tbuckley/cabot-search huggingface dataset:
PARP inhibitors (PARPi) for the treatment of <i>BRCA</i>-mutated HER2-negative (HER2-) metastatic breast cancer (MBC) patients: A systematic review and meta-analysis.
Authors: Francesca Poggio, Marco Bruzzone, Marcello Ceppi, Benedetta Conte, Samuel Martel, Christian Maurer, Marco Tagliamento, Giulia Viglietti, Lucia Del Mastro, Evandro De Azambuja, Matteo Lambertini
Journal: Journal of Clinical Oncology (2018)

e13098 Background: The PARPi olaparib has been recently approved as the first targeted therapy available for BRCA-mutated HER2- MBC patients. This meta-analysis aimed to better evaluate the activity, efficacy and safety of single agent PARPi in this population. Methods: A systematic search of MEDLINE, Embase and conference proceedings up to January 31th2018 was conducted to identify randomized controlled trials (RCTs) investigating single agent PARPi versus chemotherapy (CT) in BRCA-mutated HER2- MBC. Using the random-effect model, we calculated summary risk estimates (pooled hazard ratio [HR] and odds ratio [OR] with 95% confidence intervals [CI]) for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), any grade and grade 3-4 adverse events (AEs) and time to deterioration in quality of life (QoL). Results: Two RCTs with 733 patients were included: the OlympiAD (olaparib) and the EMBRACA (talazoparib). In both trials, physician’s choice mono-CT (i.e. capecitabine, eribulin, gemcitabine or vinorelbine) was the comparator. As compared to mono-CT, PARPi significantly improved PFS (HR 0.56, 95% CI 0.45-0.70) and ORR (OR 4.15, 95% CI 2.82-6.10), with no difference in OS (HR 0.82, 95% CI 0.64-1.05), AEs of any grade (OR 1.37, 95% CI 0.49-3.85) and of grade 3-4 (OR 0.76, 95% CI 0.43-1.33). Use of PARPi was associated with a significant increased risk of anemia (any grade: OR 3.07, 95% CI 1.16-8.10; grade 3-4: OR 7.69, 95% CI 2.55-23.19) and any grade headache (OR 1.57, 95% CI 1.06-2.33), but a reduced risk of neutropenia (any grade: OR 0.53, 95% CI 0.29-0.96; grade 3-4: OR 0.40, 95% CI 0.23-0.67) and any grade palmar-plantar erythrodysestesia syndrome (OR 0.04, 95% CI 0.02-0.10). No significant difference in other types of AEs between PARPi and mono-CT was observed. Patients treated with PARPi experienced a significant delayed time to clinically meaningful QoL deterioration (HR 0.40, 95% CI 0.29-0.54). Conclusions: Single agent PARPi is effective and well tolerated in BRCA-mutated HER2- MBC. Although the optimal sequence is still to be determined, PARPi should now be considered as standard of care in these patients.
Comprehensive investigation of adverse event (AE)-related costs in patients with metastatic breast cancer (MBC) treated with first- and second-line chemotherapies.
Authors: Sara A. Hurvitz, Annie Guerin, Melissa G. Brammer, Ellie Guardino, Zheng-Yi Zhou, Michael S Kaminsky, Eric Q. Wu, Deepa Lalla
Journal: Journal of Clinical Oncology (2012)

1037 Background: MBC is incurable and managed with ongoing therapy. This study examined the incremental costs of chemotherapy-associated AEs in MBC. Methods: The PharMetrics Integrated Database (2000-2010) was used to identify MBC pts treated either 1 st or 2 nd line with a taxane (T) (paclitaxel or docetaxel) or capecitabine (C)-based regimen for ≥30 days (defined as a treatment episode (TE)). Incremental costs attributable to AEs were assessed by comparing costs incurred during TEs with and without AEs. AEs were identified using medical claims with a diagnosis for ≥1 event of interest (e.g., infections, fatigue, anemia, neutropenia). Pt characteristics were balanced between comparison groups (with and w/o AEs) using inverse probability weighting method. Incremental monthly costs due to AEs were estimated during the TEs and included the following cost components: inpt (IP), outpt (OP), emergency room (ER), other medical service, pharmacy costs (chemotherapy and other drugs), and total healthcare costs. Statistical comparisons were conducted using Wilcoxon tests. Results: 3,222 women (mean age=57) received a T or C as 1st or 2nd-line therapy for MBC. Of the 2,678 1st-line pts, 69.7% received T and 30.3% with C; average monthly total costs ranged from $9,159 to $10,298. AEs were commonly seen in pts treated with 1st-line T and C (94.6% and 83.7%). On average, the total monthly incremental cost associated with AEs was 38% higher ($3,547) for T and 9% higher ($854) for C. IP and other drug costs accounted for a majority of these costs. Of 1,084 2nd-line pts, 66% received T and 34% C, with average monthly total costs ranging from $5,950 to $12,979. 94.4% of T pts and 84% of C pts in the 2nd-line had an AE. The average total monthly incremental cost associated with AEs for T was $5,320 and $4,933 for C (69.5% and 82.9% higher vs pts w/o AEs). Pharmacy costs accounted for a majority of increased costs seen in pts with AEs treated with T; IP and OP accounted for a majority of these costs in pts treated with C. Conclusions: This is the 1 st study assessing costs associated with AEs for tx of mBC. AEs are associated with a substantial economic burden that is mainly explained by increased IP, OP, and pharmacy costs.
Comparison of different adjuvant therapy after radical surgery in early stage cervical carcinoma: A 3-arm randomized control study.
Authors: He Huang, Li Yang, Yue Wei Zuo, Li Guo Ma, Yi Le Chen, Shu Zhong Yao, Li Li, Hong Ping Zhang, Min Zheng, Yanna Zhang, Xin Huang, Judong Li, Yanfang Li, Xin Ping Cao, Ji Hong Liu
Journal: Journal of Clinical Oncology (2018)

