tbuckley/cabot-search huggingface dataset:
Enoxaparin use during chemotherapy induced thrombocytopenic phase in cancer patients with venous thromboembolism.
Authors: Jiaxiang Liu, Jayasree Krishnan, Lisa Diep, Mousami Shah
Journal: Journal of Clinical Oncology (2018)

e18852 Background: Enoxaparin is the recommended treatment in patients with active cancer who develop venous thromboembolism (VTE). With active cancer treatment, patients might develop thrombocytopenia especially with platelet (PLT) counts < 50K. There are no clear guidelines universally accepted so far in the management of such clinical settings. In our institute, once PLT < 50K, enoxaparin was normally held, but it was sometimes continued at the therapeutic dose. Methods: We conducted a retrospective chart view, identifying patients with active cancer and VTE on enoxaparin who developed PLT < 50K from chemotherapy and who were treated at our institute from 1/2011 to 12/2017. It mainly focuses on the recurrence VTE and bleeding during these episodes. Results: 51 patients met the study criteria with 67 episodes of PLT < 50K. The mean lowest platelet count was 24K. There were 3 episodes of major bleeding, 7 episodes of minor bleeding, 3 episodes of recurrent VTE, and 4 deaths during the episodes. Here are the summaries between the group of continuing enoxaparin and the group of holding enoxaparin: Conclusions: Based on our retrospective review, major and minor bleeding events were not different in both groups of patients and enoxaparin at the therapeutic dose can be considered safe to continue, especially if anticipated duration of PLT < 50K is less than 7 days. When anticoagulation is held for severely thrombocytopenic patients, the risk of recurrent VTE should be kept in mind. This review addresses the need for assessing the best practice for cancer patients with VTE and thrombocytopenia where full dose anticoagulation may be harmful but no anticoagulation may lead to a recurrent VTE. Group of continuing enoxaparin Group of holding enoxaparin Number of episodes (PLT < 50K) 22 45 Mean lowest PLT count 28 22 Duration of PLT < 50K 2-18 Days 2-21 Days Episodes of PLT < 50K more than 7 days 8/22 (36.3%) 28/45 (62.2%) Episodes of major bleeding 1 2 Episodes of minor bleeding 3 4 Episodes of recurrent VTE 0 3 IVC placement during the episodes 0 4 Death total 2 2 Death related to recurrent VTE 0 1
Phase Ib/II trial of expanded and activated autologous natural killer (NK) cells with trastuzumab (Tras) in refractory HER2+ metastatic breast cancer (MBC).
Authors: Soo-Chin Lee, Si Yin Chin, Noriko Shimasaki, Lip Kun Tan, Liang Piu Koh, Jedidah JM Lieow, Koji Kono, Hsueh Yin Kwan, Elaine Coustan-Smith, Andrea Li Ann Wong, Ross A. Soo, Belinda Tan, Michelle Li Mei Poon, Yoon Sim Yap, Wei-Peng Yong, Boon C. Goh, Dario Campana
Journal: Journal of Clinical Oncology (2016)

