tbuckley/cabot-search huggingface dataset:
A novel CD3xPSMA bispecific antibody for efficient T cell mediated killing of prostate tumor cells with minimal cytokine release.
Authors: Starlynn Clarke, Kevin Dang, Yuping Li, Preethi Sankaran, Duy Pham, Aarti Balasubramani, Laura Davison, Katherine Harris, Brett Jorgensen, Ute Schellenberger, Nathan Trinklein, Harshad Ugamraj, Roland Buelow, Wim Van Schooten, Shelley Force Aldred, Ben Buelow
Journal: Journal of Clinical Oncology (2019)

324 Background: Castration resistant prostate cancer (CRPC) remains an incurable disease and new therapeutics are urgently needed. Prostate specific membrane antigen (PSMA) is expressed on the surface of prostate cancer cells and expression increases with disease progression. Therapies directed against PSMA such as radiolabeled antibodies and T cell redirecting therapies including chimeric antigen receptor T cells (CAR-Ts) and T-cell engaging bispecific antibodies (T-BsAbs) have shown promising efficacy in clinical trials but also induce significant toxicity. In particular CAR-Ts and T-BsAbs potently kill tumor cells but induce cytokine release-related toxicities. Novel anti-CD3 engaging domains may be required to create T-BsAbs with a broader therapeutic window. We have developed fully human CD3xPSMA bispecific antibodies that efficiently eliminate prostate tumor cells while minimizing cytokine release. Methods: Antibodies targeting CD3 and PSMA were generated in transgenic rats that produce human antibodies (UniRat, OmniFlic) followed by repertoire deep sequencing of lymph nodes isolated from immunized animals and high-throughput gene assembly/expression. CD3xPSMA T-BsAbs were assembled and evaluated for T cell activation and ability to eliminate PSMA+ tumor cells in vitro. Results: Primary human T cells were activated only in the presence of both bispecific CD3xPSMA antibodies and PSMA (either plate-bound or on the surface of tumor cells). Potent and selective cytotoxicity against PSMA+ prostate tumor cells was observed in co-cultures of primary human T cells and tumor cells treated with CD3xPSMA bispecific antibodies. Strikingly, CD3xPSMA bispecifics containing a novel low affinity anti-CD3 domain produced similar levels of tumor cell cytotoxicity compared to CD3xPSMA bispecifics containing a traditional high affinity anti-CD3 domain, but with reduced cytokine production. Conclusions: We have created novel CD3xPSMA bispecific antibodies that mediate T-cell killing of PSMA+ tumor cells with minimal production of cytokines. Such T-BsAbs may improve safety, efficacy, and opportunities for combination therapy to treat CRPC.
enFlow fluid warming device: warning over risk of aluminium toxicity
Authors: Harriet Pike
Journal: BMJ (2019)

The enFlow IV fluid warming device should only be used if no alternative is available because of the risk of aluminium toxicity, the UK’s medicines devices agency has warned.

The device, manufactured by Vyaire Medical, is used to warm fluids and blood before they are infused into patients during surgery.

But a recent paper in Anaesthesia 1 showed that uncoated aluminium plates in fluid warming systems, such as those used in the enFlow system, yielded potentially harmful concentrations of aluminium when using balanced electrolyte solutions.

A spokesperson for …
Analysis of <i>EGFR</i> mutant upper tract and bladder urothelial carcinoma (UC) reveals distinct mutational landscape.
Authors: Russell Madison, Sumati Gupta, Jeffrey S. Ross, Alexa Betzig Schrock, Luke Juckett, Vincent A. Miller, Brian Michael Alexander, Sumanta K. Pal, John Heymach, Andrea Necchi, Jay L Koyner, Siraj Mahamed Ali, Jon Chung, Venkataprasanth P. Reddy
Journal: Journal of Clinical Oncology (2019)

