tbuckley/cabot-search huggingface dataset:
Therapy of gastrointestinal malignancies with an anti-Trop-2-SN-38 antibody drug conjugate (ADC) (sacituzumab govitecan): Phase I/II clinical experience.
Authors: Alexander Starodub, Allyson J. Ocean, Wells A. Messersmith, Vincent J. Picozzi, Michael J. Guarino, Aditya Bardia, Sajeve Samuel Thomas, Jordan Berlin, Manish A. Shah, Pius P Maliakal, William A. Wegener, Robert M. Sharkey, Francois Wilhelm, David M. Goldenberg
Journal: Journal of Clinical Oncology (2015)

3546 Background: Sacituzumab govitecan (IMMU-132) is a conjugate of a humanized anti-Trop-2 (trophoblast cell-surface antigen) coupled site-specifically to SN-38 (7.6 moles SN-38/IgG), an active metabolite of irinotecan, using a proprietary linker. Trop-2 is widely expressed in most epithelial cancers, including gastrointestinal (GI) tumors, and therefore the safety and efficacy of this new ADC is being examined in esophageal (EAC), gastric (GC), pancreatic (PC), and colorectal cancers (CRC). Methods: A Phase I/II clinical trial (ClinicalTrials.gov, NCT01631552) was initiated in patients with diverse epithelial cancers, administering IMMU-132 i.v. on days 1 and 8 of 21-day treatment cycles. Treatment was continued based on tolerance or until progression. Results: In Phase I, 23 assessable pts were given 8, 10, 12, or 18 mg/kg. Dose-limiting neutropenia occurred at 18 mg/kg. For Phase II, enrollment was expanded to multiple cycles of 8 and 10 mg/kg. Safety data from 123 patients given 8-10 mg/kg showed neutropenia (G3, 18%; G4, 6%), febrile neutropenia (G3, 2%; G4, 2%), but only 3% G3 diarrhea (no G4). Other G3 toxicities included anemia (6%), fatigue (5%), leucopenia (2%), vomiting (2%), and asthenia (1%). No pt developed antibodies to the ADC. Among assessable patients by RECIST 1.1, of 15 EAC pts (median 3 prior therapies), 2 had PR (1 confirmed, duration 6 mo, 1 continuing; 13% ORR), and 7 (46%) SD (median time to progression (TTP) = 5.0 mo). All 3 GC pts had SD (one continuing for 11 mo). Of 14 PC pts (median 2 prior therapies), 7 (50%) had SD with a median TTP of 3.4 mo. In 26 CRC pts (median 4 prior therapies), there was 1 PR (confirmed, duration 10 mo), 14 SD (54%), and a median TTP of 5.1 mo. Conclusions: Repeated cycles of IMMU-132 monotherapy are well tolerated with seemingly more favorable neutropenia and diarrhea rates compared to irinotecan. Objective responses in esophageal cancer and extended stabilization in colorectal cancers are encouraging for this monotherapy. The manageable toxicity and promising disease control in these pts warrant further study in combination with other appropriate agents for GI malignancies. Clinical trial information: NCT01631552.
Strengthening Integrated Care Through Population-Focused Primary Care Services: International Experiences Outside the United States
Authors: Rene Loewenson, Sarah Simpson
Journal: Annual Review of Public Health (2017)

Many high- and middle-income countries (HMICs) are experiencing a burden of comorbidity and chronic diseases. Together with increasing patient expectations, this burden is raising demand for population health–oriented innovation in health care. Using desk review and country case studies, we examine strategies applied in HMICs outside the United States to address these challenges, with a focus on and use of a new framework for analyzing primary care (PC). The article outlines how a population health approach has been supported by focusing assessment on and clustering services around social groups and multimorbidity, with support for community roles. It presents ways in which early first contact and continuity of PC, PC coordination of referral, multidisciplinary team approaches, investment in PC competencies, and specific payment and incentive models have all supported comprehensive approaches. These experiences locate PC as a site of innovation, where information technology and peer-to-peer learning networks support learning from practice.
The addition of imatinib mesylate to estramustine/docetaxel (E/D) for the treatment of hormone refractory prostate cancer (HRPC) patients: Results of a phase I trial
Authors: M. Randall, B. Rini, C. Ryan, J. Rosenberg, J. Garcia, G. Bubley, E. J. Small
Journal: Journal of Clinical Oncology (2004)

