tbuckley/cabot-search huggingface dataset:
Glutaminase (PEG-PGA) increases antitumoral efficacy of cytotoxic agents
Authors: R. Harzmann, N. Esser, R. Loewe, J. Roberts, F. Leenders, W. Seifert, C. Unger, J. Drevs
Journal: Journal of Clinical Oncology (2004)

3183 Background: Glutamine is essential for the survival of cancer cells. It is therefore a possible target for cancer therapy. Glutaminase (PEG-PGA) depletes the glutamine serum level and withdraws the supply of glutamine to the neoplastic cells. The tumor cells begin to either arrest in the cell cycle or enter apoptosis. This study investigated the combination of PEG-PGA with different cytotoxic agents in vitro and in vivo. Methods: Different cancer cell lines (HCT-15, HT29, SW-60, SF-539, A549, DMS-114, NCI-H23, NCI-H460, MCF7) were incubated with PEG-PGA and in addition perfused with different cytotoxic agents (6-Diazo-5-oxo-L-norleucine [DON], Actinomycin D, Mitomycin, Mitoxantrone, Cisplatin, Melphalan, Etoposid, 5FU,antracyclines, Paclitaxel and Tamoxifen). After fixation the cells were incubated with Sulfohodamin B and measured photometric at 575 nm absorption. In vivo, A549 cells were implanted subcutaneously into nude mice. Treatment was initiated after visible tumors had developed. Mice were treated with either PEG-PGA, DON, Cisplatin, the combination of DON and Cisplatin with PEG-PGA or vehicle. Tumor volumes and animal weights were taken every other day. Results: The combination of PEG-PGA with cytotoxic agents showed statistically significant increased activity in vitro. This finding could be confirmed by the in vivo study. Here, the combination of PEG-PGA and DON was more effective than the mono-therapy with DON. The efficacy of Cisplatin was synergistically increased by PEG-PGA as well, nevertheless, this finding was accompanied by an increase in toxicity. Conclusion: PEG-PGA is a promising new therapeutic reagent for the use in combination with cytotoxic agents to increase antitumoral efficacy. Therefore, PEG-PGA should enter phase I trials using cisplatin or other chemotherapeutics. No significant financial relationships to disclose.
Creating a multi-payer provider database for cancer outcomes research.
Authors: Anne-Marie Meyer, David Barkhurst, Adrian Meyer, Saray Shai, Justin G Trogdon, Peter Mucha
Journal: Journal of Clinical Oncology (2017)

138 Background: Cancer care is multi-disciplinary in nature and relationships between healthcare providers may potentially influence outcomes. Yet understanding how patient care or outcomes are affected by these relationships has been hindered by the paucity of temporal and multi-relational data on physicians. We demonstrate a method for uniquely identifying and linking providers across multiple databases longitudinally. Methods: We identified unique, individual healthcare providers in Medicare, Medicaid, and private payer data in North Carolina (NC) from 2003-2014. In order to link the providers between the different identifiers (e.g., NPI, UPIN, etc.), five provider data sets were obtained. These databases included the National Plan and Provider Enumeration System (NPPES), the Medicare Physician Identification and Eligibility Records (MPIER), the NC State Medicaid provider file, private payer provider files and the NC medical license file. Identification and linking was performed using a novel approach leveraging relational database tools in Oracle and then verified via a second approach applying network analysis in Python. Sub-set validation was performed using claims from cancer cohorts in NC with continuous enrollment in multiple payers. Results: There was significant variation in data quality as well as temporal and geographic overlap between datasets. Linking across all data resulted in a Cartesian product of over 50 billion combinations. This was overcome by aligning provider identifiers under unique combinations of matching variables (given name, last name, zip code and specialty). From all five datasets, approximately 158,000 unique physicians were identified. In subset validation, the NPI and UPIN matches agreed 99-100% with the 2008 Medicare professional claims in a cohort of NC cancer patients. The NPI and private provider ID matches agreed between 73-79% of the time for those cancer patients with claims aligned in both payers. However, only about 30% of the Medicaid provider IDs were individually attributable and matched. Conclusions: Providers can be uniquely identified and matched across disparate databases enabling us to measure and contrast provider networks and their variation across payers and systems.
A phase I study of biweekly combination chemotherapy with gemcitabine (GEM) and carboplatin (CBDCA) for inoperable stages IIIB and IV non-small-cell lung cancer (NSCLC)
Authors: Y. Hasegawa, S. Takanashi, H. Nakagawa, K. Okudera, M. Kumagai, A. Hayashi, T. Morimoto, K. Taima, K. Okumura
Journal: Journal of Clinical Oncology (2004)

