tbuckley/cabot-search huggingface dataset:
Comparison of poly(ADP-ribose) polymerase inhibitors (PARPi's) as maintenance therapy for platinum-sensitive ovarian cancer: Systematic review and network meta-analysis.
Authors: Amos Stemmer, Dalia Tsoref, Salomon M. Stemmer
Journal: Journal of Clinical Oncology (2020)

e18070 Background: Over the past decade, 3 PARPi's (olaparib, niraparib and rucaparib) have been approved by the FDA as maintenance therapy for recurrent ovarian cancer. However, thus far, no trial compared the 3 approved PARPi's in the overall population, in patients with BRCA mutations (BRCAm), or in those with wild-type BRCA (BRCAwt). Methods: We performed a systematic review and identified relevant literature from Embase, Pubmed and Cochrane Library. To be included in the analysis, studies had to be phase 2 or 3 randomized controlled trials (RCT) of platinum-sensitive recurrent or newly diagnosed ovarian cancer, randomized to placebo or PARPi as maintenance therapy and where complete or partial response was documented. A frequentist network meta-analysis was used for indirect comparisons between the different PARPi's to assess superiority in terms of progression free survival (PFS), overall survival (OS), and adverse events. Results: Overall, 6 RCTs involving 2,770 patients, were included in the network meta-analysis. Results from the indirect comparisons revealed no statistically significant differences between the 3 different PARPi's with respect to OS. PFS results demonstrated a nonsignificant trend supporting superiority for niraparib in all patients as well as in BRCAm patients (Table). Only 2 studies reported OS results for niraparib and none reported OS results for rucaparib. Niraparib showed a statistically significant increased risk for all grade thrombocytopenia and neutropenia. Conclusions: Our analysis demonstrates no statistically significant differences between the 3 PARPi’s in any of the analyzed groups, and a trend supporting PFS superiority for niraparib in all patients and in BRCAm patients, while having greater risk for thrombocytopenia and neutropenia. Additional OS results are pending from current studies, and would be useful for elucidating the relative roles of the different PARPi's in platinum-sensitive ovarian cancer. [Table: see text]
Assessment of FcgRIIIA single nucleotide polymorphisms (SNPs) on the efficacy of IgG1 monoclonal antibodies (mAbs) in PANGEA study patients (pts) with advanced gastroesophageal adenocarcinoma (aGEA).
Authors: Anthony Serritella, Bryan Peterson, Katherine I. Zhou, Nicole Arndt, Daniela Del Gaudio, Kelly Arndt, Soma Das, Samuel J Klempner, Ping Liu, Daniel V.T. Catenacci
Journal: Journal of Clinical Oncology (2020)