4617 Background: The E/D combination is used widely to treat metastatic HRPC. Imatinib mesylate inhibits the platelet-derived growth factor receptor which is overexpressed in HRPC, and is synergistic with docetaxel in preclinical models. A phase I trial of E/D was therefore undertaken to determine the maximum tolerated dose of docetaxel in this combination. Methods: Metastatic HRPC patients with progressive disease by Consensus Criteria and no prior chemotherapy or investigational therapy were treated in a standard phase I design. All patients received therapy every 21 days consisting of fixed doses of estramustine phosphate, (280 mg po tid D 1–5) dexamethasone (8 mg po bid D 1–3), warfarin (2 mg po qd) and imatinib (400 mg po qd D 1–21). Docetaxel on day 1 was dose-escalated by cohort from 50 to 60 to 70 mg/m2 iv. Results: A total of 13 patients were treated. On dose level 3 (400 mg qd imatinib, 70 mg/m2 docetaxel), 2 patients experienced grade 3 elevated prothrombin times attributed to the interaction between imatinib and warfarin, so an additional 3 patients were treated at an intermediate level utilizing 300 mg qd imatinib and 60 mg/m2 docetaxel. While this dose level was initially established as the recommended phase II level, overall in the entire study, 5/13 patients had unacceptable toxicity as defined by the protocol, which exceeded pre-specified boundaries, mandating study closure. These events were thromboembolic in nature and included 2 cerebrovascular accidents, 1 myocardial infarct, 1 mesenteric ischemia and 1 deep vein thrombosis. Conclusions: The combination of estramustine, docetaxel and imatinib results in excessive thromboembolic toxicity, potentially due to interactions between estramustine, a known thrombogenic agent, and imatinib. This toxicity precludes the use of this combination in HRPC patients. No significant financial relationships to disclose.
The World Health Organization Adult Attention-Deficit/Hyperactivity Disorder Self-Report Screening Scale for<i>DSM-5</i>
Authors: Berk Ustun, Lenard A. Adler, Cynthia Rudin, Stephen V. Faraone, Thomas J. Spencer, Patricia Berglund, Michael J. Gruber, Ronald C. Kessler
Journal: JAMA Psychiatry (2017)

Recognition that adult attention-deficit/hyperactivity disorder (ADHD) is common, seriously impairing, and usually undiagnosed has led to the development of adult ADHD screening scales for use in community, workplace, and primary care settings. However, these scales are all calibrated to DSM-IV criteria, which are narrower than the recently developed DSM-5 criteria.
Margaret McCartney: There’s no magic GP production line
Authors: Margaret McCartney
Journal: BMJ (2017)

The new plan to save the NHS in England is for “every hospital A&E department” to have GP triage. I’m a fan of GPs—after all, I am one. General practice is terrific, even when we’re not all wearing Wonder Woman bustiers. But this is another example of calamitous policy making.

Firstly, GPs are not rabbits, which breed regularly, easily, and joyously. It takes a long time to train GPs, and they then have an awful tendency to look at the NHS and think: maybe only part time, maybe only after I’ve been to Australia.

