tbuckley/cabot-search huggingface dataset:
A radiomics signature for treatment stratification in advanced and recurrent nasopharynx cancer.
Authors: Grace Kusumawidjaja, Youquan Li, Soon Ann Gan, Jun Hao Phua, Yan Yee Ng, Melvin Chua
Journal: Journal of Clinical Oncology (2018)

e18060 Background: Viral-associated head and neck cancers are associated with distinct radiological features that may predict tumor biology. Radiomics involves multi-feature analyses of voxel intensity, tumor shape and texture, and may offer additional information on the tumor biological architecture, complementing clinical indices in predicting tumor behavior and prognosis. Here, we investigate a 104-feature radiomics algorithm in predicting outcomes in advanced and recurrent EBV+ nasopharynx cancer (NPC). Methods: We utilized a cohort of 225 NPC cases (107 treatment-naïve locally advanced [LA-NPC]; 118 locally recurrent cases [LR-NPC]), treated at a single academic institution from 2002 - 2014. Gross tumor volume (GTV) was segmented on a CT dataset. Radiomics features were extracted using Pyradiomics v1.3.0. Primary clinical endpoint was overall survival (OS). Results: Multivariable analyses revealed that age, T-cat, GTV were significant predictors of OS in the LA-NPC and LR-NPC cohorts; clinical model alone offered a Harrell’s C index of 0.61 and 0.71 for OS, respectively. Of the 104 indices, 14 were significantly associated with GTV (R > .750, p < 0.001); 7 (firstorder: energy, range, total energy; glszm: zone entropy; ngtdm: coarseness; shape: max 2D diameter row, surface vol ratio) were enriched in the LR-NPC compared to the LA-NPC cohort, suggesting that they may be associated with radioresistance. Next, these enriched features were significantly associated with OS in the LR-NPC cohort on multivariable analyses; the radiomics-alone signature provided a C index of 0.72 for OS. Importantly, a combinatorial clinico-radiomics model strongly predicted for 3-y and 5-y OS in the LA-NPC (AUC = 0.803, 3-y; 0.756, 5-y) and LR-NPC (AUC = 0.814, 3-y; 0.791, 5-y) cohorts. Conclusions: Radiomics-extracted features have the potential to predict for therapeutic resistance in EBV+ NPC. Here, we developed a radiomics signature that complements conventional clinical indices in OS prediction.
Translating a clinical trial to daily practice: Outcome of palliative treatment in patients with advanced cholangiocarcinoma and gallbladder cancer in the Netherlands.
Authors: Joeri Dierks, Robert-Jan Coelen, Jan Willem De Groot, Albert J. Ten Tije, Willem Meijer, Hans Pruijt, Thymen Van Voorthuizen, Dick Johan van Spronsen, Diederik ten Oever, J. M. Smit, Hans-Martin Otten, Thomas M van Gulik, Johanna Wilmink, Heinz Josef Klümpen
Journal: Journal of Clinical Oncology (2016)