5529 Background: To determine whether the addition of concurrent chemotherapy (CCT) or sequential chemotherapy (SCT) to adjuvant pelvic radiotherapy (RT) will improve prognosis of patients with early-stage cervical carcinoma who had adverse pathological factors. Methods: After radical surgery, patients with FIGO stage IB1 to IIA2 cervical cancer who had one or more of the following pathological factors were recruited: lymph node metastases (LNM), positive parametrium or margins (PPM), lymphatic vascular space involvement (LVSI), deep invasion of cervical stroma (DIS). Eligible patients were randomized to the three groups. Group A underwent 50 GY pelvic RT alone. Group B received concurrent weekly cisplatin and RT (CCRT). Group C received paclitaxel and bolus cisplatin every three weeks for two cycles before RT, followed by two cycles of chemotherapy (SCRT). Results: From February 2008 to August 2015, a total of 1055 cases were randomized and eligible for evaluation, with 352 cases in group A, 348 in group B and 355 in group C. The disease-free survival (DFS) was 132.3 month in group C versus 94.4 month in group A and 92.3 month in group B (P = 0.047), and the corresponding overall survival (OS) were 140 month, 105.4 month and 99.5 month (P = 0.20). In the intergroup analysis, a better DFS was found in group C (87 months) than the other two groups (79 month in group B and 69 months in group A, P< 0.05) among patients with LNM or/and PPM (high risk). While there was no significant difference in DFS was found between three groups in the patients with DIS and/or LVSI (intermediate risk), or in those patients who had indications for adjuvant treatment according to Sedlis Criteria. Alopecia (87.1%, P < 0.05) and pelvic lymph cyst (14.1% P < 0.05) were significantly higher in group C. There is no significant difference of grade 3/4 hematologic and gastrointestinal toxicities between group B and C. Conclusions: SCRT brought a better DFS in patients especially with high-risk cervical carcinoma. The sequential strategy may constitute an alternative treatment for the high-risk patients. However, CCRT and SCRT did not show survival benefit in patients with intermediate risk factors. Clinical trial information: NCT00806117.
MRI texture features and outcomes to immune checkpoint inhibitors in melanoma brain metastases.
Authors: Ankush Bhatia, Maxwell Birger, Harini Veeraraghavan, Hyemin Um, Anna Sophia McKenney, Marina Cugliari, Annalise Caviasco, Angelica Bialczak, Rachna Malani, Zhigang Zhang, T. Jonathan Yang, Robert J. Young, Alexander Noor Shoushtari
Journal: Journal of Clinical Oncology (2018)