But lo! We’re getting 5000 extra doctors in general practice, delivered jointly …
Relation of metastatic stage at the diagnosis of non-small cell lung cancer (NSCLC) to XRCC1 and TP53 single nucleotide polymorphisms (SNPs).
Authors: Mehmet Artac, Caglayan Geredeli, Selman Yildirim, Isa Dede, Ali Inal, Tunc Guler, Melih Cem Boruban, Ayse Gul Zamani, Ahmet Demirkazik, Hakan Sat Bozcuk
Journal: Journal of Clinical Oncology (2014)

e19109 Background: DNA repair pathway genes are associated with lung cancer development. The aim of this study was to evaluate the association of XRCC1, ERCC1, ERCC2 and, TP53 SNPs with the stage at the diagnosis in NSCLC patients. Methods: In total 275 patients, who had been treated for NSCLC between 2000 and 2012, were included in this study. Analysis of SNPs from peripheral blood cells was performed by polymerase chain reaction. XRCC1 Arg399Gln, ERCC1 Asn118Asn, ERCC2 Lys751Gln and, TP53 Arg72Pro polymorphisms were evaluated in conjunction with clinical and pathological parameters. Logistic regression analysis were used. Results: In the univariate analysis for the metastatic stage at the diagnosis of patients XRCC1 genotype (Wald = 34.37; P<0.001), ERCC2 genotype (Wald = 5.15; P=0.07), TP53 genotype (Wald=10.06; P=0.007) and non-squamous histology (Wald=10.28; P=0.001) were significant parameters. ERCC1 genotype, age and smoking amount were not significant. In the multivariate analysis XRCC1 genotype (Wald = 39.27; P<0.001), TP53 genotype (Wald = 13.59; P=0.001), and non-squamous histology (Wald=15.03; P<0.001) were the independent risk factors associated with the metastatic stage at the diagnosis of patients. The risk of metastatic stage at the diagnosis for the XRCC1 normal (AA) versus mutant (GG) genotypes (Exp(B)=24.29; P<0.001) and heterozygote (AG) versus mutant (GG) genotypes (Exp(B)= 5.39; P=0.001) were significantly increased. The risk of metastatic stage at the diagnosis for the TP53 normal (CC) versus mutant (GG) genotypes (Exp(B) = 5.02;P=0.002) were significantly increased. Conclusions: XRCC1 and TP53 genotypes are independently associated with metastatic stage at the diagnosis of NSCLC patients. Future prospective studies are needed for the further evaluation of the relationship between DNA repair system SNPs and the stage at the diagnosis in NSCLC.
Subclinical cardiac toxicity and health-related quality of life (hql) in childhood cancer survivors
Authors: C. L. Cox, S. N. Rai, D. Rosenthal, S. Phipps, M. M. Hudson
Journal: Journal of Clinical Oncology (2007)

9018 Background: Despite substantial information about late cardiotoxicity, little is known about its impact on the adolescent/young adult survivor's health-related quality of life (HQL). Using cross-sectional data, we assessed how HQL and New York Heart Association (NYHA) functional classification are related to survivors’ cardiac performance, cardiac risk factors, and treatment history. Methods: HQL indicators were examined in 164 long-term survivors of pediatric cancer (age 16–40 years), who had (n=132; 10 years (mean) after diagnosis of predominantly leukemia or lymphoma) or had not (n=32; 11 years (mean) after diagnosis of predominantly solid tumors) received anthracyclines and/or thoracic irradiation. Survivors underwent extensive noninvasive clinical and laboratory cardiac risk evaluation and completed a self-report questionnaire on selected subscales of the SF-36 (HQL). Results: Reported general health was lower in the cardiotoxic-therapy group (P = 0.05). Sex, current age, time since diagnosis, cardiac function, and cardiac risk factors were independent predictors of HQL subscales and NYHA class in multivariable analysis. Female sex and higher LDL cholesterol interacted to predict diminished reported vitality (P = 0.04) and physical health (P = 0.05) shown in table . Conclusions: Even in the absence of clinically evident cardiotoxicity, cardiac dysfunction and cardiac risk were strongly linked to decreased HQL and NYHA class, particularly among female survivors. Reduced HQL may be an indicator of unidentified sequelae that should be investigated and monitored. No significant financial relationships to disclose. [Table: see text]
Observational study in patients with pulmonary metastases of renal cell carcinoma receiving inhaled recombinant interleukin-2 (rIL-2)
Authors: A. G. García, E. Esteban, C. G. Girón, P. Maroto, R. Andrés, A. Canelas, J. Caballido, J. Carles, E. Espinosa, A. J. Lacave
Journal: Journal of Clinical Oncology (2006)

