tbuckley/cabot-search huggingface dataset:
Effects of U.S. Preventive Services Task Force (USPSTF) guidelines on cervical cancer screening, incidence, and mortality.
Authors: Alexander Melamed, Jose Alejandro Rauh-Hain, Günther Fink, Kaitlyn James, Laurel Rice, Deborah Schrag, Marcela G. del Carmen, Alexi A. Wright
Journal: Journal of Clinical Oncology (2018)

1556 Background: To evaluate the consequences of USPSTF recommendation to stop pap testing in well-screened women age ≥65 years on cervical cancer incidence and mortality. Methods: In 2003, the USPSTF recommended that women age ≥65 years with prior normal cervical cancer screening could discontinue screening. Using nationally-representative survey data from the Behavioral Risk Factor Surveillance System, we constructed a joinpoint model to evaluate if the guideline affected pap smear discontinuation (defined as no pap for ≥5 years). We performed interrupted time-series to evaluate whether guideline-related pap-smear discontinuation affected stage-specific cervical cancer incidence and mortality in women ages ≥65, using women ages 30-64 as controls. Incidence and mortality rates were obtained from the Surveillance, Epidemiology, and End Result program, and adjusted for age and hysterectomy prevalence. Results: After declining from 1992 to 2004, the proportion of women reporting no pap smear for ≥5 years increased from 2004 to 2014 among women age ≥65 years and 30-64 years (p < 0.001 for both). However, the proportion of women who discontinued screening was greater in those age ≥65 years (10.7 versus 2.7 percentage points from 2004 to 2014, p < 0.001). Despite this, women age ≥65 had greater-than-expected declines in the incidence of localized (-2.3% per year, p = 0.05) and regional (-3.0% per year, p = 0.03) cervical cancer after 2004, compared with 30-64-year-old women. Incidence of distant cancer increased slightly in both groups, but the magnitude of the change did not differ between groups (p = 0.23). Cervical cancer mortality rates declined in both groups throughout the study period (p < 0.001), and there was no evidence that guideline-related pap-smear discontinuation led to excess mortality among women ≥65 compared to those 30-64 years. Conclusions: Compared to women unaffected by the USPTF guidelines, women age ≥65 years had larger declines in the incidence of locally- and regionally-confined cervical cancer, and no difference in the incidence of metastatic cancer. Recommendations to stop pap testing in women age ≥65 did not appear to have led to increased cervical cancer mortality.
A survey on the clinical actionable somatic variations among 1,000 Chinese cancer patients to provide personalized global clinical decision roadmap.
Authors: Qiang Xu, Guan Wang, Yang Cai, Linda Wu, Haining Wang, Mars Wei, Chun Dai, Weibing Fan, Angela Wu, Xiaoman Xu, Jiping Wang
Journal: Journal of Clinical Oncology (2016)

e14036 Background: Precision medicine has become a major paradigm shifting effort in cancer care globally to improve the outcome of cancer patients. More and more patients receive individualized cancer treatments based on their tumor-specific characteristics at both gene and genomic level. Methods: We have sponsored a translational research project to sequence the whole exome of tumor specimen and case-matched normal samples among 1,000 Chinese cancer patients, to prospectively provide clinical decision roadmap recommendations based on globally available treatment options, and to follow up the treatment implementation and disease evolvement of each patient. These patients are from more than 70 hospitals across 18 provinces in China. The preliminary data yields rich tumor specific genomic variations and the potential precision clinical treatments among a few common tumor types in China, including Lung cancer, Gastric cancer, Colorectal cancer and Breast cancer. Results: Within this dataset, we demonstrated the use of tumor-normal matched whole exome sequencing to measure a wide spectrum of molecular abnormalities closely related to targeted therapy and immune therapy clinical decision for Chinese cancer patients. The information includes somatic mutations (such as EGFR and BRAF), somatic copy number changes (such as ERBB2 and cMET), genome wide mutation load measurement (for immune check-point inhibitors), and microsatellite instability status (in Gastric and Colorectal cancer). By working with the treating physicians, we have also demonstrated the clinical value of such roadmap recommendations for Chinese cancer patients, by providing the facilitation for the patients to access these drugs and clinical trials globally. Conclusions: This project laid the foundation for future implementation of genomic-based clinical trials in China.
