tbuckley/cabot-search huggingface dataset:
TCT-114 Comparing Effectiveness of Different Atherectomy Device Systems in Occlusive Lower Extremity Peripheral Artery Disease: Analysis of a Large National Database
Authors: Tonga Nfor, Payal Sharma, Daniel Ortiz, M. Fuad Jan, Suhail Q. Allaqaband, Tanvir Bajwa, Mark W. Mewissen
Journal: Journal of the American College of Cardiology (2018)
Computer extracted nuclear features from Feulgen and H&amp;E images to predict biochemical recurrence in prostate cancer patients following radical prostatectomy.
Authors: Anna Gawlik, George Lee, Jonathan I. Epstein, Robert W. Veltri, Guangjing Zhu, Kenneth J. Pienta, Anant Madabhushi
Journal: Journal of Clinical Oncology (2016)

5067 Background: After radical prostatectomy, around 30% of prostate cancer (PCa) patients experience biochemical recurrence (BCR), for which the best predictor has been the qualitative Gleason score (GS). Computerized image analysis methods have allowed for enumeration of quantitative histomorphometric (QH) measurements from H&E images and been predictive of BCR. Additionally the Feulgen (FG) stain reflects nuclear DNA content, a feature linked to PCa presence and aggressiveness. We show that BCR can be accurately predicted by combining QH measurements of morphology and architecture from H&E and FG tissue images. Methods: We used 69 patients (20 BCR and 49 non-recurrence (NR)) with follow up to 14 years, T2 or T3 stage, and GS of 6 to 9. Each patient had 242 QH features calculated from the stained TMA core images. Feature selection chose the 10 most discriminating features of each stain which were combined via a random forest classifier to predict BCR. Kaplan-Meier analysis evaluated classifier predictions of BCR. Results: QH features extracted from FG and H&E images revealed statistically different outcomes. Combining GS, H&E and FG yielded the highest classification accuracy, the lowest p-value and a high concordance index (Table 1). GS did not show statistically significant (p > 0.05) differences in BCR-free survival via a log-rank test and had the lowest concordance index (Table 1). Conclusions: Combining nuclear morphology and DNA related features predicted BCR more accurately than GS. With validation of these findings, the combined H&E + FG classifier would allow better risk stratification and post-surgical patient management. Accuracy, concordance index, mean survival rates with 95% confidence interval, and p-value of each classifier. Accuracy Concordance Index Mean Predicted NR Survival Rate (yrs) Mean Predicted BCR Survival Rate (yrs) p-Value GS 0.69 +/- 0.03 0.75 4.8 (3.6 - 6.1) 2.2 (0.8 - 3.6) 0.199 FG 0.72 +/- 0.04 0.82 5.3 (3.7 - 7.0) 3.2 (2.1 - 4.4) 0.019 H&E 0.69 +/- 0.03 0.77 5.1 (3.7 - 6.5) 4.0 (2.4 - 5.7) 0.002 H&E + FG 0.74 +/- 0.04 0.95 5.1 (3.8 - 6.3) 3.0 (1.7 - 4.3) 9.13e-6 GS + H&E + FG 0.75 +/- 0.03 0.94 5.2 (3.9 - 6.5) 3.0 (1.7 - 4.3) 3.002 e-7
Computer extracted measurements of vessel tortuosity on baseline CT scans to predict response to nivolumab immunotherapy for non-small cell lung cancer.
Authors: Monica Khunger, Mehdi Alilou, Rajat Thawani, Anant Madabhushi, Vamsidhar Velcheti
Journal: Journal of Clinical Oncology (2017)