4603 Background: Patients with metastatic renal cell carcinoma have a poor prognosis, including those with pulmonary metastases (PMRCC). The objective of this study was to obtain efficacy and safety data on inhaled rIL-2 used in clinical practice in PMRCC patients. Methods: Data provided from 107 PMRCC patients from 48 centres in Spain and 6 in Portugal, treated with inhaled rIL-2 between 2000 and 2005 were evaluated. Data were analyzed by ITT, considering a valuable patient when receiving the first dose of inhaled rIL-2. The treatment schedule was: 3 cycles of 36 MIU rIL-2 per day for 5 days/week for 12 weeks (with one week treatment free between cycles) in Spain and for 3 weeks (out of each 4 weeks) for 12 weeks in Portugal. Efficacy was assessed by best response following each treatment cycle and overall (WHO criteria). The Kaplan-Meier method was used to estimate progression free survival (PFS) and overall survival (OS) that were measured from the time of administration of the first dose of inhaled rIL-2 until progression or death. Safety data were analysed using descriptive statistics, with toxicities expressed as number of weeks in which each toxicity was reported by cycle and by grade. Results: After 1902 treatment weeks administered (median 17.8), the overall objective response rate (complete and partial response,) was 12.2% (95% CI: 6.0–18.4) and a stable disease rate of 22.45% (95% CI: 14.5–30.3). Median PFS and OS were 3.72 (95% CI: 2.86–4.57) and 18.5 (12.69– 23.61) months, respectively. Non-haematological toxicities were the most notable adverse events observed, especially in terms of cough (20.4% of weeks) and fatigue (4.4%) being grade 1 or 2 in severity and reversible by removing the treatment in all cases. Conclusions: This study provides data of efficacy and mild toxicity of inhaled rIL-2. On the basis of these findings inhaled rIL-2 might be considered as an alternative to its systemic administration to treat patients with PMRCC. No significant financial relationships to disclose.
Chemotherapy use near end of life (EOL): Measuring real world benchmarks.
Authors: Joshua Kraut, James Gippetti, Dylan Peterson, Vineeta Agarwala, Cindy Revol, Kristen Lee Fessele, Amy Pickar Abernethy
Journal: Journal of Clinical Oncology (2017)

228 Background: Use of anti-cancer therapies in the last 14-30 days of life may worsen patient outcomes and increase cost; accordingly, rate of chemotherapy use near EOL is an important quality measure. Contemporary benchmarks are needed, with transparent methods describing the cohort in which the measure is assessed, and criteria for calculation. Methods: Data on chemotherapy use, mortality, and cancer diagnosis was sourced from electronic health records (EHRs) of &gt;8,000 patients seen between 2014-2016 at two large US academic centers, for whom dates of death were available. Death dates were sourced from the EHR and public records (e.g., obituaries). Patients were grouped by diagnosis using ICD-10 codes. Rates of infusional chemotherapy receipt within 14 or 30 days of death were calculated. Results: Across 10 tumor types, 3-7% of patients received chemotherapy within 14d of death, and 6-16% received it within 30d. Rates were stable from 2014-2016 and did not differ by cancer center. Rates were highest in diseases where patients may experience rapid clinical decline near EOL: in pancreatic and rectal cancer, 30d rates were 16% and 13%. The 30d rate was lowest (6%) in kidney cancer. When the cohort was restricted to only treated patients (who received &gt;=5 chemotherapy administrations at the center), rates of chemotherapy use at EOL increased to 6-12% (14d) and 17-28% (30d). Conclusions: This study provides baseline estimates of current rates of EOL chemotherapy use at academic centers. Transparency in methodology is critical; for example, when the whole population of cancer patients seen at a center is considered, rates are low, but when the analysis is limited to patients who received chemotherapy there, rates nearly double. Further studies should focus on whether this quality measure is a meaningful driver of patient and health system outcomes. This work also demonstrates that it is possible to assess this metric across multiple centers; this approach could be easily scaled to all oncology practices integrated in a data sharing network. [Table: see text]
Gender difference in vulnerability and geriatric syndromes among elderly cancer survivors.
Authors: Lin Fan, Katia Noyes, Ning Zhang, Kevin Fiscella, Supriya Gupta Mohile
Journal: Journal of Clinical Oncology (2012)