3045 Background: A mechanism of Tras is antibody-dependent cell cytotoxicity (ADCC) exerted by NK cells. ADCC may be impaired in cancer patients. We hypothesize that this can be restored by NK activation, and developed a method to generate large numbers of activated NK cells from MBC patients (pts) and tested the effects of NK infusion with Tras. Methods: Peripheral blood harvested from 11 refractory HER2+ MBC pts aged 32-67 (median 59), was co-cultured for 10 days with irradiated K562-mb15-41BBL cells. Expanded NK cells were infused 24 hours (H) post-Tras, with interleukin-2, 1MU/m2 thrice weekly for 6 doses starting 24H pre-infusion. Tras was continued 3 weekly up to 8 cycles (C); pts with sustained stable disease (SD) at C4 or C6 received a 2nd and 3rdinfusion at C6 and C8 respectively. Blood was taken serially for NK cell counts and function. Results: 16 NK cell products were prepared for the 11 pts; 3 pts had a 2nd, and 2 a 3rd infusion. Median NK cell expansion was 337-fold (range 91-478). Products contained 81±16% NK cells, virtually all CD16+ and highly cytotoxic: ADCC on HER2+ SKBR3 cells at 4H with Tras was 85.8±10.1% at 2:1 effector:target ratio (E:T). Pts had 2-13 (median 6) prior lines of palliative therapy. 3 of 16 infusions were at 1st dose level (106 NK cells/kg), and 13 at target dose (107/kg). NK infusion was well tolerated; worst toxicity was transient G2 thrombocytopenia (n = 1). There was no objective response but 7/10 evaluable pts, including 6 who had 107/kg at C1, had SD. Median progression free survival was 1.8 vs 8.5 months for pts who received 106/kg vs 107/kg cells at C1. NK cell counts increased from day (D) 1 (0.16±0.11x103/µL) to D8 (0.32±0.19x103/µL) or D22 post-infusion (0.36±0.20x103/µL) (p < 0.01), although levels were only slightly higher than baseline (0.31±0.22x103/µL). NK cells were 13±8% of PBMCs on D1 and 17±9% on D8; ADCC on SKBR3 cells with Tras without NK enrichment was 11±4% on D1 and 16±5% on D8 (2:1 E:T). Conclusions: This first-in-human study shows that large numbers of highly potent NK cells can be reliably generated from MBC pts and safely infused with Tras. The disease control seen in heavily pre-treated pts is encouraging and warrants further studies. Clinical trial information: NCT02030561.
Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-RT regimen in unresectable locally advanced NSCLC: The ETOP NICOLAS phase II trial.
Authors: Solange Peters, Dirk De Ruysscher, Urania Dafni, Enriqueta Felip, Matthias Guckenberger, Johan F. Vansteenkiste, Rudolf M. Huber, Ernest Nadal-Alforja, Antonio Irigoyen, Annemarie Becker, Anne-Christine Piguet, Marie Kassapian, Adriana Gasca-Ruchti, Alex Martinez Marti, Nicolaus Andratschke, Maarten Lambrecht, Claus Belka, Heidi Roschitzki-Voser, Rolf A. Stahel
Journal: Journal of Clinical Oncology (2018)

8510 Background: The feasibility of combined chemo-radiotherapy (chemo-RT) and concurrent PD-1 inhibition is of high scientific interest and has shown promising results in pre-clinical models. So far, concurrent immune-checkpoint inhibition and radical thoracic RT has never been assessed in a clinical trial. Methods: NICOLAS is a phase II trial evaluating the safety of the addition of nivolumab to first-line chemo-RT in stage III NSCLC. Efficacy will be evaluated if a safety conclusion has been achieved, based on a hierarchical design. Patients received 3 cycles of platinum-based chemotherapy (etoposide, vinorelbine or pemetrexed) and radical RT of 66 Gy. Nivolumab treatment (240 mg / Q4W) started concurrently to RT. The primary safety endpoint is defined as the rate of pneumonitis grade ≥3 at 6 months post RT. An interim analysis was scheduled when the first 21 patients reached 3 months follow-up after completion of RT, based on the assumption that 70% of the pneumonitis events occur within the first 3 months. An early positive safety conclusion is reached at interim analysis if there is no incidence of pneumonitis grade ≥3 in the initial 21 patients (exact group sequential design at one-sided significance level of 0.05 and power = 83%, testing a 6-month pneumonitis rate ≥33% versus ≤15%). Results: Up to December 14, 2017, 49 patients have been recruited with a median follow-up of 6.6 months [95% CI: 5.6, 7.8]. The median age is 63 years, with the majority of the patients being male (67.3%), former smokers (75.5%) and with tumor stage IIIb (65.3%). The most frequently observed adverse events (AEs) are fatigue and anemia. No unexpected AEs or increased safety risk were observed. For the first 21 patients, no pneumonitis grade ≥3 was observed by the end of the 3-month post RT follow-up period. The majority of these patients (18 patients) were on a concurrent chemo-RT schedule. Conclusions: This early interim safety analysis provides evidence that the addition of nivolumab to concurrent chemo-RT is safe and tolerable. In a next step, the 1-year progression-free survival will be evaluated according to the hierarchical design in an expanded patient cohort. Clinical trial information: NCT02434081.
Chronic hydroxychloroquine/chloroquine exposure for connective tissue diseases and risk of Alzheimer’s disease: a population-based cohort study
Authors: Laurence Fardet, Irwin Nazareth, Irene Petersen
Journal: Annals of the Rheumatic Diseases (2018)