4526 Background: Targeted therapies (Ttx) have had limited efficacy in aGEA. The phase IIa PANGEA trial assessed the outcomes of pts treated with IgG1 mAbs targeting receptor tyrosine kinases (RTKs) or PD-1 based on predefined molecular groups. The fragment C (Fc) portion of mAbs binds to IgG receptors (FcgR) of immunologic effector cells such as natural killer (NK) cells, leading to antibody-dependent cell-mediated cytotoxicity (ADCC). The FcgR subclass, FcgRIIIA, has genetic variants with different Fc binding affinities. A single nucleotide polymorphism (SNP) in FcgRIIIA substitutes phenylalanine (F) with valine (V) at amino acid position 158, enhancing FcgR’s affinity for the IgG1 Fc domain. Pts with V/V or V/F FcgRIIIA allotypes have enhanced NK cell binding affinity compared to the homozygous F/F allotype. We evaluated the association of FcgRIIIA SNPs on Ttx outcomes amongst PANGEA pts and another cohort of aGEA pts treated with IgG1 mAbs. Methods: Whole-blood samples were identified from aGEA pts (N = 104), including 70/80 available PANGEA pts, who were treated with an IgG1 mAb (trastuzumab 24, anti-EGFR 21, anti-PD1 30, ramucirumab 48) in at least 1 Ttx line. After lymphocyte DNA extraction, FcgRIIIA genotyping was performed. The Cox proportional hazard model and log-rank tests, adjusted for pt age, were used to assess for an association of genotype with overall survival (OS). Results: Of 104 genotyped pts, the F/F, F/V &amp; V/V genotypes were observed at a frequency of 32%, 51% and 17% respectively. There was no significant difference in median OS (mOS) between the F/F, F/V or V/V or comparing F/F vs V/F+V/V overall, nor in the PANGEA-only cohort. A trend of increased mOS was seen in 20 non-PANGEA pts harboring F/V or V/V compared to 14 F/F pts (mOS 43.4 vs 23.1 months, HR 0.41 [0.15-1.14] p = 0.09). However, 3-year OS rates trended higher in V/F+V/V pts (22%, 16/71) compared to F/F pts (7%, 2/33) (p = 0.09). At 3 years, 50% of V/V+V/F non-PANGEA pts were alive versus 13% of F/F pts (p = 0.04), while 13% of V/V+V/F PANGEA pts were alive versus 0% of F/F pts (p = 0.32). Conclusions: Amongst pts receiving IgG1 mAbs, the high affinity V FcgRIIIA SNP enriched for a subgroup of ‘extreme responders’ alive 3 years from diagnosis. Multivariate analyses accounting for baseline characteristics in a larger number of pts are ongoing to further elucidate the role of FcgRIIIA SNPs as predictive biomarkers. These findings may have implications on IgG1 mAb ADCC optimization.
Rates of Adverse Events per Patient-Year in a Randomized, Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Newly Diagnosed, Treatment-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes
Authors: Bruno C Medeiros, Jeffrey E. Lancet, Jorge E. Cortes, Laura F. Newell, Tara L. Lin, Ellen K Ritchie, Robert K. Stuart, Stephen A. Strickland, Donna Hogge, Scott R Solomon, Richard M. Stone, Dale L. Bixby, Jonathan E. Kolitz, Gary J. Schiller, Matthew J. Wieduwilt, Robert J. Ryan, Michael Chiarella, Arthur C Louie, Geoffrey L. Uy
Journal: Blood (2017)
Machine learning for prospective identification of immunotherapy related adverse events (irAEs).
Authors: Daniel Margalski, Thomas Lycan, Suraj Rajendran, Umit Topaloglu
Journal: Journal of Clinical Oncology (2020)

e14064 Background: The ubiquitous implementation of immunotherapy has significantly improved outcomes in the treatment of cancer patients; however, once rare adverse events from these therapies have increased in lock step. We now face an increased burden of identification on providers with limited experience in the diagnosis of irAEs. We use machine learning to develop prediction models that will aid providers in identifying patients at high risk for developing irAEs as well as for multiple downstream applications. Methods: We have manually extracted progress notes from 462 patients with non-small cell lung cancer treated with immunotherapy who had known irAEÕs, with focus on pneumonitis, colitis, and rash; the most common symptomatic irAEÕs. Labels were applied by clinician review to train the machine learning algorithm to identify the predictive signals at the earliest stage of recognition possible. As a standard Natural Language Processing method, we cleaned the notes to standardize punctuation, numbers and special characters. Next, we created a word embedding matrix utilizing word2vec as well as Google News Vector. Finally, we implemented a Convolutional Neural Network (CNN) on the Microsoft Azure Databricks platform. Due to class imbalance, we deployed a Synthetic Minority Over-sampling Technique algorithm as a correction. We prioritized F1 score in the analysis given the heterogeneity of the data, but will present accuracy, precision and recall as well. Results: We trained our CNN with 10 epochs resulting in an F1 of 0.428, accuracy of 0.895, precision of 0.75 and recall of 0.3. There was no significant difference in results between the word embedding matrices. Conclusions: Using machine learning, we created an algorithm for irAE prediction that was accurate but lacked recall. This will serve as the foundation of implementations including the creation of a clinical decision support tool to guide focused and appropriate treatment of the unique toxicity of irAEs. Although informative as a starting point, this model had a final F1 score that was lower than expected presumably due to class imbalance of input data and the temporal nature of progress notes, which limits the utility of a CNN. Future iterations of the algorithm will include supplementary documentation and implement recurrent neural networks with long short-term memory architecture to address these limitations.
The potential role of extracellular matrix in the activity of trabectedin.
Authors: Alessandro De Vita, Federica Recine, Giacomo Miserocchi, Federica Pieri, Anna Farnedi, Francesco Fabbri, Valentina Fausti, Chiara Liverani, Chiara Spadazzi, Claudia Cocchi, Roberto Casadei, Giorgio Ercolani, Nada Riva, Lorena Gurrieri, Toni Ibrahim, Laura Mercatali
Journal: Journal of Clinical Oncology (2020)