9091 Background: Few studies have evaluated the gender difference of vulnerability and geriatric syndromes (GS) among cancer survivors. Methods: Using 2003 Medicare Current Beneficiary Survey, we applied multivariable logistic regression to evaluate the association of gender with vulnerability and GS among cancer survivors. Vulnerability is measured by Vulnerable Elders Survey-13 (VES-13), which is calculated from age, self-rated health status, difficulty with physical activities and functional activities. Vulnerability is defined by a VES-13 score of 3 or higher. 8 common geriatric syndromes were assessed: sight trouble, hearing trouble, nutrition problem, incontinence, falls, depression, memory loss and osteoporosis. Cancer survivors are defined as patients with cancer diagnosed more than one year ago. Results: Among the 1,883 cancer survivors, 749 (40.0%) were male; 1,134 (60.0%) were female. Female survivors had a higher prevalence of vulnerability (47.8% vs 35.7%), and GS (65.5% vs 44.6%) than male survivors. Mean GS number was 1.19 for female survivors, while 0.77 for male survivors (p&lt;0.001). More specifically, female survivors had significantly higher prevalence of sight trouble (7.73% vs 5.0%), incontinence (14.3% vs 7.1%), falls (28.9% vs 22.1%), depression (13.8% vs 7.7%) and osteoporosis (38.2% vs 6.7%). After adjusting for confounders, female survivors were more likely to be vulnerable (adjusted OR (AOR): 1.62; CI: 1.21-2.17; p=0.001); have a geriatric syndrome (AOR: 2.39; CI: 1.91-3.00; p&lt;0.001); have sight trouble (AOR: 1.70; CI: 1.00-2.87; p=0.049); have incontinence (AOR: 2.48; CI: 1.67-3.69; p&lt;0.001); have depression (AOR: 1.87; CI: 1.29-2.71; p&lt;0.001); and have osteoporosis (AOR: 8.48; CI: 6.07-11.84; p&lt;0.001). Conclusions: Female cancer survivors experience a higher prevalence of vulnerability and overall geriatric syndromes.
Response rates, toxicity, and quality of life for locally regionally advanced head and neck squamous cell carcinoma after induction chemotherapy with weekly <i>nab</i>-paclitaxel, carboplatin, and cetuximab.
Authors: Jared Weiss, Jill Gilbert, Juneko E. Grilley-Olson, Allison Mary Deal, Bhishamjit S. Chera, Jay Justin Liao, Barbara A. Murphy, Mark C Weissler, David N. Hayes
Journal: Journal of Clinical Oncology (2015)

