tbuckley/cabot-search huggingface dataset:
Ultrasound and microbubble enhanced treatment of inoperable pancreatic adeonocarcinoma.
Authors: Georg Gjorgji Dimcevski, Spiros Kotopouli, Tormod Bjåne, Dag Hoem, Jan Schjött, Björn Tore Gjertsen, Martin Biermann, Anders Molven, Halfdan Sorbye, Emmet McCormac, Michiel Postema, Odd Helge Gilja
Journal: Journal of Clinical Oncology (2016)

e15703 Background: Pancreatic Adenocarcinoma (PDAC)represents one of the most lethal human cancers. Surgery is often unfeasible, and the tumors respond poorly to radiation or chemotherapeutic drugs. Consequently, pancreatic cancer represents a huge burden to society and the need for new therapeutic options is evident. Experimental research using ultrasound to improve therapeutic delivery has soared in the past decade. We aimed toevaluate the safety and potential toxicity of gemcitabine combined with microbubbles under sonication in inoperable pancreatic cancer patients. The secondary goal was to develop a novel image-guided microbubble-based therapy, based on commercially available technology, towards improving chemotherapeutic efficacy, preserving patient performance grade, and prolongation of survival. Methods: Ten patients were enrolled and treated in this Phase I clinical trial. Gemcitabine was infused intravenously over 30 min. Subsequently patients were treated using a commercial clinical ultrasound scanner for 31.5 min. SonoVue was injected intravenously (0.5 ml followed by 5 ml saline every 3.5 min) during the ultrasound treatment with the aim of enhancing therapeutic efficacy. Results: The combined therapeutic regimen did not induce any additional toxicity or increase side effect frequency when compared to gemcitabine chemotherapy alone (historical controls). Combination treated patients (n = 10) tolerated an increased number of gemcitabine cycles compared with historical controls (n = 63 patients; average of 8.3±6.0 cycles, versus 13.8±5.6 cycles). In five patients, the maximum tumor diameter was decreased during treatment. The median survival in our patients was also increased from 7.0 months to 17.6 months (p = 0.0044). Conclusions: We perform the first-in-human study evaluating the toxicity and efficacy of ultrasound and microbubble enhanced chemotherapy. It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting with no additional toxicity. This combined treatment may improve the clinical efficacy of chemotherapeutic agents, prolong the quality of life, and extend survival in patients with PDAC. Clinical trial information: NCT01674556.
Outcomes of advanced pulmonary large cell neuroendocrine carcinoma stratified by <i>RB1</i> loss, SLFN11 expression, and tumor mutational burden.
Authors: Joshua K. Sabari, Ricklie Ann Julian, Ai Ni, Darragh Halpenny, Matthew David Hellmann, Alexander E. Drilon, Bob T. Li, John T. Poirier, Charles M. Rudin, Natasha Rekhtman
Journal: Journal of Clinical Oncology (2018)

e20568 Background: LCNEC is a biologically heterogeneous disease comprised of distinct subgroups characterized by genomic signatures of either SCLC or NSCLC (e.g. RB1 loss or retained). We assessed how molecularly defined subtypes of LCNEC associated with outcomes to specific therapies, including platinum (P) based chemotherapy and immunotherapy (IO). Methods: Patients with stage IV LCNEC underwent targeted NGS (MSK-IMPACT). ORR, PFS and OS to P-based chemotherapy and IO were correlated with molecular subtype (small cell or non-small cell-like [SC-like or NSC-like], defined by RB1 status). SLFN11 expression (emerging biomarker of chemotherapy response), PD-L1 expression and tumor mutation burden (TMB) was obtained. TMB of LCNEC was compared to other lung cancer histologies (NSCLC n = 1,769 and SCLC n = 163). Results: Among 37 pts with LCNEC, 17 (43%) were SC-like and 20 (57%) were NSC-like. SC-like had higher smoking exposure (median pack year 50 vs 33, P= 0.001) and higher Ki67 (90% vs 70%, P < 0.001) compared to NSC-like. ORR, PFS, and OS were similar with P-based chemotherapy across both subtypes. High SLFN11 expression was associated with improved response to platinum-based chemotherapy (ORR 80% (4/5) vs 16% (2/12) in SLFN11 high vs low tumors, P= 0.03). ORR to IO in any line of therapy was 43% (3/7) in SC-like and 13% (1/8) in the NSC-like; P= 0.28, despite negative or minimal PD-L1 expression in all cases. Median TMB in LCNEC was significantly higher compared to unselected NSCLC (15.3 vs 5.7, P< 0.0001) and SCLC (15.3 vs 8.2; P= 0.0016), but did not differ by genomic subtype of LCNEC. Two patients achieved CR to single agent IO, both of whom had TMB in the 90th percentile. Conclusions: SC- and NSC-like LCNECs have distinct clinical and pathologic features, but have similar responses to P-based chemotherapy and IO. Response to chemotherapy in SC-like LCNEC was lower than expected for conventional SCLC. SLFN11 is an encouraging predictor of chemotherapy response and high TMB may be predictive of response to IO in LCNEC.
Evolving oncology clinical pharmacology strategies oncology: An analysis of approved small molecule cancer drugs by the FDA 2011-2016.
Authors: Eric Masson, Matthew Reeves, Sarit Rabbie, David J Carlie, Helen Tomkinson
Journal: Journal of Clinical Oncology (2017)