2069 Background: Brain metastases (BM) in patients (pts) with melanoma historically portend a dismal prognosis, but immune checkpoint inhibitors (ICI) are associated with durable responses in a subset of pts. There are no validated imaging biomarkers associated with outcomes in pts with melanoma BM receiving ICI. We hypothesized that texture analysis of contrast T1-weighted magnetic resonance images (MRI) could identify “higher order” features associated with progression-free (PFS) and overall survival (OS). Methods: Between 2010 and 2017, we retrospectively reviewed pts with measurable ( > 1.0cm) melanoma BM on MRI who received ICI with or without concurrent radiation therapy (RT). Volume-of-interests were drawn around up to 5 BM per pt, and Haralick textures (n = 5), and Gabor edge features (n = 4) at angles (0°, 30°, 45°, 90°) and a bandwidth (γ = 2) were extracted for each lesion. Progression for BM was determined using RANO-BM; pts who died without repeat MRI were considered to have progressed. OS was calculated from date of ICI receipt. Cox regression was performed for each texture feature. Results: 88 pts with 196 total BM were identified. Median age was 63.5 (19-91), ECOG (0-54%, 1-34%, 2-3 12%), 38% had elevated LDH, and 42% had prior systemic treatment. ICI was CTLA-4 monotherapy in 77%, PD-1 monotherapy in 9%, and PD-1 + CTLA-4 in 14%. 79% received concurrent RT (38% focal, 62% whole brain). Median OS was 5.4 months (0.3-80.9). Increased energy (HR = 1.04, 95%CI 1.01-1.07, p = 0.02) was associated with a poorer progression-free (PFS) and OS (HR = 1.04, 1.00-1.07, p = 0.03). Increased entropy was associated with an improved PFS (HR = 0.82, 0.69-097 p = 0.02) and OS (HR = 0.84, 0.72-.99, p = 0.03). Both features remained significantly associated with OS (Energy HR = 1.15, 1.03-1.20, p = 0.02; Entropy HR = 0.84, 0.71-0.98, p = 0.03) after adjusting for receipt of RT and ICI (PD-1 vs. CTLA-4 vs. PD-1+CTLA-4). Conclusions: In the first ever analysis of higher order MRI features in pts with melanoma BM receiving ICI, Haralick texture features are associated with both PFS and OS. Further research is required to determine whether these features are independently associated with OS in a multivariate analysis.
BTC1.05 Role and significance of ZBTB18-CTBP2 interaction in Glioblastoma
Authors: A P Masilamani, R Ferrarese, G Andrieux, E Kling, M Börries, M Carro
Journal: Neuro-Oncology (2018)

The Zing Finger And BTB Domain Containing 18 (ZBTB18; formerly ZNF238) is a transcriptional repressor with a crucial role in brain development and neuronal differentiation. We recently showed that ZBTB18 represses poor prognosis-associated genes and that it is primarily silenced in mesenchymal GBMs through promoter methylation. To further elucidate the mechanism of ZBTB18 function, we performed Mass Spectrometry (MS) analysis of ZBTB18 co-precipitated proteins in SNB19 cells upon ZBTB18 overexpression. Our data revealed that the corepressors CTBP1 and CTBP2 could be potential ZBTB18 interactors. CTBPs are co-repressors which are implicated in human cancer by promoting several pro-oncogenic activities including EMT, cell survival, migration and invasion. We validated the interactions between ZBTB18 and CTBP2 by co-immunoprecipitation; interestingly, ZBTB18 contains a putative CTBP2 interaction motif (VLDLS) further supporting its role as new CTBP2 interactor. Gene expression analysis followed by gene set enrichment showed that both ZBTB18 overexpression and CTBP2 silencing affect the expression of EMT-signatures, suggesting that the two proteins play an opposite role. As such, ZBTB18 binding to CTBP2 could interfere with CTBP2 function. SILAC-based quantitative mass spectrometry analysis suggests that upon ZBTB18 overexpression, CTBP2 is sequestered by CTBP2 causing the disruption of the CTBP1/2 repressive complex and consequent deregulated gene expression. Overall our data suggest a new mechanism of EMT suppression by ZBTB18 through sequestration of CTBP2 and disruption of the CTBP1/CTBP2 repressive complex. A deeper examination of the proposed mechanism of ZBTB18 function could be used to reverse the mesenchymal phenotype of GBM.
Doctors who turn down flu vaccine could be redeployed
Authors: Declan C Murphy
Journal: BMJ (2018)

Doctors and other hospital workers in England who have direct contact with patients may have to move department if they refuse to be vaccinated against flu, NHS bosses have said.

A letter to hospital trusts from NHS England and NHS Improvement said, “In hospital departments where patients have a lower immunity and are most at risk of flu, it may be appropriate for healthcare workers who choose not to be vaccinated to be redeployed to other areas where this promotes patient safety.” High risk areas include haematology, oncology, bone marrow transplantation, neonatal intensive care, and special care baby units, although trusts may identify other areas with high proportions of more vulnerable patients.

