventions are needed. Reimagine is an online symptom self-management program that teaches coping skills. This presentation will report on the impact of Reimagine on key health outcomes. Methods: Adult breast cancer survivors with chronic pain were recruited from the Susan Love Army of Women volunteer registry. Consenting participants were randomized 1:1 to the treatment or usual care condition and completed surveys at Baseline and 18 weeks (post-intervention). Treatment arm participants accessed content online; required activities included viewing online videos, attending online group meetings, and completing cognitive reframing exercises. Surveys were administered via REDCap to assess for pain severity and interference (primary outcome), depression, fatigue, and program satisfaction. An independent-samples t-test was conducted to compare change in pain, depression, and fatigue outcomes in treatment and usual care conditions. Results: Participants (n = 91) were: mean age 56.4 ± 8.8 years; 99% female; 94% white; 67% married; 46% employed; mean time since diagnosis 7.9 ± 6.4 years; and 89% were in remission or cured of their breast cancer. There was a significant difference in the change in depression scores for treatment (M = -1.7, SD = 4.7) and usual care (M = 0.3, SD = 3.8) conditions; t (82) = -2.1, p = 0.035. Difference in the change in fatigue scores was significant for treatment (M = 4.8, SD = 9.1) and usual care (M = 1.2, SD = 6.6) conditions; t (84) = 2.1, p = .038. No significant differences were found in the change in pain outcomes for treatment and usual care conditions (p &gt; .05). Most treatment arm participants (94%) would recommend Reimagine to others and 85% felt more resilient at study completion. Conclusions: These results suggest that Reimagine has an effect on depression and fatigue symptoms for breast cancer survivors. Additional research is recommended with larger and more diverse samples. Trial (NCT02465892) was funded by Pfizer, Inc. Clinical trial information: NCT02465892.
Interim analysis of a phase 2 study of lenvatinib (LEN) monotherapy as second-line treatment in unresectable biliary tract cancer (BTC).
Authors: Chigusa Morizane, Makoto Ueno, Takashi Sasaki, Fumio Nagashima, Nobumasa Mizuno, Satoshi Shimizu, Nozomi Hayata, Hiroki Ikezawa, Takuya Suzuki, Ryo Nakajima, Corina E. Dutcus, Masafumi Ikeda
Journal: Journal of Clinical Oncology (2017)

310 Background: LEN inhibits the activity of vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor–α. These targets have been shown to be expressed in patients (pts) with BTC. The objective of this study is to evaluate LEN as a potential treatment option for these pts. Methods: This is an open-label, phase 2 study conducted in Japan. Pts aged ≥ 20 years with confirmed diagnosis of unresectable BTC, measureable disease per Response Evaluation Criteria in Solid Tumors v1.1, and 1 prior gemcitabine-based doublet chemotherapy, will receive LEN 24 mg/d. The primary endpoint is objective response rate. Secondary objectives include disease control rate (DCR), safety, and pharmacokinetics. Enrollment of 25 pts is planned. The study includes an interim evaluation for futility. If there is no objective response and disease control is achieved in &lt; 5 pts of 15‒17 pts, the study will end. Results: An interim evaluation was performed with 17 pts enrolled (data cutoff: 25 July 2016). Ten (59%) pts were aged &lt; 65 years, 10 (59%) were male, 2 (12%) had prior surgery, and 13 (76%) received prior gemcitabine + cisplatin therapy. Efficacy results appear in the table. One pt had a partial response (PR) and 13 had stable disease (SD). The DCR was 82%. All pts experienced treatment-emergent adverse events (TEAEs). Grade ≥ 3 TEAEs occurred in 11 (65%) and serious AEs (SAEs) occurred in 7 (41%) pts. There were no fatal SAEs. TEAEs leading to LEN discontinuation, dose reduction, and dose interruption occurred in 1 (6%), 12 (71%), and 9 (53%) pts, respectively. Analysis of trough plasma concentration in 13 pts from this study showed no difference versus that observed in a previous phase 3 study of LEN in differentiated thyroid cancer. Conclusions: Because results of this interim evaluation did not meet futility criteria, the study was continued, with findings suggesting possible activity of LEN in pts with unresectable BTC who failed gemcitabine-based doublet chemotherapy. Toxicities were generally manageable with dose modifications as only 1 pt required discontinuation from LEN. Clinical trial information: NCT02579616. [Table: see text]
Outcomes of cancer treatment for technology assessment and cancer treatment guidelines. American Society of Clinical Oncology.
Journal: Journal of Clinical Oncology (1996)

In 1993, the Health Services Research Committee of the American Society of Clinical Oncology (ASCO) charged an Outcomes Working Group with defining the outcomes of adult and pediatric cancer treatment to be used for technology assessment and development of cancer treatment guidelines. The Working Group defined by consensus outcomes for technology assessment and guideline development, focusing on cancer treatments. The Working Group considered a variety of perspectives on outcomes, including those of patients, physicians, clinical investigators, ASCO, and policy makers. Because ASCO's guidelines will define what constitutes the best treatment and not whether that treatment should be paid for, the Working Group gave higher priority to the clinical and clinical research perspectives than to the health policy perspective. Survival is the most important outcome of cancer treatment. An improvement in at least disease-free survival is a prerequisite for recommending adjuvant therapy. In the case of metastatic cancer, treatment can be recommended even without an improvement in survival, if it improves quality of life. Quality of life includes global quality of life, as well as its physical, psychologic, and social dimensions. To be an outcome of cancer treatment, quality-of-life measures must be sensitive to clinically meaningful changes produced by treatment; evaluations must control for placebo effects and determinants of quality of life not related to cancer or its treatment. Toxicity, both short and long term, is vitally important, with the latter being particularly critical in children. The value of cancer outcomes like tumor response (eg, complete or partial response) and biomarkers (eg, CA-125) for technology assessment and guideline development depends on their ability to predict patient outcomes (survival and quality of life) or to influence decisions about treatment. Complete response is an important outcome when it predicts survival. Progression is important because it signals the need to change or stop treatment. Cost-effectiveness is an especially important outcome to consider when the benefits of treatment are modest or the costs are high. Patient outcomes (eg, survival and quality of life) should receive higher priority than cancer outcomes (eg, response rate), but both types of outcomes are important in technology assessment and guideline development. Multiple outcomes should be considered because no single outcome adequately describes the results of cancer treatment. In general, there is no minimum benefit above which treatments are justified; rather, benefits should be balanced against toxicity and cost.