416 Background: Genomic alterations (GA) of EGFR, are well recognized as druggable oncogenic drivers in NSCLC, but the druggable GA EGFR L858R and exon 19 deletion (ex19del), are rarely observed in genitourinary cancer. We reviewed the genomic landscape of advanced upper tract and bladder UC (UTUC and BUC) to assess the frequencies of druggable EGFR GA. Methods: Tissue specimens from patients with UTUC (407) and BUC (2,402) were assayed using hybrid capture-based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Results: EGFR alterations ( EGFR alt ) were present in 17 UTUC and 93 BUC (4.2% and 3.9%). Age distribution between the two subgroups was similar, but UTUC was more prevalent in female patients (47% v 29%). BUC had a higher median TMB (5.2mut/mb v 7.8 mut/mb; p = 0.046) and the prevalence of MSI-H cases was not significantly different. TERT (55% v 66%) and TP53 (58% v 74%) were the most frequently mutated genes in EGFR alt UTUC and BUC. Within EGFR alt , amplifications were the most common alterations in both UTUC and BUC (13/17, 76%; 57/93, 63%). Amplifications were mutually exclusive from cases with EGFR short variants (SV) in BUC (0/34, 0%), and co-occurred with EGFR SV in four UTUC cases (4/8 50%). The majority of EGFR SV were EGFR exon 20 insertions ( EGFR exon20 ), which made up a larger proportion of EGFR alt in UTUC than BUC (7/17, 38% v 13/93, 14%; p = 0.01). Compared to other EGFR alt , EGFR exon20 trended towards mutual exclusivity of GA in commonly altered UC genes: TP53 (0% v 100%, p = 5.1E-5; 0% v 86%, p = 2.2E-7) , PIK3CA (14% v 10%; 0% v 19%) , RAF1 (0% v 10%; 0% v 16%) , or FGFR3 (0% v 10%; 0% v 6.3%) alterations. Only 2.2% (2/93) of BUC EGFR alt were L858R mutations and none were ex19del (0/93), while neither mutation was detected in UTUC. Conclusions: EGFR exon20 defines a subset of UC cases, and is the most common non-amplification GA seen in EGFR in UC, with some enrichment in UTUC. Consideration should be given to developing a trial for EGFR exon20 UC patients given the recent investigational work on inhibitors with activity against EGFR exon20 , such as poziotinib and TAK-788.
Outcomes of active surveillance for African-American men with prostate cancer: Results of a matched analysis.
Authors: Lewis Thomas, Yaw A. Nyame, Ahmed El-Shafei, Charles Dai, Vishnuvardhan Ganesan, Anna Zampini, Hans Arora, Alice Crane, Daniel Hettel, Khaled Fareed, Robert Stein, Michael C. Gong, Eric A. Klein, Andrew J. Stephenson
Journal: Journal of Clinical Oncology (2019)