Effects of TKI on patients with non-small cell lung cancer of different stages: A meta-analysis.
Authors: Di Lu, Zhizhi Wang, Siyang Feng, Xiguang Liu, Xiaoying Dong, Kaican Cai
Journal: Journal of Clinical Oncology (2018)

e20503 Background: A survival improvement of adjuvant chemotherapy for non-small-cell lung cancer (NSCLC) at 5 years after radical resection was yielded, especially for stage pII-IIIA patients. A former meta-analysis showed that adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy might enhance disease-free survival (DFS) in patients with EGFR-mutant NSCLC, and it was found by the SELECT study and a few newly reported studies that stage II-IIIA patients might benefit more from the TKIs. Methods: MEDLINE, Embase and the Cochrane Library were searched and the results were screened according to certain criteria independently by two authors. Quality was accessed by the Newcastle–Ottawa scale or the Cochrane Collaboration’s tool. DFS and overall survival (OS) with hazard ratios (HRs) at different time points were used as the summary statistics. Heterogeneity and publication bias for each analysis were measured. Results: 2915 publications were achieved and screened. 6 randomized control trials (RCTs) and 3 retrospective cohort studies (RCSs) of 1517 patients were included with acceptable quality, and the overall EGFR mutation rate was 66.84%. 2-year DFS were significantly improved in all the patients (HR = 0.72, 95% CI: 0.64-0.82, P < 0.01) and in the subgroup of EGFR mutant patients (HR = 0.44, 95% CI: 0.36-0.54, P < 0.01). And the difference of 5-year OS in the subgroup of EGFR mutant patients (HR = 0.54, 95% CI: 0.35-0.82, P < 0.01) was statistically significant, while in all the patients (HR = 1.04, 95% CI: 0.88-1.23, P = 0.65), it wasn’t. In the subgroups of studies that less than 15% patients were stage pI (HR = 0.38, 95% CI: 0.29-0.49, P < 0.01), and that more than 50% patients were stage pIIIA (HR = 0.39, 95% CI: 0.30-0.52, P < 0.01), 2-year DFS were significantly improved, while in the subgroups of studies that less than 15% patients were stage pIIIA (HR = 0.90, 95% CI: 0.72-1.13, P = 0.35), and that more than 50% patients were stage pI (HR = 0.90, 95% CI: 0.77-1.04, P = 0.16), 2-year DFS weren’t significantly improved. Conclusions: Stage pIIIA NSCLC patients might benefit more from adjuvant TKIs than stage pI NSCLC patients after radical resection.
Long-term benefit of niraparib treatment of recurrent ovarian cancer (OC).