“Our …
A phase II trial of bevacizumab-GemAOD regimen for newly diagnosed extranodal NK/T cell lymphoma.
Authors: Zhiming Li, Yu Wang, Jia Jia Huang, Tian Xiao Gao, Ke Wu, Fan Feng, Peng Sun, PanPan Liu, XiWen Bi, Yi Xia, Huilan Rao, Suxia Lin, Hanyu Wang, Wenqi Jiang
Journal: Journal of Clinical Oncology (2018)

7564 Background: Efficacy of L-asparaginase-based regimens has been confirmed for patients with extranodal natural killer/T-cell lymphoma (ENKTL). However, targeted therapy and optimal chemotherapy regimens for ENKTL remain to be determined. As high levels of vascular endothelial growth factor A (VEGF) is associated with a poor prognosis in ENKTL, we evaluated the efficacy and safety for bevacizumab (BEV) in the combination with gemcitabine, PEG-asparaginase, oxaliplatin and dexamethasone (BEV-GemAOD) regimen in untreated ENKTL in the Phase II Study (NCT 01921790). Methods: Patients with newly diagnosed ENKTL in stageⅠ-Ⅳ from 18 to 80 years were eligible for enrollment. BEV-GemAOD regimen (bevacizumab 7.5 mg/kg d1; gemcitabine 1000 mg/m2 d1, d8; PEG-aspargase 2500 U/m2 d1; oxaliplatin 130 mg/ m2 d1; dexamethasone 20 mg, d1-3; q3w) was planned as the protocol treatment. Patients with stage I/II received sandwich chemoradiation (BEV-GemAOD×3 cycles followed by RT 50.4 Gy followed by BEV-GemAOD×3 cycles). For stage III/IV, BEV-GemAOD regimen was repeated for six cycles. The primary endpoint was overall response rate (ORR) after six cycles of BEV-GemAOD. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. Results: 56 patients were enrolled from Oct 2013 to Feb 2018. 43 patients were evaluable for response: the median age, 37 years (range: 18-65 years); female, 25.6%; ECOG PS > 1, 20.9%; stageⅣ, 37.2%; elevated LDH, 39.5%; elevated EBV DNA, 60.5%. After 2 cycles of BEV-GemAOD, ORR were 100%. CR rate (CRR) in stage Ⅰ/Ⅱ and Ⅲ/Ⅳ were 88.9% (24/27) and 25% (4/16), respectively. After 6 cycles ORR were still 100%. CRR increased to 100% (27/27) and 87.5% (14/16), respectively. At median follow-up of 25.3 months, 2-year PFS and OS were 83.3% and 78.8%. The most common hematologic adverse event of grade 3/4 was neutropenia (32.6%). No patient died of treatment related toxicity. Conclusions: These results demonstrate that BEV-GemAOD regimen is feasible and provides high ORR, CRR and survival for either early- or late-stage patients with newly diagnosed ENKTL. Clinical trial information: NCT01921790.
Selumetinib plus docetaxel as second-line chemotherapy in KRAS mutant, KRAS amplified or MEK signatured gastric cancer patients: First arm of the umbrella trial in GC though the molecular screening, VIKTORY trial.
Authors: Jeeyun Lee, Seung Tae Kim, Iwanka Kozarewa, Hee Kyung Kim, Kyung Kim, Peter G. Mortimer, Simon J. Hollingsworth, Ju Lee, Minhwa Park, Se Hoon Park, Kyoung Mee Kim, Elizabeth Harrington, Won Ki Kang
Journal: Journal of Clinical Oncology (2018)

4061 Background: This trial was a phase II study with selumetinib (AZD6244)/docetaxel as second-line treatment for metastatic GC patients with MEK signature or RAS gene alterations as part of the GC umbrella trial, guided through the molecular screening, the VIKTORY trial (NCT#02299648). Methods: Selumetinib was administered orally 75mg twice a day continuously. Docetaxel was administered as an IV infusion over 1 hour at 60 mg/m2 every 3 week of a 21 days schedule. The primary objective was to investigate response rate (RR) and secondary objectives were to perform pre-planned analysis using ctDNA and tumors to identify an optimal biomarker for selumetinib. Results: Twenty seven patients who were identified through the VIKTORY screening to harbor KRAS mutation, KRAS amplification or MEK signature were enrolled onto the study. Of 27 patients, 12 patients had GC harboring KRAS mutation and two KRAS amplification. The remaining 13 patients were KRAS wild type with either low MEK signature (N = 7) or high MEK signature (N = 6). Only one of 12 KRAS mutant GC had high MEK signature. Of 25 patients who received the study drug, there were 7 partial responses (PRs), 8 stable diseases (SDs), 6 progressive diseases (PDs) and 4 non-evaluable diseases. The overall RR for the study combination was 28.0% (95 CI, 0.12 – 0.49). The most commonly observed any grade adverse events (AEs) were skin rash (7.4%) but no grade 3 or 4 skin rash. The second common AE was diarrhea (5.5%) which was all grade 1/2. In biomarker analysis, the two patients with had typical KRAS mutation (G12) or KRAS amplification with high MEKsignature achieved a PR from selumetinib/docetaxel . However, three with atypical KRAS mutation (i.e. A146P, Q61R, Q61H) with low/intermediate MEK signature showed PD to the combination therapy. Conclusions: Selumetinib plus docetaxel as 2nd line therapy revealed the useful efficacy and tolerable safety in GC patients with MEK signature or RAS gene alterations. Especially, the specific subset of patients with had typical KRAS mutation or KRAS amplification with high MEK signature were likely to benefit from selumetinib/docetaxel. Clinical trial information: NCT02448290.
Adrenocortical function during prolonged critical illness and beyond: a prospective observational study
Authors: Bram Peeters, Philippe Meersseman, Sarah Vander Perre, Pieter J. Wouters, Dimitri Vanmarcke, Yves Debaveye, Jaak Billen, Pieter Vermeersch, Lies Langouche, Greet Van den Berghe
Journal: Intensive Care Medicine (2018)