e23542 Background: Soft tissue sarcomas (sts) represent a rare group of solid neoplasm of mesenchymal origin with a 1% incidence of all adult cancers. Liposarcoma and leiomyosarcoma (L-sarcoma) are the most common histotypes. The current first-line treatment for advanced/metastatic L-sarcomas is represented by anthracycline based-regimens. Second-line therapy options include trabectedin, eribulin, ifosfamide, gemcitabine and dacarbazine. In particular, the activity of trabectedin, a tetrahydroisoquinoline molecule, as well as its mechanism of action is not completely elucidated. Methods: The study involved six patient affected L-sarcoma. Patient-derived primary cultures were established after patient surgical treatment. Primary cells were cultured in standard monolayer culture and 3D collagen-based scaffolds. In order to gain inside into the mechanism of action of the drugs, genomic-, chemobiogram, proteomic-, cytometer and in silico analysis were performed. Results: The results confirmed the preservation of tumor gene expression in 3D culture model compared to standard monolayer culture. In particular 3D culture system was able to resemble the patient gene expression of TGFb, SLUG, SNAIL, MMP9 compared to 2D. In silico analysis showed an upregulation of COL1A1 gene, the extracellular matrix component of the present 3D model, in sts compared to other tumors. Pharmacological analysis displayed an increased sensitivity to trabectedin in all the 3D L-sarcoma primary culture compared to 2D culture system, while this was not observed with the other drugs. As previous preclinical evidences suggested that trabectedin mechanism of action include the impairing of ECM proteolytic degradation mediated by tumor cells, we think that its high observed sensitivity depend on the presence of collagen in our 3D- model. Conclusions: These results were suggestive of the losing credibility of monolayer standard culture for pharmacology studies and highlight the promising role of 3D patient-derived culture model for the study of sts biology. Moreover these results shed the light on the potential role of ECM in the mechanism of action of trabectedin in L-sarcomas. The work points out the role of this tumor microenvironment component in predicting response to trabectedin and provide the rationale for better stratifying patients which will be candidate for this drug. Further researches are needed to confirm these evidences.
Envafolimab plus chemotherapy in advanced gastric or gastroesophageal junction (G/GEJ) cancer.
Authors: Xianli Yin, Yun Zhang, Yanhong Deng, Nong Xu, Jianming Xu, Lei Li, Xiaotong Song, Haolan Lu, John Gong, Dongfang Liu
Journal: Journal of Clinical Oncology (2020)

e16585 Background: Envafolimab is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc, formulated for subcutaneously (SC) injection. This study examined the feasibility of combining envafolimab with chemotherapy in advanced G/GEJ cancer. Methods: This study was a single arm, phase Ⅱ trial in adult subjects with previously untreated advanced G/GEJ cancer. Subjects received 8 cycles (2 weeks each) of envafolimab plus FOLFOX regimen followed by envafolimab and 5-FU until progression or unacceptable toxicity. Envafolimab was administrated SC at 5 mg/kg on day 1 of each cycle; FOLFOX consisted of 80 mg/m 2 oxaliplatin, 400 mg/m 2 5-FU and 400 mg/m 2 leucovorin intravenous infusion on day 1, 2400 mg/m 2 5-FU administered with a 48-hour continuous infusion on day 1 and 2. Tumor was assessed every 6 weeks per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Primary endpoints were safety and tolerability. Toxicity was graded using CTCAE v5.0. Secondary endpoints included objective response rate (ORR), duration of response (DoR). and progression free survival (PFS). Results: A total of 15 subjects were treated and evaluable for response. ECOG performance status was 1 in 80% of subjects. Majority had gastric cancer (86.7%). At the data cutoff, the minimum follow-up was 6 months. The treatment emergent adverse event (TEAE) occurrence was 100% (all grades) and 73.3% (grades 3-4). The most frequent grade 3-4 TEAE included neutrophil count decreased 46.7%, anemia 20.0%, and platelet disorder 20% (3/15). Confirmed ORR was 60% (unconfirmed ORR: 73.3%). Median DOR was not reached. Median PFS was 6.8 months. Conclusions: Envafolimab plus FOLFOX demonstrated a manageable safety profile with promising clinical efficacy as a first line therapy for advanced G/GEJ cancer. Clinical trial information: CTR20181124 .
Results of crossover phase II component of randomized placebo-controlled trial evaluating oral THC/cannabis extract for refractory chemotherapy-induced nausea and vomiting (CINV).
Authors: Peter S. Grimison, Martin R. Stockler, Adrienne Kirby, Anna Walsh, Nicholas Lintzeris, Yvonne Cheung, Antony Mersiades, Annette Tognela, Paul Haber, John Simes, Rachael L. Morton, Ian N. Olver, Iain McGregor, Craig Gedye, Peter Fox, Karen P. Briscoe, Morteza Aghmesheh, Ehtesham A. Abdi, Stephen John Clarke, Stephen Della-Fiorentina
Journal: Journal of Clinical Oncology (2020)