e15596 Background: Cholangiocarcinoma is an uncommon cancer, often treated in a palliative setting, with an unfavorable prognosis. Since 2010, the standard of care for patients with advanced cholangiocarcinoma or gallbladder cancer is a combination of gemcitabine and cisplatin, based on the landmark Phase III ABC-02 trial. It is unknown whether this treatment is also useful in patients treated in daily practice, who do not meet the inclusion criteria initially defined in the clinical trial. Methods: We reviewed data of consecutive patients with advanced cholangiocarcinoma and gallbladder cancer between 2010 and 2015. We included patients based on fulfilling the following criteria: advanced disease with an indication for gemcitabine and cisplatin and age of 18 years or older. We divided these patients into 3 groups: (I) patients who received chemotherapy and met the criteria of the ABC-02 trial, (II) patients who received chemotherapy and did not meet these criteria and (III) patients who were eligible for chemotherapy but received best supportive care without any chemotherapy. Primary outcome was overall survival and secondary outcome was progression free survival. Results: We collected data of 156 patients. Of those, 92 patients received first line chemotherapy with gemcitabine and cisplatin. Median overall survival of 51 patients in group I, 41 patients in group II and 64 patients in group III was 9.7 months (95% CI: 6.9-12.5), 9.0 months (95% CI: 6.5- 11.5) and 7.0 months (95% CI: 4.5-9.5) respectively (p = 0.018). Median progression free survival was 5.6 months (95% CI: 3.8-7.4 months) in group I and 4.5 months (95% CI: 2.4-6.6 months) in group II (p = 0.5). The 2- year survival of patients who met the criteria, who did not meet the criteria and who did not receive chemotherapy was 28% compared to 8% and 4% respectively. Conclusions: Median overall survival in patients who meet the criteria for the ABC-02 trial is comparable to patients who did not meet these criteria. In contrast the 2- year overall survival is significantly higher in patients that meet the criteria compared with patients that did not meet the criteria of the Phase III trial.
Melphalan + bortezomib (MelVel) and Mel + Vel + thalidomide (MelVelThal) as a conditioning regimen for autologous peripheral blood stem cell transplantation (ASCT) in patients (pts) with advanced multiple myeloma (MM): An updated analysis of 2 phase I/II studies.
Authors: Shijia Zhang, Noa Biran, David Samuel DiCapua Siegel, Michele Donato, David H. Vesole, Andrew Pecora, Joshua Ryan Richter, Alan P. Skarbnik, Andre Goy, Stuart L. Goldberg, Tatyana A. Feldman, Emily Brown, Kathryn Buttner, Marie DelFavero, Sung H. Hong, Daniel Kim, Scott D. Rowley
Journal: Journal of Clinical Oncology (2016)

8027 Background: Escalating doses of Vel with high dose Mel (Rowley, ASH 2009) and escalating doses of Thal with Vel + Mel (Hong, ASH 2012) as ASCT conditioning in pts with advanced MM were previously reported. We performed an updated analysis of these studies. Methods: MM pts with either disease progression or less than PR (MelVel study) or CR (MelVelThal study) after a prior Mel ASCT were enrolled in 2 single arm studies. In MelVel, Vel was dose escalated in steps of 1, 1.3 and 1.6mg/m2 (3x3 design) on day (d) -4 and -1 with Mel 200 mg/m2 given on d -2. In MelVelThal, Thal was dose escalated in steps of 600, 800 and 1000 mg daily (3x3 design) on d -5 through -1 with Vel 1.6mg/m2 on d -4 and -1 and Mel 200 mg/m2on d -2. In phase II, an additional 20 pts were given the maximum tolerated doses of Vel and Thal, respectively. Results: MelVel: 32 pts (median [M] age 57) were enrolled: 12 in phase I and 20 in phase II. 24 (75%) were DSS III, and 12 (37.5%) had > 2 prior lines of therapy. 2 pts died of sepsis. The overall response rate (ORR, ³ PR) was 43.8%. M PFS and OS were 15.7 and 59.5 mos, respectively with a M follow-up of 31.7 mos. The most common grade 3-4 non-hematologic adverse events (AEs) were neutropenic fever (25%), nausea (18.8%), and mucositis (9.4%). Serious AEs (SAEs) included ICU admission (9.4%), seizure (3.1%), prolonged diarrhea (3.1%), and Guillain Barre syndrome (3.1%). MelVelThal: 29 pts (M age 56) were enrolled: 9 in phase I and 20 in phase II. 27 (93.1%) were DSS III, and 13 (44.8%) had > 2 prior lines of therapy. The ORR was 69%. M PFS and OS were 9.3 mos and not reached, respectively with a M follow-up of 17.8 mos. The most common grade 3-4 non-hematologic AEs were neutropenic fever (58.6%), mucositis (6.9%), and diarrhea (6.9%). SAEs included somnolence (13.8%), autologous GVHD (3.4%), and profuse diarrhea (3.4%). Conclusions: The addition of Vel or VelThal to Mel as conditioning for the 2nd ASCT has a toxicity profile similar to Mel alone. More importantly, it can provide durable remissions for pts who have suboptimal response to a single Mel ASCT. Larger, randomized prospective studies are required. Clinical trial information: NCT00784823, NCT01242267.
Clinicopathologic features and survival in immunocompromised vs. immunocompetent patients with Merkel cell carcinoma: An exploratory analysis of a series of consecutive patients.
Authors: Michael Del Rosario, Eric Anderson, Yani Lu, Stephanie Farrell, Steven C. Plaxe, Constantin Dasanu
Journal: Journal of Clinical Oncology (2017)