11566 Background: Immune-checkpoint blockade treatments, particularly drugs targeting the programmed death-1 (PD-1) receptor, demonstrate promising clinical efficacy in patients with non-small cell lung cancer (NSCLC). We sought to evaluate whether computer extracted measurements of tortuosity of vessels in lung nodules on baseline CT scans in NSCLC patients(pts) treated with a PD-1 inhibitor, nivolumab could distinguish responders and non-responders. Methods: A total of 61 NSCLC pts who underwent treatment with nivolumab were included in this study. Pts who did not receive nivolumab after 2 cycles due to lack of response or progression per RECIST were classified as ‘non-responders’, patients who had radiological response per RECIST or had clinical benefit (defined as stable disease &gt;10 cycles) were classified as ‘responders’. A total of 35 quantitative tortuosity features of the vessels associated with lung nodule were investigated. In the training cohort (N=33), the features were ranked in their ability to identify responders to nivolumab using a support vector machine (SVM) classifier. The three most informative features were then used for training the SVM, which was then validated on a cohort of N=28 pts. Results: The maximum curvature ( f1), standard deviation of the torsion ( f2) and mean curvature ( f3) were identified as the most discriminating features. The area under Receiver operating characteristic (ROC) curve (AUC) of the SVM was 0.84 for the training and 0.72 for the validation cohort. Conclusions: Vessel tortuosity features were able to distinguish responders from non-responders for patients with NSCLC treated with nivolumab. Large scale multi-site validation will need to be done to establish vessel tortuosity as a predictive biomarker for immunotherapy. [Table: see text]
Tepotinib in patients with advanced non-small cell lung cancer (NSCLC) harboring <i>MET</i> exon 14-skipping mutations: Phase II trial.
Authors: Enriqueta Felip, Leora Horn, Jyoti D. Patel, Hiroshi Sakai, Jürgen Scheele, Rolf Bruns, Paul K. Paik
Journal: Journal of Clinical Oncology (2018)

9016 Background: MET mutations causing exon 14 skipping (METΔex14) produce c-Met receptors lacking a negative regulatory site, with the result that METΔex14 mutations are oncogenic drivers. 3-4% of NSCLCs harbor METΔex14 mutations; these tumors appear to be sensitive to c-Met inhibition. Selective c-Met inhibitors have the potential to be effective and well tolerated in patients (pts) with NSCLC. This single-arm phase II trial (NCT02864992) is investigating the efficacy and safety of the potent, selective c-Met inhibitor tepotinib in pts with METΔex14+ NSCLC. Methods: Adults with stage IIIB/IV METΔex14+ NSCLC without EGFR-activating mutations or ALK rearrangements who have received 0–2 lines of prior therapy are eligible. METΔex14 mutations are identified in tumor and/or circulating tumor DNA (ctDNA) in plasma by a central laboratory. Pts receive tepotinib 500 mg QD until disease progression, intolerable toxicity, or withdrawal for other reasons. Primary endpoint: objective response. Secondary endpoints include safety. Recruitment of approx. 90 pts (60 tumor + 60 ctDNA METΔex14+, overlap anticipated) in Europe, USA, and Japan is planned. Results: 34 pts have been treated to date; data are available for 22 (male, n=16; Caucasian/Asian, n=17/5; median age 73.5 years; prior lines of therapy: 0, n=8, 1, n=8; 2, n=5; 3, n=1; METΔex14+ tumor and ctDNA, n=11, METΔex14+ tumor only, n=10, METΔex14+ ctDNA only, n=1); 19 remain on treatment. Based on investigator assessment, 9/15 (60.0%) evaluable pts had a confirmed PR and 3 (20.0%) had SD. All responders remain in response. 13 pts were evaluable for response by independent review: confirmed PR, n=6 (46.2%); SD, n=1 (7.7%). 13/22 pts with data available had tepotinib-related treatment-emergent adverse events (TRTEAEs; G1/2 peripheral edema = 9, G1/2 diarrhea = 7), with 3 having G3 TRTEAEs (asymptomatic amylase increase = 2; GGT increase = 1) and one a serious TRTEAE (interstitial pneumonia). 2 deaths not related to therapy have occurred (disease progression and bronchopulmonary hemorrhage). Conclusions: Tepotinib 500 mg QD has promising activity in METΔex14+ NSCLC. Its safety profile is as expected based on prior studies. Recruitment is ongoing. Clinical trial information: NCT02864992.
A phase 2, single-arm trial of neoadjuvant axitinb plus avelumab in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx).
Authors: Axel Bex, Johannes V. Van Thienen, Mariette Schrier, Kees Hendricksen, Christian U. Blank, John B. A. G. Haanen
Journal: Journal of Clinical Oncology (2018)