7237 Background: The purpose of this study was to determine maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of a combination of gemcitabine plus carboplatin administration in a biweekly schedule for inoperable NSCLC. Methods: Patients with inoperable stages IIIB and IV NSCLC included in this study were treated with carboplatin followed by gemcitabine. Carboplatin was given intravenously over 30 minutes, and gemcitabine was given intravenously over 30 minutes. Results: Fifteen patients were treated at 4 dose levels. As DLT, treatment delay occurred at dose level 4 in 2 of the 6 patients. No DLT was experienced in dose levels 1, 2, and 3. No other grade 3/4 toxicity was observed. Twelve patients were available for evaluation of efficacy. Four patients achieved partial response. Conclusions: MTD was not reached in this study. Considering the treatment continuation, the recommended dose for phase II study is carboplatin AUC 3 and gemcitabine 1000mg/m2 administration every 2 weeks. No significant financial relationships to disclose.
Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia
Authors: Hiroshi Okuda, Boban Stanojevic, Akinori Kanai, Takeshi Kawamura, Satoshi Takahashi, Hirotaka Matsui, Akifumi Takaori-Kondo, Akihiko Yokoyama
Journal: Journal of Clinical Investigation (2017)

The eleven-nineteen leukemia (ENL) protein family, composed of ENL and AF9, is a common component of 3 transcriptional modulators: AF4-ENL-P-TEFb complex (AEP), DOT1L-AF10-ENL complex (referred to as the DOT1L complex) and polycomb-repressive complex 1 (PRC1). Each complex associates with chromatin via distinct mechanisms, conferring different transcriptional properties including activation, maintenance, and repression. The mixed-lineage leukemia (MLL) gene often fuses with ENL and AF10 family genes in leukemia. However, the functional interrelationship among those 3 complexes in leukemic transformation remains largely elusive. Here, we have shown that MLL-ENL and MLL-AF10 constitutively activate transcription by aberrantly inducing both AEP-dependent transcriptional activation and DOT1L-dependent transcriptional maintenance, mostly in the absence of PRC1, to fully transform hematopoietic progenitors. These results reveal a cooperative transcriptional activation mechanism of AEP and DOT1L and suggest a molecular rationale for the simultaneous inhibition of the MLL fusion-AF4 complex and DOT1L for more effective treatment of MLL-rearranged leukemia.
Quality of care improvements resulting from a model of care that incorporates the primary clerk into the care team.
Authors: Jennifer Anne Cox, Caroline Hamm
Journal: Journal of Clinical Oncology (2017)

122 Background: One common model of care within the oncology outpatient clinic setting is composed of the physician and primary nurse. We propose that the quality of care provided to oncology patients can be improved in this setting by incorporating the primary clerk into the care team, working in the same office space with the physician and nurse. Methods: Three care teams operating under the new model of care were observed during oncology outpatient clinics periodically from February 2016 to May 2016. The primary clerk’s interactions with the other team members were recorded, along with other tasks completed by the clerk that did not require team interactions but impacted quality of care. Data was later complied and organized into four domains that impacted the quality of care provided to patients. Results: The contributions to the care team by the primary clerk include improved clinic flow (e.g., ensuring treatment orders are inputted by the physician), patient convenience (e.g., identifying regularly scheduled blood work that is no longer necessary), patient safety (e.g., identifying patients scheduled for treatment with rituximab that have not had the required Hepatitis B &amp; HIV screening), and hospital flow (e.g., preventing additional workload in the hospital laboratory by identifying when lab work can be combined in already scheduled appointments, and rescheduling clinic visits when results are not yet ready, which translates into time and cost savings to the hospital). Conclusions: As a result of the enhanced quality of care delivered, it is recommended that this model of care be adopted in the place of the traditional model, which lacks the essential element of interaction between the primary clerk and the rest of the care team.
First-in-human evaluation of CO-1686, an irreversible, selective, and potent tyrosine kinase inhibitor of EGFR T790M.
Authors: Lecia V. Sequist, Jean-Charles Soria, Shirish M. Gadgeel, Heather A. Wakelee, D. Ross Camidge, Andrea Varga, Panos Fidias, Antoinette J. Wozniak, Joel W. Neal, Robert Charles Doebele, Edward B. Garon, Sarah S. Jaw-Tsai, Jennifer C. Stern, Andrew R. Allen, Jonathan Wade Goldman
Journal: Journal of Clinical Oncology (2013)