12008 Background: The aim of this multi-centre, randomised, double-blinded, placebo-controlled, phase 2/3 trial is to determine efficacy of addition of oral cannabis in adults with any malignancy of any stage, experiencing CINV during moderate-highly emetogenic intravenous chemotherapy, despite guideline-consistent anti-emetic prophylaxis, requiring ≥ 2 chemotherapy cycles. Here we report the crossover phase 2 component results. Methods: Treatment consisted of 1 cycle of oral THC 2.5mg/CBD 2.5mg (TN-TC11M) capsules tds days -1 to 5 and 1 cycle matching placebo in a crossover design, then blinded patient preference for a 3 rd cycle. Primary end-point is difference in proportion of patients with ‘complete response’ (no emesis &amp; no use of rescue medications) during 0-120 hours from chemotherapy between cycles. 80 patients provides 80% power with 2p of 0.1 to detect a 20% difference. Results: 81 patients recruited (2016-9). 72 completing 2 cycles are included in efficacy analyses. 78 not withdrawing consent are included in safety analyses. Median age was 55 years (range 29-80), 78% were female, 42% report historic cannabis use, 55% were treated with curative intent. Most common regimens were AC (26%), FOLFOX (17%). All received steroids &amp; 5-HT3 antagonist, 79% received NK-1 antagonist, 4% received olanzapine. Efficacy is shown in table. 83% preferred cannabis to placebo. Most common bothersome cannabinoid-related adverse events (cannabis, placebo) were sedation (19%,4%), dizziness (10%,1%), disorientation (3%,0%). No SAEs were attributed to THC/CBD. Conclusions: Addition of oral THC/CBD to standard anti-emetics was associated with less nausea &amp; vomiting but additional side effects. Most preferred THC/CBD to placebo. Based on these positive results, the definitive parallel phase 3 trial component continues (additional n=170). Acknowledgements: Trial participants, investigators, research staff. Funding from NSW Government Dept of Health. Clinical trial information: ACTRN12616001036404 . [Table: see text]
Montelukast sodium combined with fluticasone propionate for children with cough variant asthma
Authors: Jianchuan Chen, Feng Pan, Sijie Yu, Jihong Dai
Journal: BMJ (2016)

Objective
To investigate the efficacy and safety of montelukast sodium combined with fluticasone propionate in treatment of children with cough variant asthma.


Methods
Two hundred and forty children diagnosed as cough variant asthma in our hospital during February 2013 to January 2015 were randomized into three groups.Children in group Mon+ Flu were given montelukast sodium combined with inhaled fluticasone propionate, children in group Flu was given inhaled corticosteroids alone and children in group Mon was given montelukast sodium alone.Cough, lung function and adverse reactions were observed after 8 and 12 weeks of treatment and the recurrences of cough symptoms were followed up within 24 weeks.


Results
After 8 weeks of treatment, the score of cough in group Mon+ Flu (1.1±0.7) was lower than those in groups Flu (1.7±0.8) and Mon (1.6±0.8) (t=4.973, 4.353, P 0.05). Meantime, the percentage of predicted in FEV1 in group Mon+ Flu (93.4±15.8) was significantly higher than those in group Flu (87.4±11.0) and group Mon (86.5±9.8)(t=2.804, 3.315, P 0.05). After 12 weeks of treatment, there was no significant difference in scores of cough and percentage of predicted in FEV1 and PEF among three groups (P>0.05). There was no significant difference in incidence of adverse reactions among three groups (χ2=1.026, P>0.05). The recurrence rate of group Mon+ Flu (3.85%) and group Flu(5.26%) were significantly lower than that of group Mon(17.33%)(χ2=7.428, 5.505, P 0.05).


Conclusions
For children with cough variant asthma montelukast sodium combined with fluticasone propionate has better efficacy than monotherapy in 8 weeks of treatment, but there was no difference in 12 weeks of treatment.The recurrence rate in group Mon+ Flu and group Flu is lower than that in group Mon.