Authors: Ursula A. Matulonis, Jorn Herrstedt, Anna Tinker, Frederik Marme, Andres Redondo, Elsa Kalbacher, Jonathan A. Ledermann, Joanna Pikiel, Rene dePont Christensen, Jonathan S. Berek, Trine Juhler-Nøttrup, Amit M. Oza, Werner Meier, Marta Gil-Martin, Anne-Claire Hardy-Bessard, Bradley J. Monk, Per Rosenberg, Robert Michael Wenham, Sebastien Hazard, Mansoor Raza Mirza
Journal: Journal of Clinical Oncology (2017)

5534 Background: Current therapies for recurrent OC include chemotherapy (C) or bevacizumab (B) in combination with C followed by continuous B, which showed improved progression-free survival (PFS) compared with C followed by placebo (P) over 3.4 months (GOG-0213) or 4.0 months (OCEANS). Potential impact of B on effectiveness of subsequent therapies has not been described. Niraparib (N) is a highly selective PARP 1/2 inhibitor (PARPi). In preclinical studies, N concentrates in the tumor; N showed significantly longer PFS vs P in patients (pts) with recurrent OC following complete/partial response (CR/PR) to platinum based chemotherapy (Plat) in the randomized, controlled, double-blind phase 3 ENGOT-OV16/NOVA trial. We report the long term effect of treatment with N and its impact on subsequent therapy. Methods: Eligibility for NOVA included recurrent OC, fallopian tube or peritoneal cancer, no prior PARPi use, and completion of ≥2 prior courses of Plat, with a CR or PR following the most recent Plat. Pts were enrolled into g BRCAmut or non-g BRCAmut cohorts based on BRCA mutation test results and randomized 2:1 to receive N 300 mg qd or P until progression of disease or death (PD). Tumors were tested for homologous recombination deficiency (HRD). Estimated probability of PD in each cohort at 12, 18 and 24 months post randomization, representing ~18, 24 and 30 months post chemotherapy initiation, was determined; the difference between PFS2 and PFS (PFS2-PFS) was evaluated in all randomized pts. Results: 203 pts were randomized in the g BRCAmut cohort. Of 350 pts randomized in the non-g BRCAmut cohort, 162 had HRD+ and 134 HRD− tumors. Estimated probability (product-limit method) of PFS at 12, 18 and 24 months was greater in the niraparib arm than in the placebo arm in each cohort and subgroup at each time interval. Probabilities (95% CI) at 24 months for niraparib vs control were 0.42 (0.30, 0.55) vs 0.16 (0.07, 0.28) (gBRCAmut) and 0.27 (0.19, 0.35) vs 0.12 (0.06, 0.21) (non-gBRCAmut). PFS2-PFS was similar in the 2 treatment arms in the combined cohorts (HR 1.02, 95% CI 0.765, 1.349). Conclusions: Niraparib provided long term benefit in pts with recurrent OC irrespective of g BRCAmut or HRD status, and no decrement in the benefit of subsequent therapy was observed. Clinical trial information: NCT01847274.
Visceral primary non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) in patients &lt; 30 years of age: Findings of Children’s Oncology Group (COG) study ARST0332.
Authors: Meena Kadapakkam, Jingying Weng, Sheri L. Spunt, Mary B McCarville, Lynn Million, Susan M. Hiniker, Donald A. Barkauskas, Douglas S. Hawkins
Journal: Journal of Clinical Oncology (2018)

10545 Background: Little is known about the clinical features, optimal management, and prognosis of young patients with primary visceral NRSTS. Methods: We analyzed clinical features, treatment, and outcomes of patients with visceral tumors (defined as intrathoracic, intraperitoneal, retroperitoneal, pelvic and perineal) enrolled in COG ARST0332, which evaluated a risk-based treatment strategy for NRSTS patients aged < 30 years (surgery +/- radiotherapy +/- chemotherapy based on tumor size, grade, extent of surgery, and extent of metastases). Variables analyzed included gender, age, race, ethnicity, tumor grade/size/invasiveness, extent of metastases, extent of surgery, and event-free and overall survival. Results: Visceral tumors occurred in 114/551 enrolled patients (21%), were most likely to occur in patients > 10 years (67%) and be > 5 cm (92%), high-grade (89% by POG, 73% by FNCLCC), non-metastatic (78%), and grossly resected prior to study entry (58%). Compared to patients with non-visceral tumors, those with visceral tumors were more likely to have high-risk features: high POG and FNCLCC grade, > 5 cm diameter, deep location, and invasiveness (all p < 0.001), metastases (p = 0.03), and microscopic residual tumor after gross total resection (p = 0.01). Due to these features, they were more often assigned to intermediate-/high-risk therapy (87% vs. 50%). Event-free and overall survival by risk group were 85.1% and 82.5% (low), 67.9% and 82.8% (intermediate), and 44.0% and 44.0% (high), and did not differ significantly from outcomes for the rest of the population. Conclusions: Patients with primary visceral tumors were more likely than those with tumors at other anatomic sites to have high risk features such as > 5 cm tumor diameter, high grade, deep location, invasiveness, metastases, and microscopic disease after gross resection. However, with risk-adapted therapy, their event free and overall survival were similar to those of patients with non-visceral tumors. Clinical trial information: NCT00346164.