Autophagy is an intracellular pathway by which cells generate energy and metabolites by recycling their own non-essential, redundant or damaged components.1 Pathophysiological studies have demonstrated that the impairment of autophagy contributes to protein aggregate accumulation that occurs during Alzheimer’s disease and experiments have shown that autophagy inhibitors, such as chloroquine and hydroxychloroquine, block amyloid plaque degradation.1 2 Further, a recent case–control study found that patients with rheumatoid arthritis who used hydroxychloroquine were at increased risk of dementia.3 We investigated whether chronic exposure to chloroquine/hydroxychloroquine increases the risk of Alzheimer’s disease.

Data from The Health Improvement Network (THIN) were used (January 1990–December 2016). THIN is a UK primary care database on >12 million people. Participating general practitioners prospectively enter clinical information on individuals so that the database provides a longitudinal medical record for each individual. THIN is representative of the UK population. …
£580m boost to general practice isn’t enough, say GP leaders
Authors: Adrian O’Dowd
Journal: BMJ (2018)

Doctors’ leaders have questioned the impact of a 3.9% real terms rise in investment in general practice in England over the past year, saying not all the money is reaching frontline care and the amount is insufficient to deal with existing problems.

NHS England said that it was ahead of its own target to invest £12bn (€13bn; $17bn) a year by 2020-21 in general practice—indicated by figures published by NHS Digital on 20 September1 that showed £10.8bn was invested in general practice in 2017-18—a real terms increase of 3.9% on the previous 12 months.

NHS Digital said, however, that the …
Increased Hepatotoxicity Associated with Sequential Immune Checkpoint Inhibitor and Crizotinib Therapy in Patients with Non–Small Cell Lung Cancer
Authors: Jessica J. Lin, Emily Chin, Beow Y. Yeap, Lorin A. Ferris, Vashine Kamesan, Inga T. Lennes, Lecia V. Sequist, Rebecca S. Heist, Mari Mino-Kenudson, Justin F. Gainor, Alice T. Shaw
Journal: Journal of Thoracic Oncology (2018)
Development of a prognostic index for gastric cancer with liver metastasis at the initial diagnosis: A single center retrospective study.
Authors: Yakun Wang, Lin Shen, Ming Lu, Xiaotian Zhang
Journal: Journal of Clinical Oncology (2018)

e16001 Background: The prognosis of gastric cancer patients with liver metastasis (GCLM) at the initial diagnosis is poor, unlike colorectal cancer with synchronous LM, the optimal treatment modality remains unclear. Recently, it’s reported that patients with favorable prognostic factors might benefit from active treatment. Therefore, we sought to investigate the prognostic factors of GCLM at the initial diagnosis. Methods: Between 2005 and 2016, 516 patients were diagnosed with GCLM, we only enrolled subjects who had LM at the initial diagnosis, leaving 389 cases for analysis. Univariate and multivariate analysis were conducted with log-rank tests and a Cox’s proportional hazard model, respectively. Results: The median overall survival (OS) was 13.6m (95% confidence interval (CI): 12.5-14.7months). In general treatment of metastatic GC, palliative chemotherapy was suggested by most guidelines. Other treatment modality beyond chemotherapy varies mainly based on patients’ response. Therefore, all factors that may affect clinician’s treatment attitude were analyzed. As a result, Lauren classification (P= 0.006), baseline serum AFP level (P= 0.039), extrahepatic metastasis (P= 0.047), and response to first-line chemotherapy (P< 0.001) were independent factors for overall survival. In addition, a simple prognostic index was generated using three risk groups, survival data of three groups were detailed in Table 1, differences between them were highly significant (P< 0.001). Conclusions: Four prognostic factors were identified for patients of GCLM at the initial diagnosis. Using a simple prognostic index, the patients were divided into three different risk groups. This prognostic model could help clinicians in decision-making on treatment modality after first-line systemic chemotherapy. Table1:. Comparison of survival stratified into three risk groups according to prognostic risk Risk group Prognostic index No. pts (%) Median OS(m) 95% CI P Good 0-1 61(41.5%) 20.7 17.8-23.6 < 0.001 Moderate 2 53(36.1%) 13.7 10.2-17.2 Poor 3-4 33(22.4%) 10.5 9.1-11.9
Impact of pretreatment neutrophil-lymphocyte and platelet –lymphocyte ratio in metastatic papillary renal cell cancer.
Authors: Meet Kadakia, Abhinav Sidana, Julia C. Friend, Akhil Muthigi, Louis Spencer Krane, Geri Hawks, Martha Ninos, W. Marston Linehan, Ramaprasad Srinivasan
Journal: Journal of Clinical Oncology (2016)