2524 Background: Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 50% of patients, and significant skin rash and diarrhea, caused by wild-type (WT)-EGFR inhibition, compromises tolerability. CO-1686 is an orally active TKI that targets common activating EGFR mutations and T790M, while sparing WT-EGFR. Animal models suggest maximal efficacy when trough plasma concentrations exceed 200ng/ml. Methods: This is a first in human phase 1 (3+3) dose-finding study of oral CO-1686, administered continuously in 21-day cycles. To be eligible, patients must have EGFR-mutant NSCLC and prior therapy with an EGFR TKI. Endpoints include safety, pharmacokinetics (PK), and efficacy. All patients undergo a biopsy for genotyping before starting study drug. Results: As of 18 Jan 2013, 35 patients (18/28 (64%) T790M+; 7 pending) have been treated with CO-1686. Dosing started at 150mg QD and escalated in steps to 900mg QD, 600mg BID and 400mg TID, with a maximum tolerated dose not yet reached. A recommended phase 2 dose is expected to be reached soon. Related AEs of grade 3 or higher were hypoglycaemia (n=1) and hyperglycaemia (n=1). AEs typical of WT-EGFR inhibition (rash, diarrhea) have not been observed. Dose-proportional PK was observed; plasma half-life was 4-5 hrs and at 900mg QD Cmax=3000ng/ml but trough concentrations were &lt; 200ng/ml. At ≥300mg BID and TID dosing, trough concentrations can exceed 200ng/ml. At 900mg QD, 2 of 3 patients showed clinical benefit after 2 cycles of CO-1686 including one with clinically-relevant tumor shrinkage (18%) and a second with stabilization of a pleural effusion that had previously required repeat thoracenteses at ~10 day intervals. At 300mg BID, one patient (Del(19)/T790M+) with PK trough concentration &gt;200ng/ml exhibited significant tumor shrinkage (29%) after 2 cycles. Further efficacy data from BID/TID cohorts and centrally-confirmed genotypes will be presented at the meeting. Conclusions: CO-1686 offers potential for improved activity and better tolerability over current EGFR TKIs, particularly in the treatment of T790M+ disease, an area of high unmet clinical need. Clinical trial information: NCT01526928.
Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis
Authors: Mathew S. Maurer, Perry Elliott, Raymond Comenzo, Marc Semigran, Claudio Rapezzi
Journal: Circulation (2017)

Advances in cardiac imaging have resulted in greater recognition of cardiac amyloidosis in everyday clinical practice, but the diagnosis continues to be made in patients with late-stage disease, suggesting that more needs to be done to improve awareness of its clinical manifestations and the potential of therapeutic intervention to improve prognosis. Light chain cardiac amyloidosis, in particular, if recognized early and treated with targeted plasma cell therapy, can be managed very effectively. For patients with transthyretin amyloidosis, there are numerous therapies that are currently in late-phase clinical trials. In this review, we address common questions encountered in clinical practice regarding etiology, clinical presentation, diagnosis, and management of cardiac amyloidosis, focusing on recent important developments in cardiac imaging and biochemical diagnosis. The aim is to show how a systematic approach to the evaluation of suspected cardiac amyloidosis can impact the prognosis of patients in the modern era.
Use of patient-reported outcome measures in Quality Oncology Practice Initiative registered practices: Results of a national survey.
Authors: Biqi Zhang, Whitney Lloyd, Mohammad Jahanzeb, Michael J. Hassett
Journal: Journal of Clinical Oncology (2017)