TPS4604 Background: Surgery is the standard treatment for non-metastatic RCC. Despite curative intent, pts with a high risk of relapse have a 5-year metastasis-free survival rate of only 30 % and prevention of recurrence is an unmet need. In a phase 1b study (JAVELIN Renal 100), the axitinib + avelumab response rates (RR) and safety profile were promising with objective RR of 60 % and toxicity profiles as seen with VEGFR-treatment. The combination is currently being tested in a phase III trial against sunitinib in untreated metastatic RCC. We initiated a neoadjuvant study of axitinib + avelumab in pts with high-risk of relapse (NCT03341845). Methods: The study is designed as a open label, single arm, phase 2 trial with a Simon’s two-stage design evaluating neoadjuvant axitinib + avelumab followed by complete surgical resection in 40 pts with high-risk non-metastatic clear-cell (cc) RCC. Key inclusion criteria are planned radical or partial nephrectomy with curative intent; biopsy proven ccRCC; clinical high risk defined as cT1b-cT2a grade (G) 4, cT2b G3, cT3a G 3-4, cT3b-cT4 any G cN0 cM0, or cT any cN1 cM0; World Health Organization (WHO) performance status of 0-1, and completely resectable primary tumours. Key exclusion criteria are metastatic disease, corticosteroid or immunosuppressive systemic treatment, active autoimmune disease, prior systemic treatment for RCC including immunotherapy, biologic therapy, investigational therapy or hormonal therapy. Pts receive axitinib 5 mg BID escalated to 10 mg BID if tolerated and avelumab 10 mg/kg iv Q2W for 6 cycles following H1 blockers and acetaminophen every 2 weeks . Pts with a tumour increase from baseline at CT after the first 6 weeks or no change after dose escalation will be taken off trial and undergo surgery. All others will complete 3 months followed by resection. Primary endpoint (ept): Partial RR (RECIST 1.1) following neoadjuvant therapy. Secondary epts: DFS, OS, rate of recurrence, safety, and tolerability. Exploratory epts include investigation of effects on neoangiogenesis, immune infiltrates and MDSC components to support a rationale for the combined use of axitinib and avelumab. Clinical trial information: NCT03341845.
General medical oncologists assessment and use of targeted treatment for patients (pts) with metastatic nonsquamous non-small cell lung cancer (nsqNSCLC).
Authors: Neil Love, Geoffrey R. Oxnard, Lynette M. Sholl, Lecia V. Sequist, William N. Harwin, Gloria Kelly, Kirsten Miller, Douglas Paley, Jonathan Moss, Kathryn Ziel
Journal: Journal of Clinical Oncology (2017)

e18186 Background: Current guidelines endorse biomarker assessment for all pts with nsqNSCLC. However, variability in actualizing these recommendations may exist. This pilot project evaluated how MO in a large practice group approach mutation analysis and targeted treatment in nsqNSCLC, both hypothetically and in real pts. Methods: In fall 2016, 10 MO from Florida Cancer Specialists each provided information on biomarkers assessed and therapies administered for 10 nsqNSCLC pts(5 without an identified target and 5 with tumor driver mutations). A survey evaluating general practice patterns was also executed. IRB exemption was obtained and a modest honorarium was provided. Results: All MO reported that ideally all nsqNSCLC pts should be tested for EGFR mutations (EGFRm) and ALK rearrangement (ALKr) but only half stated that they would recommend next-generation sequencing (NGS). Of the 54 pts without a mutation, 52 (96%) had EGFRm and ALKr testing but only 12 (22%) had undergone NGS. Among the 45 pts with an actionable target, 41 (91%) had EGFRm and 4 (9%) had ALKr. 37 (80%) of these pts received first-line TKIs, and all MO agreed they would typically recommend this approach. 8 (20%) EGFRm pts initially received chemotherapy, 5 because the MO and/or pt preferred immediate treatment. All MO indicated that EGFRm pts progressing on first-line EGFR TKIs should be evaluated for T790M and indeed 9 pts with disease progression on an EGFR TKI since November 2015 had undergone plasma or tissue testing, and of these 5 are currently receiving osimertinib. Conclusions: The self-stated and actual practice patterns of MO related to nsqNSCLC biomarker assessment largely adhere to current guideline recommendations, but the limited use of NGS suggests that many pts with potentially targetable mutations other than EGFRm and ALKr are not being identified. These findings support growing evidence that interrogation of case-level data can elucidate practice gaps, and an integrated CME platform is being developed to assess whether discussion of documented deficiencies can enhance quality of care.
Patient reported distress in head and neck cancer patients receiving radiotherapy.
Authors: Katherine Gaines, Laeticia Hollant, Bridget Smart, Megan Paige Single, Jacob Habboush, Katherine S. Tzou, Stephen Ko, Heather Biers, Atiya Day, Katey Wert, Byron C. May, Robert Clell Miller
Journal: Journal of Clinical Oncology (2016)