e18130 Background: Understanding the clinical pharmacology properties of new drugs is essential, enabling correct prescribing with respect to dose, interactions and organ impairment. In the era of targeted therapy and resurgence in oncology R&amp;D there is a need to consider how and when to define clinical pharmacology, since many drugs are given accelerated reviews, limiting the development time. This assessment was undertaken to understand how FDA review the clinical pharmacology components of NDAs. Methods: The Clinical Pharmacology and Biopharmaceutics Review documents of small molecule approvals in oncology by FDA from 2011 -2016 were analysed. Information regarding clinical pharmacology studies, in addition to post marketing requirements (PMR) was analysed. Results: Of 42 small molecules identified, 35 had clinical pharmacology review information. There were 16 accelerated approvals and in only 3 approvals were there no PMRs issued. A particular issue concerns the dose, 14 NDAs had identifiable issues in review, resulting in a 10 PMRs which include conducting a further pivotal study with additional doses. The majority of submissions (33) included clinical assessment of drug effect on the QTc interval. 7 PMRs were issued, 4 requesting completion of ongoing studies. A number of PMRs (24) were issued to assess organ impairment and DDI assessment (12). In all orally administered drugs a food interaction study was conducted with 1 PMR issued. In 32 submissions an excretion balance study was conducted, only 1 of the remaining 3 drugs was issued a PMR. Conclusions: Whilst a number of PMRs for clinical pharmacology studies were issued it is encouraging that these did not limit approval, ensuring patient access. For accelerated approvals, there will be insufficient time to complete many studies prior to filing. However, there were a significant number of PMRs regarding dose, reflecting FDA concerns that there is inadequate characterisation of the dose. Clinical pharmacology characterisation of NMEs is still required, but could be conducted through PMRs to enable early patient access. A major focus for sponsors should be a clearer understanding of the dose response relationship.
Identification of nonalcoholic fatty liver disease following pancreatectomy for noninvasive intraductal papillary mucinous neoplasm
Authors: Carrie Luu, Ram Thapa, Trevor Rose, Katherine Woo, Daniel Jeong, Kerry Thomas, Dung-Tsa Chen, Mark Friedman, Mokenge P. Malafa, Pamela J. Hodul
Journal: International Journal of Surgery (2018)
TCT-697 Left ventricular decompression during extracorporeal membrane oxygenation for cardiogenic shock: A systematic review and meta-analysis
Authors: Juan Russo, Natasha Aleksova, Ian Pitcher, Mohammad Faraz, Etienne Couture, Simon Parlow, Sarah Visintini, Trevor Simard, Paul Boland, Pietro Di Santo, Jeffrey Marbach, Francisco Ramirez, Derek So, Marino Labinaz, Michel Le May, Benjamin Hibbert
Journal: Journal of the American College of Cardiology (2018)
KEYNOTE-412: Pembrolizumab (pembro) in combination with chemoradiation versus chemoradiation alone in locally advanced head and neck squamous cell carcinoma (LA-HNSCC).
Authors: Jean-Pascal H. Machiels, Lisa Licitra, Danny Rischin, John Waldron, Barbara Burtness, Vincent Gregoire, Tulin Shekar, Holly M. Brown, Jonathan D. Cheng, Lillian L. Siu
Journal: Journal of Clinical Oncology (2017)