e16115 Background: Neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are markers of inflammation and have been demonstrated as important prognostic factors in various benign disorders and malignancies. Recently, there have been reports on the utility of NLR and PLR as prognostic factors in patients with metastatic renal cell cancer (RCC) but there is a little data to determine their role in metastatic papillary RCC (pRCC). We aim to evaluate the significance of NLR and PLR in determining overall survival (OS) in metastatic pRCC patients. Methods: Retrospective evaluation of the medical records of patients with metastatic pRCC seen at National Cancer Institute (2000-2014) was undertaken. Patient demographics, tumor characteristics and outcomes were studied. NLR > 5 and PLR > 210 were considered elevated based on previous reports in literature. Kaplan-Meier Survival analysis was done to estimate OS. Results: Out of a total of 106 patients with metastatic pRCC seen during the study time period, 68 had data for NLR and PLR between the time of diagnosis of metastasis and initiation of systemic therapy. Mean age at the time of diagnosis of metastatic disease was 49.7 (±14.3) years. NLR > 5 and PLR > 210 was found in 12 (17.6%) and 26 (38.2%) patients. There was no difference in mean age, gender, histologic subtypes and stage between the patients with elevated NLR vs NLR ≤ 5 or those with elevated PLR vs PLR ≤ 210. Fifty (73.5%) patients died during median follow up of 34.1 mon. All 12 patients with elevated NLR and 24 (92.3%) patients with elevated PLR died. Median estimated OS of patients with elevated NLR was significantly worse than the patients with NLR ≤ 5 (19.2 vs 46.5 mon, p = 0.001). Similarly, elevated PLR portended worse OS (27.3 vs 49.0 mon, p = 0.004). Median OS of patients with neither, either one or both markers elevated was 50.7, 33.0 and 19.2 mon respectively (p = 0.002). Conclusions: To our knowledge, this is the first report evaluating the prognostic impact of NLR and PLR in metastatic pRCC. Elevated PLR and NLR significantly impact OS in these patients. If validated in larger cohorts, it might be reasonable to incorporate NLR and PLR in nomograms predicting OS in metastatic pRCC.
A phase 1, open label, dose escalation study of MGD009, a humanized B7-H3 x CD3 DART protein, in combination with MGA012, an anti-PD-1 antibody, in patients with relapsed or refractory B7-H3-expressing tumors.
Authors: Sadhna Shankar, Alexander I. Spira, James Strauss, Liqin Liu, Ross La Motte-Mohs, Tony Wu, Syd Johnson, Ezio Bonvini, Paul A. Moore, Jon M. Wigginton, Jim Vasselli
Journal: Journal of Clinical Oncology (2018)