e18086 Background: Patients undergoing head and neck (H&N) radiotherapy (RT) in our clinic are prospectively screened for distress. We performed a retrospective review of this assessment to identify patterns in patient reported distress (PRD). Methods: H&N cancer patients treated with RT at our institution were eligible for inclusion in this study if they had completed a 30 question PRD survey at the beginning of and/or during RT. Each question on the PRD questionnaire concentrated on a particular possible cause of distress. Patients could rate distress on a scale of 1 to 5, corresponding to low and high distress level respectively. The assessment also included the National Comprehensive Cancer Network (NCCN) Distress Thermometer visual scale that ranges from 1 (low overall distress) to 10 (high overall stress). We retrospectively reviewed PRD. Results: 185 patients completed PRD screening forms. Ages ranged from 23 to 93 years old with a median of 67 years. There were 152 (82.2%) male and 33 (17.8%) female. Definitive external beam RT was used to treat all patients. The primary tumor histology was squamous cell carcinoma in 131 patients (70.8%). Chemotherapy was given to 132 (71.4%) patients and 144 (77.8%) underwent also a surgical intervention. NCCN distress thermometer results ranged from 0 to 10, with a median of 4.6. The mean distress scores ranged from 1.44 to 2.83. The top five concerns were “How will I feel during treatment” (2.83), “Pain that affects daily functioning” (2.69), “Out of pocket medical costs” (2.63), “Fatigue” (2.48), and “Sleep difficulties” (2.50). The least concerning complaints were, “A loved one relying on me for their physical care” (1.44), “Transportation” (1.49), “Spirituality” (1.50), “Family communication about my illness” (1.54), “My job” (1.55), and “Controlling my anger” (1.55). Conclusions: Patients receiving definitive H&N RT in our patient population were most worried about symptomatic changes affecting them due to treatment side effects, as well as tumor and treatment related pain. Notably, concerns with financial burdens of treatment ranked in the top five concerns. These distresses should be assessed in patients who will receive H&N RT.
Can oral chemotherapy parity laws reduce patients’ out-of-pocket (OOP) costs?
Authors: Andrea Phillips Sitlinger, Peter A. Ubel, Tian Zhang, Charlene Wong, Rishi Sachdev, David Anderson, Yousuf Zafar
Journal: Journal of Clinical Oncology (2018)

97 Background: Insurance plans vary coverage for infusional (IV) vs oral drugs, leading some to suggest that patients on oral drugs pay more OOP than those on IV drugs. 43 states have passed laws requiring insurers to cover oral drugs equivalently to IV drugs. Yet, there is little evidence that these “parity laws” are effective. Our aim was to estimate impact of parity laws on OOP expenses for oral vs IV drugs. Methods: We sought to determine how quickly patients on oral vs IV drugs reach their plan’s annual OOP maximum (max) as a surrogate for OOP expense. We used 2017 data from Healthcare.gov public use files to generate cost-sharing profiles for all 3,092 unique Marketplace plans. Chronic lymphocytic leukemia (CLL) and metastatic hormone sensitive prostate cancer (mHSPC) were chosen as two representative malignancies since both have accepted, first-line, IV and oral treatment options. We created guideline-concordant, first-line treatment regimens for simulated patients with CLL (oral ibrutinib vs IV bendamustine/rituximab) or mHSPC (oral abiraterone vs IV docetaxel). Drug, professional, facility, imaging, and lab claims were simulated to calculate OOP costs. The mean number of days to reach the OOP maximum for each Marketplace plan and treatment regimen were recorded. We assessed variation according to insurance coverage levels (“metal tier”: Catastrophic, Bronze, Silver, Gold, Platinum). Results: For CLL patients, 95% of plans reached OOP max in approximately one month of treatment for both oral and IV drugs (oral: mean 36 days; IV: mean 29 days). 99% of mHSPC patients reached their OOP max for oral treatment in a mean 15 days, but only 57% of plans reached OOP max for IV mHSPC treatment. Metal tier impacts time to reach OOP max (table). Conclusions: Parity laws do not lower patient costs when both IV and oral treatment options are expensive. In these cases, patients reach the OOP max rapidly. The small subset of patients most likely to benefit from parity laws are those on oral therapy for a disease where the comparable IV drug is inexpensive (eg, generic docetaxel for mHSPC). [Table: see text]
Abstract A084: Reprogramming of androgen receptor gene expression by ACK1/TNK2 mediated histone H4 Tyr88-phosphorylation promotes castration resistance
Authors: Nupam Mahajan, Kiran Mahajan, Harshani Lawrence, Nicholas Lawrence
Journal: Cancer Research (2018)