TPS6090 Background: Approximately half of patients (pts) with HNSCC are diagnosed with locally advanced disease and treated with surgery or concomitant chemoradiotherapy (CRT) with cisplatin. Unfortunately, disease recurs in 40% to 60% of patients. The PD-l inhibitor pembro is approved for recurrent/metastatic HNSCC. CRT has immunomodulatory effects; preclinical data suggest that efficacy can be improved by adding pembro. The phase 3 KEYNOTE-412 trial (NCT03040999) will explore if CRT + pembro can improve outcomes of pts with LA-HNSCC. Methods: Adult pts with newly diagnosed, pathologically proven, treatment-naive LA-HNSCC will be enrolled. Study population will include p16-negative HNSCC (any T3-T4 or any N2a-N3 [AJCC 7th edition]) and p16-positive oropharyngeal cancer (any T4 or any N3). Other eligibility criteria: measurable disease per RECIST v1.1 by blinded independent central review (BICR), provision of tumor sample for biomarker analyses, ECOG PS 0 or 1, and eligible for definitive CRT but not considered for primary surgery. Pts will be randomly assigned 1:1 to receive either pembro 200 mg every 3 weeks (Q3W) plus CRT, which includes radiotherapy (RT; accelerated [70 Gy, six 2 Gy fractions/wk] or standard [70 Gy, five 2 Gy fractions/week] fractionation) plus cisplatin 100 mg/m 2 Q3W for 3 cycles only, or placebo Q3W plus CRT. Pts will be stratified by RT regimen, tumor site/p16 status, and disease stage. Treatment will continue until centrally confirmed disease progression, unacceptable AEs, decision to withdraw by pt or investigator, or completion of 17 doses of pembro/placebo. Disease status will be evaluated by CT or MRI 12 weeks after end of CRT, every 4 months during the next 2 years, and then every 6 months during years 3-5. Pts will be evaluated for neck dissection at 12 weeks after CRT. AEs will be monitored and graded using CTCAE v4.0 throughout the trial and for 30 days (90 days for serious AEs) after end of treatment. Primary efficacy end point is event-free survival per RECIST v1.1 by BICR. Key secondary end points: overall survival, quality of life, and safety and tolerability of pembro. Approximately 780 pts will be enrolled. Clinical trial information: NCT03040999.
Effect of PDL1 expression [exp] on overall survival [OS] in patients [pts] with metastatic adenocarcinoma lung [MAC]: Illinois CancerCare [ILCC] analysis.
Authors: Nikhil Kumar, Patrick Leigh Gomez, Jamie Harper
Journal: Journal of Clinical Oncology (2021)

e21005 Background: Effect of PDL1 on OS in patients with MAC is controversial. This relationship has not been studied systematically in U.S. midwestern population, a largely homogenous Caucasian group. We examined the effect of PDL1 expression on OS in MAC pts at ILCC, one of the largest practices in U.S. Midwest. Methods: We conducted a retrospective analysis of all MAC pts who presented at ILCC in 2018. PDL1 status was defined as high if PDL1 was ≥50%, low if 1≤50% &amp; -ve if 0≤1%. High and low groups together were called +. Statistical analysis was performed using the log rank Kaplan Meier method. Results: Results were available in 104/125 pts [83%]. 68/104 pts [65%] received anti PDL1 antibodies Nivolumab, Pembrolizumab, Durvalumab, &amp; Atezolizumab. 43/68 pts were PDL1+ and 25/68 were -ve. Median OS of PDL1+ high exp was 10.78 months [m] &amp; of low exp was 9.7 m. There was no statistical difference in OS in these groups [p = 0.984778]. We also evaluated this relationship between all PDL1+ pts [high and low expressers together] and PDL1- ve pts. We did not find any difference between these groups either. Median OS of all PDL1+ was 9.77 m &amp; PDL1 -ve was 6.67 m [p = 0.435038]. Conclusions: Our study suggests that OS of MAC in our pt population is not influenced by PDL1 status. The potential influence of patient ethnic, genetic &amp; molecular biomarker traits on OS needs to be explored further.[Table: see text]
Outcomes in left versus right metastatic colorectal cancer (mCRC) in patients presenting to an inner-city safety net hospital.
Authors: Sunny R K Singh, Pei Lu, Sindhu Janarthanam Malapati, Ahmed T Ahmed, Michael Russell Mullane
Journal: Journal of Clinical Oncology (2018)