TPS2601 Background: T cells naturally undergo activation-induced upregulation of co-inhibitory pathways, which may limit the antitumor immune response. Blocking these inhibitory pathways may enhance the antitumor activity of CD3 bispecifics. MGD009 is a clinical stage B7-H3 x CD3 DART protein designed to redirect T cells to kill B7-H3 expressing tumor cells. B7-H3, a member of B7 family of immune regulators, is overexpressed in a variety of solid tumors and has limited expression in normal tissues. In preclinical studies, MGD009 causes T-cell infiltration, activation and expansion in the tumors. It upregulates PD-1 on T cells and PD-L1 on tumor cells and immune cells in vitro. Preliminary observations in patients enrolled in the ongoing phase 1 dose escalation trial with MGD009 alone indicate evidence of PD-1 up-regulation on both peripheral CD4 and CD8 T-cells. MGA012 is an anti-PD-1 antibody under investigation in an ongoing Phase 1 clinical trial and has shown clinical responses. In vitro and in vivo studies have shown enhanced antitumor activity with the combination of MGD009 and MGA012 beyond that achieved with MGD009 alone. A combination approach that blocks checkpoint inhibition of T cells with MGA012, while recruiting cytotoxic and helper T cells to B7-H3-expressing tumors with MGD009, may show anti-tumor activity in a variety of tumors. Methods: This is a Phase 1, open-label, dose escalation, and cohort expansion study designed to characterize the safety, tolerability, PK, pharmacodynamics, immunogenicity, and preliminary antitumor activity of MGD009 in combination with MGA012, both administered by IV infusion. Patients with B7-H3-expressing unresectable, locally advanced or metastatic solid tumors of any histology will be enrolled in the Dose Escalation Phase. Prior checkpoint inhibitor therapy is allowed. Dose escalation uses a 3+3+3 design, with patients treated every 2 weeks with escalating doses of IV MGD009 (starting dose 3µg/kg) and MGA012 at a dose of 3mg/kg in all cohorts. Cohort expansions will be limited to 6 tumor types (N = 20/cohort) treated at the maximum tolerated dose of the combination. Clinical trial information: NCT03406949.
Induction chemotherapy (CT) with FOLFIRINOX or FOLFOX/FOLFIRI, plus cetuximab (CET) or bevacizumab (BEV) (by RAS status), in patients (pts) with primarily unresectable colorectal liver metastases (CRLM): Results of the randomized UNICANCER PRODIGE 14-ACCORD 21 (METHEP-2) trial.
Authors: Marc Ychou, Michel Rivoire, Simon Thezenas, Rosine Guimbaud, Francois Ghiringhelli, Anne Mercier Blas, Laurent Mineur, Eric Francois, Faiza Khemissa, Marion Chauvenet, Yves Bécouarn, Philippe Houyau, Thomas Aparicio, Marie Pierre Galais, Franck Audemar, Eric Assenat, Antoine Adenis, Claire Jouffroy-Zeller, Rene Adam, Olivier Bouche
Journal: Journal of Clinical Oncology (2018)

3535 Background: pts with unresectable CRLM who respond to induction CT allowing curative-intent liver surgery have longer overall survival (OS) than pts who do not. Triplet (3-) or doublets (2-) CT, combined with CET or BEV, are often used in this setting. However, the best CT regimen remains to be determined. Methods: METHEP2 assessed whether 3-CT (FOLFIRINOX) compared to 2-CT (FOLFOX or FOLFIRI), combined with CET or BEV (by KRAS/RAS status), would increase R0/R1 liver-resection rate in pts with initially unresectable CRLM. Randomization was stratified by KRAS (amended to RAS) status, meta- vs. synchronous CRLM, and reason for non-resectability (technical vs. oncological). It was designed to demonstrate a 20% increase in the R0/R1 liver-resection rate (2-CT arm, 50% vs. 3-CT arm, 70%; bilateral α-test, 5%; β, 10%). Results: 256 pts were included, 126 in the 2-CT arm (FOLFIRI, 56; FOLFOX4, 70) and 130 in the 3-CT arm. KRAS and RAS were mutated in 91 pts (35.5%) and in 109 pts (42.6%), respectively. After a median follow-up of 45.6 months (mo), R0/R1 liver resection was achieved in 74/130 pts (56.9%; 95%CI, 48-66) in the 3-CT arm vs. 61/126 pts (48.4%; 95%CI, 39-57) in the 2-CT arm (p = 0.17). The odds for R0/R1 resection were higher in the 3-CT than in the 2-CT arm (OR, 1.8; 95%CI, 1.1-2.7; p < 0.02) when using a logistic regression model adjusted on stratification factors. Median OS was 42.9 mo in the 3-CT arm vs. 37.6 mo in the 2-CT arm (HR = 0.80; 95%CI, 0.56-1.16). Efficacy by targeted agent was as follows: R0/R1 resection 86/153 (56.2%; 95%CI, 48-64) and 49/103 (47.6%; 95%CI, 38-58), objective response: 120/153 (78.4%; 95%CI, 71-85) and 58/103 (56.3%; 95CI, 46-66), mPFS: 12.8 mo (95%CI, 11.6-13.1) and 10.7 mo (95%CI, 9.7-13.1), OS: 43.6 mo (95%CI, 40.0-51.8) and 34.2 mo (95%CI, 27.8-40.4), for CET- and BEV-treated pts, respectively. Conclusions: Despite not reaching our primary objective, FOLFIRINOX tends to be superior to FOLFIRI/FOLFOX, combined with CET or BEV, in terms of R0/R1 liver-resection rate in pts with initially unresectable CRLM. Clinical trial information: NCT01442935.
Abstract 12648: Severe Aortic Stenosis With Preserved Left Ventricular Ejection Fraction: Impact of Transaortic Flow, Transaortic Gradient and Age on Outcomes
Authors: Zaher Fanari, Dimitrios Barmpouletos, Vivek K Reddy, Sumaya Hammami, Zugui Zhang, William S Weintraub, Erik S Marshall
Journal: Circulation (2015)