The addition of cycles of irinotecan/temozolomide (i/T) to cycles of vincristine, doxorubicin, cyclophosphamide (VDC) and cycles of ifosfamide, etoposide (IE) for the treatment of Ewing sarcoma (ES).
Authors: Paul A. Meyers, Srikanth R. Ambati, Emily Kanaya Slotkin, Filemon Dela Cruz, Leonard H. Wexler
Journal: Journal of Clinical Oncology (2018)

10533 Background: Treatment for ES in North America has evolved to include cycles of VDC and IE. A regimen including these 5 agents with interval dose compression has achieved 5 year EFS of 73% for localized ES. At Memorial Sloan Kettering (MSK) we have instead used the strategy of increasing doses of alkylating agents to achieve dose intensification and reported similar results. The combination of i/T given as irinotecan 20 mg/m2/day for 10 days with temozolomide 100 mg/m2/day for 5 days has achieved objective responses for patients who recur after initial therapy with the 5 drug combination. Our prospective protocol incorporates cycles of i/T with cycles of VDC and IE for the treatment of newly diagnosed patients with ES. Methods: We have enrolled patients with and without clinically detectable metastatic disease at initial presentation. For patients with localized ES we administer high dose alkylator therapy with 4 cycles of VDC and 3 cycles of IE, followed by 6 cycles of i/T. For patients who present with metastases we intercalate 10 cycles of i/T with the same 7 cycles of high dose alkylating agent therapy. Results: We have enrolled 22 patients with localized and 16 patients with metastatic ES. With a median followup of 14 (3-51) months, patients with localized ES have achieved a 3 year EFS of 95% and overall survival (OS) of 95%. With a median followup of 20 (8-51) months, patients with metastatic ES have achieved a 3 year EFS of 55% and OS of 70%. Conclusions: The addition of multiple cycles of i/T to conventional 5 drug therapy for ES is feasible and may be associated with an improved probability for both EFS and OS. Clinical trial information: NCT01864109.
Diclofenac use and cardiovascular risks: series of nationwide cohort studies
Authors: Morten Schmidt, Henrik Toft Sørensen, Lars Pedersen
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To examine the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. <h3>Design</h3> Series of 252 nationwide cohort studies, each mimicking the strict design criteria of a clinical trial (emulated trial design). <h3>Setting</h3> Danish, nationwide, population based health registries (1996-2016). <h3>Participants</h3> Individuals eligible for inclusion were all adults without malignancy; schizophrenia; dementia; or cardiovascular, kidney, liver, or ulcer diseases (that is, with low baseline risk). The study included 1 370 832 diclofenac initiators, 3 878 454 ibuprofen initiators, 291 490 naproxen initiators, 764 781 healthcare seeking paracetamol initiators matched by propensity score, and 1 303 209 healthcare seeking non-initiators also matched by propensity score. <h3>Main outcome measures</h3> Cox proportional hazards regression was used to compute the intention to treat hazard ratio (as a measure of the incidence rate ratio) of major adverse cardiovascular events within 30 days of initiation. <h3>Results</h3> The adverse event rate among diclofenac initiators increased by 50% compared with non-initiators (incidence rate ratio 1.5, 95% confidence interval 1.4 to 1.7), 20% compared with paracetamol or ibuprofen initiators (both 1.2, 1.1 to 1.3), and 30% compared with naproxen initiators (1.3, 1.1 to 1.5). The event rate for diclofenac initiators increased for each component of the combined endpoint (1.2 (1.1 to 1.4) for atrial fibrillation/flutter, 1.6 (1.3 to 2.0) for ischaemic stroke, 1.7 (1.4 to 2.0) for heart failure, 1.9 (1.6 to 2.2) for myocardial infarction, and 1.7 (1.4 to 2.1) for cardiac death) as well as for low doses of diclofenac, compared with non-initiators. Although the relative risk of major adverse cardiovascular events was highest in individuals with low or moderate baseline risk (that is, diabetes mellitus), the absolute risk was highest in individuals with high baseline risk (that is, previous myocardial infarction or heart failure). Diclofenac initiation also increased the risk of upper gastrointestinal bleeding at 30 days, by approximately 4.5-fold compared with no initiation, 2.5-fold compared with initiation of ibuprofen or paracetamol, and to a similar extent as naproxen initiation. <h3>Conclusions</h3> Diclofenac poses a cardiovascular health risk compared with non-use, paracetamol use, and use of other traditional non-steroidal anti-inflammatory drugs.