e15542 Background: Studies have shown that patients with left sided colon cancer (L-CRC) have better survival than the right sided ones. However, only few studies focused on minority population. We aim to assess the difference between left versus right sided colon cancer in an inner-city safety net hospital which has a significant proportion of minorities Methods: This is a retrospective study of 105 patients with mCRC who presented to the Medical Oncology clinic of John H Stroger Jr. Hospital of Cook County, Chicago from 2012-2014. Only those who were tested for KRAS mutation were included. Right colon cancer (R-CRC) was defined as tumor located in ascending colon and hepatic flexure. L-CRC were those arising in splenic flexure, descending colon and rectum. Chi-Square was used for categorical variables. Progression free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method, log-rank test and Cox proportional hazards regression models Results: Of the total population, 60.9% were African American (AA), 51.4% males, 48.5% R-CRC, 42.8% L-CRC, 5.7% Transverse-CRC, 3.8% Multicentric-CRC and 68.6% (n = 72) had documented progression. R-CRC showed poorer PFS compared to the left (median PFS 9.1 mo versus 15.1 mo, P = 0.003) but similar OS. KRAS mutation was found in 50.4% of the patients and the rate was higher in AA compared to Caucasians (57.8% versus 22.2%, P = 0.007). It was associated with a better PFS (HR 0.60; 95% CI 0.37, 0.98; P = 0.04) and a higher rate of lung metastasis on presentation (34.6% versus 16.9%, P = 0.03). There was no difference of KRAS mutation prevalence between R-CRC and L-CRC. In addition, having metastases at sites other than liver or lung at presentation was associated with worse PFS (HR 1.90; 95% CI 1.15, 3.14; P = 0.012) and OS (HR, 3.15; 95% CI 1.28, 7.78; P = 0.013) Conclusions: In our inner-city patient population presenting with metastatic CRC, right-sided tumor location and having metastases at sites other than liver or lung at presentation were associated with worse PFS, whereas KRAS mutation was associated with better PFS. Also, AA were more likely to have mutated KRAS than Caucasians, half of whom were Polish in our population
Beyond the guidelines: Clinical investigators' (CI) self-reported use of genomic assays (GA) to assist in decision-making regarding use of neoadjuvant (NA) and adjuvant chemotherapy for patients (pts) with ER-positive/HER2-negative (ER+/HER2-) early breast cancer (BC).
Authors: Neil Love, Harold J. Burstein, Tari A. King, Gloria Kelly, Kirsten Miller, Jonathan Moss, Douglas Paley, Kathryn Ziel
Journal: Journal of Clinical Oncology (2017)

e18187 Background: GA, specifically the 21-gene Recurrence Score (RS), have been widely used to help inform decisions regarding use of adjuvant chemotherapy in ER+/HER2- node-negative BC. Although substantial anecdotal evidence exists that clinicians, particularly BC-focused CI, are employing these tests in other situations (node-positive disease, the NA setting), ASCO guidelines do not endorse these practices. Here we aimed to quantify self-reported CI use of GA across a spectrum of hypothetical BC presentations. Methods: In December 2016, a 225-item survey was sent to 97 US-based surgical (S) and medical oncology (MO) CI from a proprietary database. A modest honorarium was provided. Results: 51 CI (26 S and 25 MO) completed the survey. CI generally recommend GA for node-negative tumors but less so for older pts with smaller lesions. 75% of CI reported that they would recommend GA for pts with 1 involved node and 55% would do so for those with 2 to 3 nodes. 31% of CI use GA to guide NA chemotherapy decisions, and 53% who do not use GA in NA decision-making altered their treatment approach when a GA result was available. Conclusions: CI prefer GA when the benefit of chemotherapy is uncertain based on tumor stage and pt age. CI are comfortable using GA in node-negative and node-positive hypothetical cases, and some do so to aid in decisions regarding NA therapy. Quantitative assessment of self-reported CI practice patterns can serve as a complement to established guidelines and provide physicians, pts and third-party payers additional viewpoints on possible appropriate management strategies. [Table: see text]
Prognostic significance of day 14 (D14) bone marrow (BM) assessment in adult patients receiving induction for Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL).
Authors: Nicholas James Short, Hagop M. Kantarjian, Koji Sasaki, Farhad Ravandi, Guillermo Garcia-Manero, Deborah A. Thomas, Sherry Pierce, Ghayas C. Issa, Jorge E. Cortes, Tapan M. Kadia, Nitin Jain, Susan Mary O'Brien, Elias Jabbour
Journal: Journal of Clinical Oncology (2016)