Abstract Aberrant androgen receptor (AR) transcriptional co-activator activity underlies the onset and progression of prostate cancer (PC) to castration-resistant (CRPC) state. While anti-androgens provide immediate palliative benefits by negating AR transcriptional activity, resistance inevitably develops—either by AR gene amplification, mutation, or expression of splice variants, such as AR-V7. To achieve complete remission, ablation of AR expression appears to be the key. However, targeted inhibition of AR and AR-V7 gene expression with small-molecule inhibitors has not yet been accomplished. Recently, we uncovered a novel chromatin-regulated mechanism of AR transcriptional regulation mediated by the tyrosine kinase ACK1 (also known as TNK2). We observed that ACK1 phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex is read by H4-Y88-phosphorylation and in turn deposits the transcriptionally activating H3K4-trimethyl marks, promoting AR transcription in androgen-deficient environment. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Interestingly, we observed that AR itself was modified by acetylation at Lys609 residue in enzalutamide-resistant PC cells, revealing an additional mechanisms underlying castration resistance. Overall, these data reveal previously undocumented epigenetic circuitry that not only sustains AR and AR-V7 expression, but also provides mechanistic insight into rapid acquisition of resistance to antiandrogens. Citation Format: Nupam Mahajan, Kiran Mahajan, Harshani Lawrence, Nicholas Lawrence. Reprogramming of androgen receptor gene expression by ACK1/TNK2 mediated histone H4 Tyr88-phosphorylation promotes castration resistance [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A084.
Frequency of brain metastases and outcomes in patients with <i>HER2-, KRAS-, and EGFR</i>-mutant lung cancers.
Authors: Mark G. Kris, Michael David Offin, Daniel L. Feldman, Ai Ni, Wei-Chu Victoria Lai, Kathryn Cecilia Arbour, Mariza Daras, Elena Pentsova, Lisa Marie DeAngelis, Kathryn Beal, Robert J. Young, Emmet Jordan, Maria E. Arcila, David Randolph Jones, James M. Isbell, Gregory J. Riely, Alexander E. Drilon, Helena Alexandra Yu, Bob T. Li
Journal: Journal of Clinical Oncology (2018)

9081 Background: HER2 mutations are oncogenic drivers in 3% of lung cancers. Here we describe the frequency and course of patients with HER2 mutant lung cancers with spread to brain and compare results to individuals with KRAS- and EGFR-driven cancers. Methods: We compared cohorts of consecutive patients with HER2-(n = 98), KRAS- (n = 200) and EGFR- (n = 200) mutant lung cancers. Multivariate logistical regressions adjusted for follow-up length were performed to evaluate baseline and subsequent development of brain metastases and survival from the date of diagnosis of stage IV disease. Results: In total, brain metastases occurred in 41% of 498 patients (95% CI 37 to 45%). At diagnosis of stage IV disease, 19% (19/98) in the HER2 cohort, 24% (48/200) in KRAS, and 31% (62/200) in EGFR had brain metastases (p= 0.8). Among those without brain metastases at baseline, 34% (27/79) of patients with HER2 vs 11% (16/152) with KRAS (p < 0.001), vs 23% (32/138) with EGFR (p= 0.048) developed brain metastases during treatment. The overall incidence of brain metastases was 47% (46/98) in patients with HER2, 32% (64/200) with KRAS), and 47% (94/200) with EGFR (p = 0.73). The occurrence of any brain metastases imparted a shorter median survival in patients with HER2- (25 vs 30 months, p< 0.001) and EGFR- (29 vs 92 months, p < 0.001) driven cancers but not with KRAS (14 vs 21 months, p= 0.44). The median overall survival was 1.6 years (range 1.3 – 2.2 years) for HER2, 1.1years (range 0.8 – 1.3 years) for KRAS, and 3.0 years (range 2.5 – 4.0 years) for EGFR (p< 0.0001). Conclusions: In our patients with lung cancers driven by HER2, KRAS, and EGFR, brain metastases occurred in 41% overall. The risk is numerically higher with HER2 and EGFR than KRAS. While the incidence of brain metastases in patients with HER2 mutant lung cancers is numerically lower than EGFR at diagnosis, it rises over the disease course to 47%, equal that of EGFR. Among those without brain metastases at baseline, a greater number of patients with HER2-mutant tumors subsequenty developed brain metastases during treatment compared to the EGFR and KRAS cohorts. With one third of patients with HER2 mutant lung cancers developing brain metastases during treatment, close surveillance is critical.