89 Background: Prior work has questioned the safety of active surveillance (AS) for African-American (AA) men with prostate cancer. However, studies of AA men on AS are rare, and some show contradictory results as more AA men may undergo definitive therapy leaving a well-selected AS population. To overcome these limitations we performed a retrospective matched cohort study of AA men on AS. Methods: We queried our AS database (2000-2016) for all AA patients. AA men were matched to non-AA men using a 1:1 algorithm based on National Comprehensive Cancer Network (NCCN) risk, age at diagnosis, and year of diagnosis. Cohorts were compared on outcomes of NCCN risk reclassification, receipt of treatment, post-treatment recurrence, development of metastases, and prostate cancer specific mortality. Results: Fifty-nine AA patients were identified and matched, including 18 very low risk (31%), 24 low risk (41%), and 17 intermediate risk patients (29%). Groups were equally matched by NCCN risk and year of diagnosis, and had similar ages at diagnosis (65.6 years AA, 65.9 years non-AA, p=0.97). Initial PSA values were similar between groups (5.2 AA versus 5.1 non-AA, p=0.77). Rates of risk reclassification during AS were higher among AA patients (54% versus 39% p=0.09), though treatment (46% vs 44%) and post-treatment recurrence (11% vs 19%) rates were similar. While AA patients were more often reclassified, many were due to PSA rise (40% AA, 8% non-AA upgraded by PSA alone) rather than pathologic upgrading. AA patients had a longer time to reclassification and treatment than non-AA patients (2.9 and 2.8 years vs 0.9 and 1.0 years, p=0.14). Similar follow-up time was noted (AA 6.0 years versus non-AA 6.4 years, p=0.91). One patient in each group developed metastases. No cancer specific mortalities occurred. Conclusions: In a matched analysis of AA versus non-AA patients on AS, rates of risk reclassification were higher among AA patients, though receipt of treatment and treatment outcomes were similar between groups. Metastatic progression and prostate cancer mortality were rare in both groups. AS appears to be a reasonable option for AA patients with long treatment free periods and reasonable post-treatment outcomes.
Uniparental Disomies (UPD) of Chromosome 13q Is Associated with Shorter Disease-Free Survival in Adult Patients (Pts) with De Novo Cytogenetically Normal Acute Myeloid Leukemia (CN-AML)
Authors: Christopher J. Walker, Jessica Kohlschmidt, Ann-Kathrin Eisfeld, Krzysztof Mrózek, Deedra Nicolet, James S. Blachly, Christopher C. Oakes, Shelley Orwick, Dimitrios Papaioannou, Bayard L. Powell, Jonathan E. Kolitz, Andrew J. Carroll, Richard M. Stone, John C. Byrd, Albert de la Chapelle, Clara D. Bloomfield
Journal: Blood (2018)
Study of growth factor receptors expression and their clinicopathological correlation in carcinoma gallbladder: Is it the way forward?
Authors: Sameer Gupta, Sanjeev Misra, Channabasappa Kori, Vijay Kumar, Nuzhat Husain
Journal: Journal of Clinical Oncology (2015)

e15158 Background: North India reports one of the highest incidences of gallbladder cancer (GBC) in the world. There are very few studies evaluating biomolecular expression profile in GBC and study its clinicopathological correlation. Methods: This study was carried out to immunohistochemically determine growth factor receptors (Her-2/neu, EGFR-1 and VEGF) and p53 expression in patients of GBC and the control group and to study their clinicopathological correlation (2010-2014). Immunohistochemical expression was quantified using standard protocol and guidelines based on percentage and the intensity of cell staining. Results: Study comprised of 209 patients of GBC and 50 control group (cholelithiasis). Out of 209 GBC patients, 76 patients (36%) underwent curative resection followed by adjuvant chemotherapy while 133 patients (64%) with inoperable disease received palliative chemotherapy. Compared to control group, all biomarkers demonstrated significant expression in GBC group (p = < .0001). On evaluation of biomarker expression within GBC group, statistically significant expression of Her-2/neu (p = < .0001), EGFR-1 (p = < .0001) and p53 (p = 0.024) was observed in subgroup of patients amenable to curative surgery compared to inoperable subgroup. No consistent correlation was observed between biomarker expression and T stage, lymph node status and histological subtype. Positive VEGF expression signified decreased Disease Specific Survival in Radical Cholecystectomy subgroup (p = .003). Increased co-expression of biomarkers correlated poorly with Disease Control Rate (D.C.R.) (p = .024) and mean overall survival in palliative treatment arm [N = 133]. Conclusions: GBC is associated with late diagnosis, unsatisfactory treatment and poor prognosis. Clearly, new therapeutic regimens are the need of the hour. Her-2/neu, EGFR-1 and VEGF expression in GBC could be predictive of disease biology and response to chemotherapy. Co-marker expression could be indicative of aggressive disease biology and poor survival. Role of targeted therapy against Her-2/neu, EGFR-1 and VEGF receptors needs further evaluation and could prove to be the Holy Grail in treatment of GBC.
Compliance to NACT in T4 oral cancers :The place, person, socioeconomic status or assistance.
Authors: Kumar Prabhash, Vijay Maruti Patil, Vanita Noronha, Sachin Dhumal, Amit Joshi
Journal: Journal of Clinical Oncology (2015)