7035 Background: The prognostic impact of D14 BM blast percentage in the context of minimal residual disease (MRD) status at complete response (CR) in pts with ALL undergoing induction chemotherapy has not been established. Methods: We evaluated the prognostic significance of D14 BM blast percentage in adults with previously untreated Ph- B-ALL or T-ALL undergoing induction chemotherapy with Augmented BFM or hyper-CVAD. All pts underwent BM examination on D14 ± 2 days. The D14 BM blast cutoff best predicting for overall survival (OS) was identified by comparing hazard ratios (HR) of various cutoffs by log-rank test. Pts with a blast-free aplastic BM were included in the < 10% group, as these groups had similar outcomes. The impact of MRD at CR was assessed using flow cytometry with a sensitivity of ≤ 0.01%. Results: Between 5/2000 and 9/2015, 389 pts were evaluable for response and BM assessment. Median duration of survivor follow-up was 28 months. Median percentage of D14 BM blasts was 2% (range: 0-97%). The optimal D14 BM blast cutoff predicting for OS was < 30% vs. ≥ 30%, which was used to stratify pts into 3 groups based on D14 BM blast percentage ( < 10% vs. 10%-29% vs. ≥ 30%). On D14 BM examination, 319 pts (82%) had < 10% blasts, 31 (8%) had 10-29% blasts, and 39 (10%) had ≥ 30% blasts. The CR/CRp rates for these 3 groups were 99.7%, 87% and 79%, and the rates of MRD negativity were 75%, 27% and 11%, respectively (P < 0.001 for both). Median event-free survival (EFS) was 49, 33 and 9 months; and median OS was 88, 37 and 21 months, respectively (P < 0.001 for both). By multivariate analysis, WBC, platelets, cytogenetics and MRD status at CR were independently associated with EFS, with a trend for worse EFS in pts with higher D14 BM blasts (HR 1.39 [0.98-1.98]; P = 0.07). Age, WBC, platelets, cytogenetics, MRD status at CR, and D14 BM blast risk group were all independently associated with OS (HR 1.43 [1.02-1.99] for D14 blast groups; P = 0.04). Conclusions: A high percentage of residual blasts on D14 BM in adult pts with Ph- ALL is highly predictive for inferior EFS and OS. Morphologic evaluation of D14 BM has prognostic value even when MRD information is taken into consideration.
Tumor cell-free DNA copy number instability (CNI) to predict therapeutic response to immunotherapy prior to cycle 2.
Authors: Glen J. Weiss, Julia Beck, Donald Peter Braun, Kirsten Bornemann-Kolatzki, Heather Barilla, Rhiannon Cubello, Walter Quan, Jordan Waypa, Ashish Sangal, Vivek Khemka, Howard Urnovitz, Ekkehard SchÃ¼tz
Journal: Journal of Clinical Oncology (2016)

3027 Background: Tumorcell-free DNA (cfDNA) provides minimally invasive patient specific biomarkers to monitor tumor burden. Gains and losses of chromosomal regions have been detected in plasma as copy number aberrations (CNAs). Tregs are reported to be modulated by immunotherapy (immuno). We measured CNAs changes during treatment by computing a genomic copy number instability index (CNI) of cfDNA and Treg-specific demethylation region (TSDR) as measure for Tregs% of leukocytes compared to response. Methods: In this prospective study, prior to treatment and before each cycle, extracted plasma-DNA was subjected to shallow whole genome sequencing with a post mapping (HG19) read coverage of 24,000-fold per 5.5Mbp bin. Read counts were transformed into (log2 ratio) Z-values, and a CNI-score was calculated. % of TSDR+ leukocytes (TSDR%) were quantified with digital PCR from PBMC DNA. Primary endpoint was best overall response by imaging (irRECIST and RECIST 1.1). Hypotheses were: a) response to immuno is reflected by CNI change vs. baseline during therapy an b) alters TSDR%. Outcome was unblinded for analysis. Results: Of 27 enrolled patients (pts), 23 were assessable for response: 4 advanced melanoma (MEL), 2 renal cell carcinoma (RCC), 5 gastrointestinal, 4 pulmonary, 3 breast, 1 ovarian cancers, 3 pancreatic adenocarcinomas, and 1 sarcoma. MEL and RCC received interleukin-2, while the rest received anti-PD-1 with chemotherapy on trials. Median age was 58 years, 12 were women. CNI was measured in 69 samples. Mean baseline cfDNA was 8,076 (CI90th:2894-13,258cp/mL) and CNI was 2,222 (CI90th:1,162-3,282). Pts with response or stable disease (n = 12) showed a significant decrease in CNI before cycle 2 (C2) (Mean: -1,386 vs.+271; p < 0.02), before cycle #3 (-2524 vs.+698, p < 0.005), and thereafter (p < 0.002) compared to pts with disease progression. cfDNA was not correlated to CNI nor response. TSDR% showed a decrease in all patients (p < 0.02) with immuno, independent of response. Conclusions: CNI change predicted response before C2 ~3-12 weeks prior to scan results, and therefore may serve as early predictor of therapeutic response to immuno. Immuno lowers Tregs % in blood, which might reflect T-cell activation.