P04.81 Calpain 2 mediates ZBTB18 proteolytic cleavage in GBM
Authors: A Masilamani, R Ferrarese, E Kling, J Helm, S Yuan, O Schilling, M Carro
Journal: Neuro-Oncology (2018)

ZBTB18 (Zinc Finger and BTB Domain Containing 18) is a zing finger transcriptional repressor which plays crucial role in brain development and neuronal differentiation. ZBTB18 is highly expressed in healthy brain but downregulated in glioblastoma (GBM) and GBM cell lines. We have shown that loss of ZBTB18 by DNA methylation contributes to the highly invasive phenotype of GBM, and the over expression of ZBTB18 reverses this phenotype and impairs tumor-forming ability. Analysis of ectopic and endogenous ZBTB18 protein expression in healthy brain and GBM cell lines revealed the presence of lower band around 30 kDa in GBM cell lines but not in healthy brain. Sequence analysis by Mass Spectrometry (MS) confirmed that the peptides correspond to the N-terminal portion of ZBTB18. Hence we hypothesized that the short ZBTB18 could be the result of a specific protease activity; since the truncated ZBTB18 protein is not detected in healthy brain it is possible that this protease activity could be tumor specific. Our findings show that the short ZBTB18 localizes in the cytoplasm and does not repress previously validated mesenchymal genes. We have identified calpain 2 (CAPN2) as a protease preferentially expressed in primary GBMs in which the short ZBTB18 is present. Calpains are a conserved family of proteases involved in several fundamental processes, including cytoskeletal remodeling, cellular signaling, apoptosis, cell survival and tumorigenesis. Interestingly, activation of calpain with CaCl2 leads to re-expression of the short form, which is conversely counteracted by addition of the calpain inhibitor PD150606. Our findings suggest a new mechanism of ZBTB18 regulation in glioblastoma which could be target to restore ZBTB18 tumor suppressive function.
Access and price of cancer drugs: What is happening in France?
Authors: Mathilde Grande, Judith Fernandez, Jade Putzolu, Sorin Stanel, Margaret Galbraith, Chantal Belorgey, Nicolas Albin, Loic Guillevin, Anne d'Andon
Journal: Journal of Clinical Oncology (2017)

6623 Background: The French National Authority for Health (HAS) is responsible for health technology assessment (HTA), providing opinion on drugs for reimbursement and pricing purposes. For all indications with a positive opinion for reimbursement, HAS assesses the clinical added value (CAV) on a 5-point scale for pricing negotiations based on clinical data. A major to moderate CAV leads to the highest prices, a minor CAV leads to a higher price than the comparator, and no CAV leads to lower price than the cheapest comparator. Countries increasingly face the policy challenge of harnessing the benefits of cancer drugs while managing healthcare budgets. In this context, we aimed to analyze cancer drugs assessment by HAS. Methods: a retrospective and descriptive analysis comparing all new hematology/oncology cancer indications versus all others new indications assessed by HAS between 2010 and 2015 has been conducted. Results: 87 cancer indications (60 drugs) have been evaluated, representing 17% (87/510) of all new drugs indications assessed by HAS. Almost all cancer indications (92%) obtained a favorable opinion for reimbursement. Seven (8%) had an unfavorable opinion versus 20% in other therapeutic areas. However, 5 of these 7 indications were related to a drug included on the list of reimbursed drugs for another indication and consequently drugs are available. Overall, only 2 drugs were not reimbursed: nintedanib in non small cell lung cancer and tegafur/gimeracil/oteracil in gastric cancer (no impact on survival and lack of results transposability). Of the 80 indications with a favorable opinion, 20 had a major to moderate CAV (25%), 32 a minor CAV (40%) and 28 have no CAV (35%). Major to moderate CAV are mostly composed of hematology drugs (12, 60%). The proportion of major to moderate CAV assessment is higher in oncology than in other therapeutic areas (66% vs. 30%). Conclusions: France benefits from a universal healthcare system offering wide coverage and large access to drugs. Almost all of the new hematology/oncology cancer drugs assessed had a favorable opinion and are fully reimbursed (100%) by health insurance. A high proportion (66%) of CAV is recognized in oncology. Nevertheless, the over DRG list can inadvertently limit access to these new cancer drugs.