Key words: 
Child; Treatment outcome; Cough variant asthma
An oro-buccal nanoparticle delivered cannabis medicine for pain management in cancer: A clinical trial in progress.
Authors: Stephen John Clarke, Luis Vitetta, Andrew J McLachlan, Jeremy David Henson, David Rutolo, Sean Hall
Journal: Journal of Clinical Oncology (2020)

TPS12127 Background: Cannabinoid molecules derived from Cannabis sativa L. have been posited to ameliorate conditions, including pain, chemotherapy induced nausea and multiple sclerosis associated spasticity. The clinical use of cannabinoids refers to a wide variety of formulations and extracts that may contain different active ingredients and adulterants as well as inter batch variability. Novel matrix formulations (e.g., water-soluble nanoparticles) for cannabis delivery may add further efficacy and tolerability to standard routes of administration (e.g., oral / gastrointestinal, inhaled, sublingual). This is further emphasized by the dysbiotic effects on the intestinal microbiome reported for oral formulations of medicinal cannabis, and which resulted in reduced efficacy. Similar results have been reported for other psychotropic compounds, such as alcohol and nicotine. Therapeutic use of cannabinoid formulations may be mode of delivery dependent in order to achieve safe, tolerable and effective doses. Methods: A water soluble oro-buccal nanoparticle spray with a racemic 1:1 mixture of Delta9Tetrahydrocannabinol (D9THC) and Cannabidiol (CBD), which bypasses the gastrointestinal system and first pass metabolism by accessing the systemic circulation via the facial lymphatics system, was investigated in patients with advanced cancer and unrelieved pain in a single ascending dose and multiple ascending dose in a first-in-human study. Results: The THC / CBD combination delivered as a submicron particle demonstrated safety, tolerability and a pharmacokinetic profile suitable for maintenance analgesic therapy. Preliminary analysis found an overall (n = 25) improvement in pain scores, especially in the subgroup of patients with bone metastases (n = 8), who obtained a greater than 30% average reduction in pain severity. 1 Clinical trial information: ACTRN12617001480370 .
Clinical outcomes of patients with gastric cancer according to pre and post-neoadjuvant chemotherapy PD-L1 immunohistochemistry (IHC) expression.
Authors: Heber Salvador de Castro Ribeiro, Wilson Luiz da Costa, Maria Dirlei de Souza Begnami, Celso Abdon Lopes Mello, Tatiane Neotti, Alessandro Landskron Diniz, André Luis Godoy, Igor Correa Farias, Silvio Melo Torres, Diego Greatti Vaz Vaz da Silva, Victor Hugo Fonseca Jesus, Rachel Pimenta Riechelmann, Emmanuel Dias-Neto, Felipe José Fernández Coimbra
Journal: Journal of Clinical Oncology (2020)

e16569 Background: The incidence, prognostic and predictive impacts of PD-L1 expression in locally advanced gastric cancer is unknown. We aimed to determine the expression of PD-L1 by CPS in the pre-treatment biopsy and surgical specimens of patients (pts) with gastric cancer who received neoadjuvant therapy and its association with pathological response and survival outcomes. Methods: Retrospective cohort of pts treated at a cancer center from 2007 to 2017. Pts with confirmed gastric or GEJ adenocarcinoma who received neoadjuvant treatment and curative-intent D2 surgery were included. Gastric stump tumors and those who had a total esophagectomy were excluded. Clinical data were obtained from medical charts. Biopsy samples and a tissue microarray with the most representative areas of the surgical specimen were used to detect PD-L1 IHC expression with 22C3 phamDx antibody. Results were analyzed using the CPS score. Overall and DFS survival included the Kaplan-Meier product-limit estimator in an ITT analysis and a Cox regression was used to obtain crude and adjusted HR for prognostic factors. Results: 270 pts were included: median age was 58.9 years, most (51.5%) had cT3-T4N+ stages, 45% had diffuse histology and 87.8% completed the preoperative regimen. 13% had a pCR, while 53% had minimal tumor regression. With a median follow-up of 60.3 months (CI 95% 54.7 – 65.8), the median OS and DFS were not reached. 11.4% of biopsies and 18.6% of surgical specimens had positive CPS, with a median score of 3 (IQR 2,0 – 7,5) and 9 (IQR 5.0 – 20.0) respectively. In 18.9% of paired samples the PD-L1 expression was found to be negative in the biopsy sample and positive in the surgical specimen. PD-L1 expression was neither associated with pathologic response after neoadjuvant chemotherapy, nor with survival outcomes. Conclusions: PD-L1 expression on the setting of locally advanced gastric cancer was low and it was different when biopsy and surgical specimens were compared. No impact on survival results could be detected. [Table: see text]