81 Background: Measuring patient-reported outcomes (PROs) improves the experience of care and reduces the burden of disease for cancer patients. Professional societies, including ASCO, encourage the collection of PROs, but little is known about how many practices collect PROs and, if so, which PROs are measured and what challenges are met in implementation. Methods: We surveyed Quality Oncology Practice Initiative (QOPI) registered practices to understand the current state of PROs use and identify areas where greater support for PROs implementation may be needed. One respondent from each practice was invited to complete an online survey that assessed views regarding PROs and challenges with implementation. Non-users were asked about their interest in and barriers to future collection of PROs. Results: Of 233 practices that viewed the request to participate, 109 completed the survey (47%). Most responding practices (73%) currently collect PROs. Of these, 79% are affiliated with hospitals/medical centers, 50% have &gt; 10 advanced practice providers, and 94% use electronic health records. PROs users see a higher volume of patients per week than non-users (p &lt; 0.01). QOPI-registered practices collect a wide variety of PROs, including validated and home-grown questionnaires. The most commonly measured PROs are distress (78%), symptom assessment (76%), and experience/satisfaction (70%). The most frequently reported implementation challenges were the same for users and non-users: patient unwillingness to complete questionnaires (34%) and insufficient staff to support collection (29%). Despite only moderate perceived patient willingness to answer PROs (2.67/5), 79% of all practices believe collecting PROs is a high priority. Conclusions: While many QOPI practices have implemented PROs, substantial barriers to implementation are apparent and may be limiting more wide-spread adoption. Efforts to identify which PROs most improve care quality are sorely needed. Sharing best practices on improving patient/provider buy-in and enabling efficient integration of PROs into clinic workflow may also facilitate adoption and maximize the utility of PROs for oncology practices.
Opioid rotation prospective longitudinal study
Authors: D. Walsh, M. P. Davis, B. Estfan, S. B. Legrand, R. L. Lagman, P. Shaheen
Journal: Journal of Clinical Oncology (2004)

8258 Background: Cancer pain can be adequately controlled by using opioids around-the-clock with provision for rescue dosing. Some develop uncontrolled side-effects or do not respond to the initial opioid and require opioid rotation. In previous studies 24 -42% required opioid rotation. We evaluated the number, reason and sequence with opioid rotation. Method: Between October 13 and December 12, 2003, 164 consecutive patients were prospectively followed by the palliative service. Initial opioid, the reason for rotation, rotations and the sequence of opioid use and route were followed longitudinally. Some were on multiple opioids or were receiving opioids by routes at the time of consultation. Results: Ninety-eight of 164 patients had cancer pain. Thirty-nine (40%) were rotated once. Ten required a second rotation (10%) three a third and one a fourth. Initial opioids were morphine (28%), hydromorphone (13%), methadone (3%), fentanyl (26%) oxycodone (56%) and other (14%). Rotations were to morphine (54%) and methadone (26%) which together accounted for 80% of second opioids. Reasons for rotation were side-effects and/or ineffectiveness (56%). Dose and route convenience and/or cost accounted for 26% of rotations and neuropathic pain 8%, other was 10%. Route changes were to oral or intravenous in 92% and subcutaneous in 8%. Conclusion: Opioid rotation was necessary in 40% of patients. A major reason for rotation was opioid ineffectiveness and/or side-effects. The most commonly used second opioids were morphine and methadone. No significant financial relationships to disclose.
Revised British Society of Gastroenterology recommendation on the diagnosis and management of Barrett's oesophagus with low-grade dysplasia
Authors: Massimiliano di Pietro, Rebecca C Fitzgerald
Journal: Gut (2017)

The most recent guidelines for the management of Barrett's oesophagus published in 2014 recommended endoscopic surveillance for patient with histological evidence of low-grade dysplasia (LGD) on random biopsies.1 In the last 2 years, new evidence on the natural history of LGD in Barrett's oesophagus and on the safety and efficacy of endoscopic treatment in this subgroup of patients has been published.

Duits et al have conducted a retrospective analysis of 293 patients with LGD diagnosed in community hospitals.2 Following consensus review, the original LGD diagnosis was confirmed in 27% of cases, while the remaining of the cases were downgraded to non-dysplastic Barrett's oesophagus or indefinite for dysplasia (IND). Patients with a LGD consensus diagnosis had a progression rate to high-grade dysplasia (HGD) or cancer of 9.1%/year over a median follow-up of 39 months. By contrast, patients whose diagnosis was down-staged to either non-dysplastic Barrett's oesophagus or IND had a conversion rate of 0.6% and 0.9%/year, respectively (evidence grade: low). This study reiterates the difficulty in …
Improved clinical trial enrollment criterion to identify patients with diabetes at risk of end-stage renal disease
Authors: Masayuki Yamanouchi, Jan Skupien, Monika A. Niewczas, Adam M. Smiles, Alessandro Doria, Robert C. Stanton, Andrzej T. Galecki, Kevin L. Duffin, Nick Pullen, Matthew D. Breyer, Joseph V. Bonventre, James H. Warram, Andrzej S. Krolewski
Journal: Kidney International (2017)
Trend for better survival after the introduction of oral fluoropyrimidine, S-1, in patients with recurrent gastric cancer (RGC)
Authors: O. Kobayashi, H. Murakami, T. Yoshida, T. Yoshikawa, A. Tsuburaya, M. Sairenji, H. Notohashi
Journal: Journal of Clinical Oncology (2004)