e17534 Background: Around 15-20% of patients default during NACT in Head and Neck cancers.The prognosis of such non compliant patient is dismal. Hence this analysis was planned to identify factors contributing towards noncompliance . Methods: This was a retrospective analysis of oral cancer patients undergoing NACT between January 2011-December 2012. Patients of T4 oral cancers who had taken 1 cycle of NACT but defaulted treatment before the second cycle were selected. Patients in whom NACT was stopped after 1st cycle in view of progression of disease or intolerable side effects were excluded. Age, gender, monthly family income , education of patient, profession of patient, socioeconomic strata, place of residence, habits and presence of government support or social support were the factors considered. The family monthly income, education, profession and socioeconomic strata were graded according to modified kuppuswamy scale (MKSS)(with adjusted for inflation till 2012). Pearson chi-square test with yates continuity correction or Fisher's exact test was used to identify factors affecting compliance. Results: 486 patients were eligible for this study out of which 91 patients (19.5%) had defaulted. On analysis of factors for non compliance.The percentage of patients with non compliance in age group below 30 years, between 30-60 years and above 60 years was 25.0%, 17.4% and 25.5% respectively (p value 0.27). The percentage of non compliance was 20.7%,20.9% and 17.1% in patients residing in local place, regional place or distant place respectively ( p value 0.44).The noncompliance distribution according to MKSS was 20.3%,15.7%,18.1% and 22.5% in upper middle, lower middle, upper lower and lower strata respectively(p = 0.60).The percentage of non compliant patients in patients with presence and absence of local support was 20.8% and 17.5% respectively. (p = 0.43). Similarly there was no difference in non compliance rate according to the occupation, education,income habits or government financial assistance. Conclusions: Our analysis failed to identify any factors associated with noncompliance . Commonly considered factors had no impact on noncompliance to NACT in T4 oral cancer patients in our setting.
Phase 1 cancer clinical trials, evolving by complexity.
Authors: Alex V Mejia, Laeeq Malik, Jonathan Gelfond, Devalingam Mahalingam, John Sarantopoulos, Marcela Mazo- Canola, Isabelle Phuong Le, Steven D. Weitman
Journal: Journal of Clinical Oncology (2015)

e17545 Background: Phase 1 trials are experiencing a constant change in their design. Thus, an efficient and successful phase 1 program can be challenging in light of the development of new targeted therapies. Methods: We evaluated 102 cancer phase 1 protocols performed in 1994, 2004 and 2014 at the Institute for Drug Development (IDD). We compared study mandated events (procedures) in the first 3 cycles. Nonparametric and regression tests were used. Results: In 1994 there were 21 trials, 32 in 2004 and 49 in 2014. In 2014, 90% of the studies tested immune or targeted therapies. Most of studies in 2014 have over 15 inclusion/exclusion criteria. Additional outpatient procedures or tests where higher in 2014: (mean ± SD) 4.1±1.5 vs 1±1.2 in 1994 vs 1.1±1.8 in 2004 ( p=<0.001). Number of procedures varied by sponsorship, (mean ± SD) 9.5 ± 7.65 [collaborative group] vs 23±17 [industry] vs 13 ± 5.2 [non sponsored/IIS] (p=0.03). The median number of procedures increased by trials in hematologic malignancies, immunotherapies and frequency of sponsor interaction (p=< 0.001). Also in those requiring new biopsies: (34 vs 25 [archived] vs 11 [none]) (p=< 0.001). Conclusions: Procedures in phase 1 trials have substantially increased. Endpoints are more complex to obtain. Complexity may hinder accrual and eligibility. 1994 2004 2014 P val Trials 21 32 49 Total procedures < 0.001 Mean (SD) 7.1 (3.1) 11.9 (6.2) 33.4 (16.6) Median 7 [5, 7] 11 [7, 15] 33 [21, 41] Range 3, 15 3, 26 13, 91 PK time points 0.02 Mean (SD) 16.4 (12.1) 32.9 (31.3) 33.8 (29.2) Median [Q1,Q3] 15 [10, 22] 23.5 [13.8, 42.2] 25 [17, 42] Range 0, 53 0, 156 0, 152 Informed consent amendments 0.002 Mean (SD) 6.2 (2.4) 6.3 (3.3) 4.5 (1.5) Median [Q1, Q3] 6 [5, 7]) 6 [3.8, 8] 4 [3, 5] Range 3, 14 1, 15 2, 10 Biopsies and BM < 0.001 Mean (SD) 0 (0.2) 0.5 (0.9) 1.9 (2.4) Median [Q1, Q3]) 0 [0, 0] 0 [0, 0.2] 1 [0, 3] Range 0, 1 0, 3 0, 13
A phase I trial of pazopanib (suspension formulation) added to a fixed dose of cetuximab in patients with incurable head and neck squamous cell carcinoma (HNSCC).
Authors: Douglas Adkins, Jessica C. Ley, Tanya Marya Wildes, Kathryn Trinkaus, Marilyn Siegel, Loren S. Michel
Journal: Journal of Clinical Oncology (2015)