6030 Background: Although induction studies of TPF have been negative, phase II studies of weekly carboplatin (CbP), paclitaxel and cetuximab (C225) have shown positive results. Nab-paclitaxel-based chemotherapy has demonstrated a higher response rate (RR) than solvent-based paclitaxel in SCC of the lung with favorable toxicity. Methods: Patients with treatment naïve SCCHN of any site with ≥ N2b disease or that was unresectable by strict criteria were eligible. Subjects were screened for risk of anaphylaxis to C225 with ELISA for IgE antibodies against galactose-α-1,3-galactose (alphagal); negativity was required for subjects residing in the SE of the US. Patients were treated with nab-paclitaxel 100mg/m2, CbP AUC 2 and C225 400mg/m2 week 1 then 250mg/m2for six weeks, followed by standard of care (SOC) chemoradiotherapy (CRT). Herein we report the results of induction, including the primary endpoint of RR. Results: 62 subjects were screened; 20 were excluded due to positivity for alphagal, 1 withdrew consent and 5 were excluded due to other reasons; 36 were eligible and 35 have completed induction chemotherapy. Primary sites were: oropharynx (OPX) (23), larynx (3) and oral cavity (OC) (9). Grade 3/4 toxicity included rash (8), decreased neutrophil count (4), decreased white blood cells (2), fatigue (1), palmar-plantar erythrodysesthesia syndrome (1), and febrile neutropenia (1); there was no anaphylaxis to C225. All patients proceeded to SOC CRT. RRs to induction were: primary site 66%, nodal 79%, ORR 74%, CRR 26%, OPX 78%, p16+ OPX (17/19 with known status) 77%, larynx 100%, OC 56%. FACT-HN scores were (mean improvement in points, p): overall (5.3, NS) head/neck subscale (4.7, .046), swallow naturally and easily (1.6, 0.002) and voice quality and strength (0.9, .06). 24 patients are alive and NED, 3 are alive with PD, and 8 have died; median follow up of survivors is .7 years. Conclusions: The combination of nab-paclitaxel, CbP and C225 is very active against locally advanced SCCHN and toxicity is low. SCCHN-specific quality of life improved, particularly in speech and swallowing. Clinical trial information: NCT01412229. N1 N2b/c N3 T1 0 3 1 T2 0 5 2 T3 1 5 1 T4 1 13 3
The effects of dexrazoxane on cardiac status and second malignant neoplasms (SMN) in doxorubicin-treated patients with osteosarcoma (OS).
Authors: Lisa M. Kopp, Mark L. Bernstein, Cindy L. Schwartz, David Ebb, Mark D. Krailo, Holcombe E. Grier, Paul A. Meyers, Leonard H. Wexler, Neyssa Marina, Richard Womer, Katherine A. Janeway, Richard Greg Gorlick, Steven E. Lipshultz
Journal: Journal of Clinical Oncology (2012)

9503 Background: Anthracyclines are highly efficacious in OS but associated with risk of cardiotoxicity. We conducted two studies using dexrazoxane as a cardioprotectant: i) AOST0121, a phase II study for metastatic OS and ii) P9754, a series of pilot studies including doxorubicin dose intensification in patients with localized OS. Methods: Patients on AOST0121 received methotrexate, doxorubicin (375 mg/m 2 ), cisplatin, ifosfamide and etoposide (MAPIE). Those with HER2-positive tumors also received trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly). On P9754, patients received MAP in Pilot 1, MAPI or MAPIE in Pilots 2 and 3. Total doxorubicin was 450 mg/m 2 or 600 mg/m 2 with each dose preceded by dexrazoxane (10:1 ratio). Etoposide was never given simultaneously with dexrazoxane. Measurements of left ventricular systolic function by echocardiography, serum troponin-T (cTnT, a myocardial injury marker) and N-terminal pro-brain natriuretic peptide (NT-proBNP, a cardiomyopathy marker) were obtained at baseline and repeated during therapy. Secondary malignancies were reported to the NCI. Results: None of the 47 patients (17 receiving trastuzumab) evaluated for cardiac toxicity on AOST0121 had significant changes in left ventricular fractional shortening, measurable cTnT, elevation of NT-proBNP or clinical evidence of cardiotoxicity (CTCv2.0). In P9754, 242 patients were evaluated for cardiotoxicity. Only 1 patient had CTCv2.0 grade 3 toxicity and 1 patient had a measurable cTnT. Three of 96 patients treated on AOST0121 and two of 272 patients on P9754 developed AML. Combining both studies: 5/398 or 1.4%. Conclusions: This large group of OS patients demonstrates that dexrazoxane is an effective cardioprotectant for doxorubicin alone (375-600 mg/m 2 ), and in combination with trastuzumab. Dexrazoxane did not lead to an increase in secondary malignancies in OS patients treated with these regimens as compared to historical rates of 1-2%. Our results do not support the findings of a recent European Medicines Agency safety review that concluded dexrazoxane was unsafe for use in children and adolescents due to risk of SMN.