4174 Background: Although early detection system and radical lymph node dissection have appeared to improve treatment results for primary gastric cancer in Japan, post-recurrence course is detrimental and improvement in survival is in doubt. Since S-1 has been introduced in Japan in 1999 after having achieved high response rates in phase II trials, it has come to be hoped as a candidate for standard drug for gastric cancer. In order to identify the efficacy of S-1 as first-line monotherapy for RGC, we studied the clinical course of the patients with RGC treated with S1 and those treated with FLP as a control; the regimen had been our chief one prior to the introduction of S1. Methods:A total of 111 patients with RGC whose performance status (PS) was ≤1, were treated with either FLP [5-FU 250mg/m2 at day1–14, Leucovorin 30mg and Cisplatin 10mg/body at day1,3,5,7,9,11,13; every 4 weeks] for 79 cases between 1988 and 99, or S-1 [40 mg/m2/body b.i.d. for 4 weeks, every 6 weeks] for 32 cases between 1999 and 02 at Kanagawa Cancer Center. Both groups of patients had been followed up by tumor marker and CAT scan twice a year and the DFS (median) was 494 days for FLP group and 558 days for S1 group. Results: The age and sex of both groups were not different. PS \(\frac{0}{1}\) and prior adjuvant chemotherapy [-/+] for FLP and S1 groups were \(\frac{36}{43}\) vs. \(\frac{22}{10}\) (p=0.03) and \(\frac{16}{63}\) vs. \(\frac{6}{15}\) (p=0.01), respectively. Recurrent sites were peritoneum in 25, liver in 24, lung and bone in 17, lymph node in 34, local in 7, and ovary in 4 patients. Median course was 2 for FLP and 3 for S-1. Response rate was 40% for FLP group and 34% for S-1 group (NS). Median survival after recurrence (MST) was 212 days for FLP group and 404 days for S-1 group, respectively (p=0.004). Second-line chemotherapy was possible for 2 cases in FLP group by S-1 and for 11 cases in S-1 group by paclitaxel. MST of the patients who received S-1 and paclitaxel sequentially was 526 days. Conclusions: Survival after recurrence in patients with RGC was prolonged by 7 months after the introduction of S-1. Feasible monotherapy sequence may impact on survival for those patients. No significant financial relationships to disclose.
Vancomycin-intermediate Staphylococcus aureus isolates are attenuated for virulence when compared with susceptible progenitors
Authors: D.R. Cameron, Y.-H. Lin, S. Trouillet-Assant, V. Tafani, X. Kostoulias, E. Mouhtouris, N. Skinner, K. Visvanathan, S.L. Baines, B. Howden, I.R. Monk, F. Laurent, T.P. Stinear, B.P. Howden, A.Y. Peleg
Journal: Clinical Microbiology and Infection (2017)

Vancomycin-intermediate Staphylococcus aureus (VISA) is associated with genetic changes that may also impact upon pathogenicity. In the current study, we compared the virulence of clinical VISA strains with their isogenic vancomycin-susceptible progenitors (VSSA).Production of the critical virulence protein, α toxin, was assessed using Western blot analysis and was correlated to agr activity using a bioluminescent agr-reporter. Cytotoxicity and intracellular persistence were compared ex vivo for VSSA and VISA within non-professional phagocytes (NPP). Virulence and host immune responses were further explored in vivo using a murine model of bacteraemia.VISA isolates produced up to 20-fold less α toxin compared with VSSA, and this was corroborated by either loss of agr activity due to agr mutation, or altered agr activity in the absence of mutation. VISA were less cytotoxic towards NPP and were associated with enhanced intracellular persistence, suggesting that NPP may act as a reservoir for VISA. Infection with VSSA strains produced higher mortality in a murine bacteraemia model (≥90% 7-day mortality) compared with infection with VISA isolates (20% to 50%, p <0.001). Mice infected with VISA produced a dampened immune response (4.6-fold reduction in interleukin-6, p <0.001) and persistent organ bacterial growth was observed for VISA strains out to 7 days.These findings highlight the remarkable adaptability of S. aureus, whereby, in addition to having reduced antibiotic susceptibility, VISA alter the expression of pathogenic factors to circumvent the host immune response to favour persistent infection over acute virulence.