e17028 Background: In pre-clinical models of HNSCC, VEGFR, PDGFR, and c-kit are frequently overexpressed. Upregulation of angiogenesis by VEGFR activation is a mechanism of resistance to EGFR inhibitors. Inhibitors of VEGFR reduce the proliferative capacity of EGFR inhibitor–resistant HNSCC. Pazopanib is a small molecule inhibitor of VEGFR, PDGFR and c-kit. We hypothesized that pazopanib added to cetuximab would be feasible and could improve the efficacy of cetuximab in incurable HNSCC. A suspension formulation was chosen due to swallowing problems or requirement for gastrostomy tube in these patients. Methods: A phase I trial was performed to determine the maximum tolerated dose (MTD) of pazopanib suspension added to fixed doses of cetuximab. Pazopanib was given once daily and cetuximab was given once weekly (400 mg/m2, then 250 mg/m2) over each 8 week cycle. Planned dose levels of pazopanib were 200 mg/d (level 1), 400 mg/d (level 2), 600 mg/d (level 3) and 800 mg/d (level 4). Fibonacci (3+3) design was utilized. Eligible pts had incurable HNSCC and adequate organ function. Tumor response assessment was performed per RECIST 1.1 criteria after each cycle. Results: Nineteen pts were enrolled: 3 on level 1 (no dose-limiting toxicity [DLT]), 6 on level 2 (1 DLT – grade 3 neutropenia), 7 on level 3 (1 DLT -grade 3 proteinuria; 1 non-evaluable due to early disease progression), and 3 on level 4 (no DLT to date with these 3 pts at cycle 1 week 3). Best overall response: 4 partial (PR, 25%), 7 stable (SD, 44%), 5 progression (31%) and 3 not evaluable. Median time-to-progression was 112 (range: 21-280) days. Disease control (PR+SD) as best overall response occurred in 2 of 2 pts with cetuximab-resistant disease, 5 of 6 (2 not yet evaluable) pts with platin- and cetuximab-resistant disease, 0 of 3 pts with platin-resistant disease, and 4 of 5 (1 not yet evaluable) pts with platin- and cetuximab-naïve disease. Conclusions: The MTD of pazopanib has not yet been reached during the phase I study. The PR (25%) and disease control (69%) rates compared favorably with prior trials of cetuximab alone. Clinical trial information: NCT01716416.
Bile Acid Homeostasis in a Cholesterol 7α‐Hydroxylase and Sterol 27‐Hydroxylase Double Knockout Mouse Model
Authors: Daniel Rizzolo, Kyle Buckley, Bo Kong, Le Zhan, Jianliang Shen, Mary Stofan, Anita Brinker, Michael Goedken, Brian Buckley, Grace L. Guo
Journal: Hepatology (2019)