Background: Combining transaortic flow and gradient defined four different aortic stenosis (AS) subgroups. The impact of transaortic flow and gradient and age on predicting the outcomes of severe AS with preserved ejection fraction (EF) is not well defined. Methods: We identified consecutive patients presenting to our echo lab with an aortic valve area (AVA) &lt; 1.0cm 2 and EF≥ 50%. We stratify patients depending on gradient (≥ 40 vs. &lt; 40 mmHg) and stroke volume index (SVI &lt; 35 vs. ≥35 ml/m 2 ). 4 groups were identified (, normal flow, high gradient [NF/HG]; normal flow, low gradient [NF/LG]; low flow, high gradient [LF/HG] and low flow, low gradient [LF/LG]. These 4 groups were also stratified depending on age (Age &lt; 75 vs. ≥75 years). All patients were retrospectively followed for the occurrence of death. Results: A total of 954 patients were included in analysis. Mean follow up was 2.45 ± 1.9 years. The mean age was 75.4 ± 5.6 years. Patients with LF had significant higher mortality than those with NF [32.6% vs. 25.8%; HR=1.39 (1.04-1.86); P=0.03]. Similarly, patients with HG had significant higher mortality than those LG [34.9% vs. 25.7%; HR=1.55 (1.17-2.06); P&lt;0.01]. Comparing all 4 AS subgroups, the mortality was higher in LF/HG followed by LF/LG, NF/HG and NF/LG (LF/HG 37.1% vs. LF/LG 33.9% vs. NF/HG 30.3%vs. NF/LG 20.2%; Log Rank Test, P=0.003). Older patients have a higher mortality rate than younger patients. [31.1% vs. 22.5%; HR= 1.55 (1.1-2.19); P= 0.01]. In Patients older than 75, comparing all 4 AS subgroups, the mortality was higher in LF/HG followed by LF/LG, NF/HG and NF/LG (LF/HG 37.9% vs. LF/LG 37.8% vs. NF/HG 35.0% vs. NF/LG 19.6%; %; Log Rank Test, P=0.003). Comparing the 4 flow-gradient groups in patients younger than 75 shows a similar, but not significant trend with the mortality is higher in LF/HG followed by LF/LG, NF/HG and NF/LG (LF/HG 32.4% vs. LF/LG 30.7% vs. NF/HG 25.8% vs. NF/LG 9.6%; Log Rank Test, P=0.058). Conclusion: Combining transaortic flow and gradient is essential in in predicting prognosis in severe aortic stenosis with preserved EF. Age add an incremental value to transaortic gradient and flow in predicting prognosis.