Cross-intolerance with bosutinib after prior tyrosine kinase inhibitors (TKIs) in patients (pts) with Philadelphia chromosome–positive (Ph+) leukemia: Phase 1/2 study update.
Authors: Carlo Gambacorti-Passerini, Jeffrey Howard Lipton, Andreas Hochhaus, Vamsi K. Kota, Michele Baccarani, Simon Durrant, Sarit E. Assouline, Dong-Wook Kim, Tim H. Brümmendorf, Eric Leip, Fiona An, Jean Aguiar, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2018)

7062 Background: Bosutinib has a distinct adverse event (AE) profile vs other TKIs used to treat Ph+ leukemia. Methods: Pts with chronic phase (CP) chronic myeloid leukemia (CML; n=403) or accelerated/blast phase CML or Ph+ acute lymphoblastic leukemia (ADV; n=167) previously treated with imatinib ± dasatinib and/or nilotinib received bosutinib (starting dose 500 mg QD) in a phase 1/2 study (NCT00261846). Cross-intolerance (AEs leading to discontinuation of both prior TKI and bosutinib) and AEs causing prior TKI intolerance and recurring as grade 3/4 AEs with bosutinib were assessed after ≥4 y of follow-up. Results: In imatinib-intolerant and dasatinib-intolerant pts, respectively, 18% and 24% in the CP CML group and 18% and 5% in the ADV group had cross-intolerance with bosutinib, which was most commonly due to hematologic AEs (Table). Cross-intolerance in imatinib-intolerant pts with CP CML due to AEs common with imatinib was low (rash 6%; diarrhea 10%; edema/fluid retention 0; myalgia 0); cross-intolerance due to pleural effusion was low in dasatinib-intolerant pts with CP CML (13%) and dasatinib-intolerant ADV pts (0). No deaths occurred due to cross-intolerance. Conclusions: Cross-intolerance with bosutinib was low and largely due to hematologic AEs, supporting bosutinib use in pts with Ph+ leukemia intolerant to prior TKIs, including those with intolerance due to rash or diarrhea. Clinical trial information: NCT00261846.Cause of intolerance* n Bosutinib discontinuation due to same AE n (%) Same grade 3/4 AE with bosutinib n (%) CP CML Imatinib intolerance Any AE 120† 21 (18) 39 (33) Thrombocytopenia 27 7 (26) 17 (63) Neutropenia 21 2 (10) 7 (33) Rash 18 1 (6) 2 (11) Anemia 14 0 6 (43) Edema 12 0 0 Diarrhea 10 1 (10) 3 (30) Hematologic toxicity 7 4 (57) 5 (71) Vomiting 7 1 (14) 1 (14) Fatigue 7 1 (14) 0 Nausea 6 0 0 Fluid retention 5 0 0 Myalgia 5 0 0 Dasatinib intolerance Any AE 50 12 (24) 18 (36) Pleural effusion 16 2 (13) 3 (19) Thrombocytopenia 8 4 (50) 8 (100) Pancytopenia 6 0 0 ADV Imatinib intolerance Any AE 22† 4 (18) 8 (36) Thrombocytopenia 7 4 (57) 6 (86) Dasatinib intolerance Any AE 21† 1 (5) 10 (48) Pleural effusion 7 0 2 (29) Thrombocytopenia 5 1 (20) 5 (100) * Causes in ≥5 pts shown † Pts with known causes shown