For patients suffering from prolonged critical illness, it is unknown whether and when the hypothalamus-pituitary-adrenal axis alterations recover, and to what extent adrenocortical function parameters relate to sepsis/septic shock, to clinical need for glucocorticoid treatment, and to survival.Patients still in ICU on day 7 (N = 392) and 20 matched healthy subjects were included. Morning blood and 24-h urine were collected daily and cosyntropin tests (250 µg) performed weekly, repeated 1 week after ICU discharge on the regular ward.In all patients free of glucocorticoid treatment up until ICU day 28 (N = 347), plasma ACTH always remained low/normal, whereas free cortisol remained high (P ≤ 0.002) explained by reduced binding proteins (P ≤ 0.02) and suppressed cortisol breakdown (P ≤ 0.001). Beyond ICU day 28 (N = 64 long-stayers), plasma (free)cortisol was no longer elevated. One week after ICU discharge, plasma ACTH and (free)cortisol always rose to supra-normal levels (P ≤ 0.006), most pronounced in long-stayers. Long-stayers always showed low incremental total (P ≤ 0.001), but normal incremental free cortisol responses to weekly cosyntropin tests, explained by low cortisol plasma binding proteins. Sepsis/septic shock patients were not different from others, patients subsequently receiving glucocorticoids (N = 45) were not different from those who did not, and non-survivors were distinguishable from survivors only by higher (free)cortisol.Irrespective of sepsis/septic shock, need for glucocorticoids and survival, low cortisol plasma binding proteins and suppressed cortisol breakdown determine systemic (free)cortisol availability in prolonged critical illness, the latter no longer elevated beyond ICU day 28. The uniform rise in ACTH and cortisol to supra-normal levels 1 week after ICU discharge indicates recovery of a central adrenocortical suppression while in ICU. Low cortisol plasma binding invalidates the cosyntropin test.
Reframing clinical trial design and intervention development.
Authors: Steven Hirschfeld
Journal: Journal of Clinical Oncology (2016)

e14044 Background: Based on Eroom's Law (Nature Rev Drug Disc 11, 191-200:March 2012) the cost per molecule and number of clinical trials for new therapies increases with a doubling time of nine years. Given the number of initial oncology approvals for new products per year over the past 21 years has a mean of 8 new products/year (std dev = 4.4; Poisson cumulative dist = 0.99), the costs of oncology product development will continue to rise with the system becoming less efficient. Common estimates are 70% of the costs are from clinical trials while high throughput and optimization efforts have focused on preclinical activities. Methods: Reframing the clinical portion of product development as a signal detection system assigns signal generation to the target population, outcome measures as signals, and outcome measure assessment as signal detection. Any intervention the target population is exposed to has the potential to be a signal modulator, and can affect any one or combinations of parameters such as phase, amplitude, frequency, jitter, or patterning. Using modeling and simulation, receiver operating characteristic (ROC) curves were generated for various outcome measures typically used in oncology such as survival, various types of response, progression free survival, and general parameters such as sleep, appetite, social interactions and ambulation. For each outcome measure, signal performance parameters were calculated, and the simulation optimized parameters based on the ROC curve. Results: Sequential optimization of signal assessment parameters, followed by adjustments in phenotypic characteristics of the patient population allowed maximal signal to noise detection. The parameters can be captured clinically to improve efficiency of signal detection and thus measure effects of signal modulation with improved precision. The improvement over conventional published methods can be up to 30% depending upon the outcome measure. Conclusions: System optimization through patient selection, signal selection and signal detection can improve the ability to detect meaningful clinical effects and consequently improve efficiency of cancer product development.