Bile acids (BAs) are diverse molecules that are synthesized from cholesterol in the liver. The synthesis of BAs has traditionally been shown to occur through two pathways. Cholesterol 7α‐hydroxylase (CYP7A1) performs the initial and rate‐limiting step in the classical pathway, and sterol 27‐hydroxylase (CYP27A1) initiates the hydroxylation of cholesterol in the alternative pathway. While the role of individual BA species as physiological detergents is relatively ubiquitous, their endocrine functions as signaling molecules and roles in disease pathogenesis have been emerging to be BA species–specific. In order to better understand the pharmacologic and toxicologic roles of individual BA species in an in vivo model, we created cholesterol 7α‐hydroxylase ( Cyp7a1 ) and sterol 27‐hydroxylase ( Cyp27a1 ) double knockout (DKO) mice by cross‐breeding single knockout mice ( Cyp7a1 –/– and Cyp27a1 –/– ). BA profiling and quantification by liquid chromatography–mass spectrometry of serum, gallbladder, liver, small intestine, and colon of wild‐type, Cyp7a1 –/– , Cyp27a1 –/– , and DKO mice showed that DKO mice exhibited a reduction of BAs in the plasma (45.9%), liver (60.2%), gallbladder (76.3%), small intestine (88.7%), and colon (93.6%), while maintaining a similar BA pool composition compared to wild‐type mice. The function of the farnesoid X receptor (FXR) in DKO mice was lower, revealed by decreased mRNA expression of well‐known FXR target genes, hepatic small heterodimer partner, and ileal fibroblast growth factor 15. However, response to FXR synthetic ligands was maintained in DKO mice as treatment with GW4064 resulted in similar changes in gene expression in all strains of mice. Conclusion: We provide a useful tool for studying the role of individual BAs in vivo ; DKO mice have a significantly reduced BA pool, have a similar BA profile, and maintained response to FXR activation.
Designing a payment system to support cancer care coordination and improve patient adherence to oral chemotherapies: A literature review.
Authors: Anne Girault, Chloe Gerves-Pinquie, Etienne Minvielle
Journal: Journal of Clinical Oncology (2015)

e17803 Background: Oral chemotherapies are increasingly being used to treat cancer patients (≈25% of antineoplastic expenditures). Beyond their costs, ensuring medication adherence at distance through follow-up is a growing issue. One recommendation is to develop clinical pathways in oncology supported by financial incentives that will foster adoption of best practice by healthcare professionals. In this context, Gustave Roussy Cancer Institute is conducting a randomized trial to test the impact of a care coordination program made of two nurse navigators supported by a dedicated online portal to improve follow-up and adherence. The objective was to understand how to design an optimal payment system to incentivize providers to adopt the program. Methods: We conducted a 2-part literature review, exploring articles published between 2010 and 2014 in Medline, the first focusing on payment in cancer care (27 articles) and the second including the use of nurse navigators (9 articles). Results: The review highlighted key issues in the design of an alternative payment model in oncology. First, there were distinctly different types of payment systems. Among them, bundling payments for episodes of care was considered as a promising payment option to encourage coordination. Second, any system must be supported by proven clinical and administrative guidelines including the economic evaluations, preferably using a micro-costing approach and adopting a societal perspective to estimate direct, indirect and intangible costs. Third, four papers insisted that professionals should be part of the design phase, and participate in resource allocation decisions to foster the adoption of coordination systems. In order to align with their preferences, one additional payment feature could be to adjust its size based on providers’ willingness to accept a financial compensation for participating in a coordination program. Conclusions: There are different options for the design of payment systems and their success depends on the ability to measure costs and benefits not only in monetary terms but on rates of acceptance. The structure of these systems should be supported by equal standards of evidence.