9568 Background: Clinicopathologic characteristics and outcomes between immunocompromised and immunocompetent Merkel cell carcinoma (MCC) patients may differ. Methods: With approval of IRB, we conducted retrospective analysis in 40 consecutive patients with MCC treated at our institution in 2006-2016. 10 patients were immunocompromised and 30 immunocompetent. Immunosuppressed patients included patients with organ transplantation (n = 3), chronic lympocytic leukemia (n = 2), metastatic skin cancer post chemotherapy (n = 1), rheumatoid arthritis on azathioprine (n = 1), myasthenia gravis on mycophenolate mofetil (n = 1), follicular lymphoma post chemotherapy (n = 1) and human immunodeficiency virus infection (n = 1). Clinicopathologic features, therapy and survival were compared between two cohorts. Significance of associations was assessed via Fishers' exact test. Survival analysis was performed via Cox proportional model and 95% confidence intervals (CI). Results: Compared to immunocompetent MCC patients, the immunocompromised had an absolute male predominance (100% vs. 67%; p &lt; 0.01), more TNM stage III disease (40% vs. 33%; p = 0.021) but less lymphovascular invasion (30% vs. 7%; p &lt; 0.01). They received more chemotherapy (50% vs. 30%; p &lt; 0.01) and radiation therapy (80% vs 57%; p &lt; 0.01). Survival was worse in immunocompromised subjects (average time to death 290.13 days vs. 618.2 days (p &lt; 0.001), and they were 5 times more likely to die (RR = 5.01, 95% CI = 1.49-16.86). Conclusions: Immunocompromised MCC patients displayed significantly shorter survival than their immunocompetent counterparts. They were all male, with more advanced disease but less lymphovascular invasion. They received more chemo- and radiotherapy presumably due to a more advanced stage. As our study is limited by sample size, larger studies are needed to confirm the significance of our findings.
Safety and feasibility of a quality of life intervention in a randomized controlled trial on patients with colorectal cancer.
Authors: Monika Klinkhammer-Schalke, Patricia Lindberg, Brunhilde Steinger, Michael Koller
Journal: Journal of Clinical Oncology (2017)

e18200 Background: The analysis of drug safety is a mandatory part of pharmaceutical studies. For quality of life (QoL) interventions equal standards are missing. We performed a safety analysis for a QoL intervention in a randomized controlled trial (RCT) on colorectal cancer (CRC) patients. Methods: A clinical pathway with QoL diagnosis and therapy was developed in a complex intervention. In a 2-arm RCT N = 220 primary CRC patients have been recruited in 4 certified colorectal cancer centres. In the intervention group (IG) QoL of patients is measured at 0, 3, 6, 12, 18 months postoperative (EORTC QLQ-C30, QLQ-CR29). The coordinating practitioner (CP: physician, responsible for outpatient treatment) is informed about the results of QoL measurement (QoL profile) and receives recommendations for QoL therapy (expert report). Control group (CG) patients` QoL is also measured but CPs neither receive QoL profile nor expert report (routine follow-up care). Safety analysis was performed after data for the first 50% of patients were available. The following safety parameters were investigated: (1) exclusion of patients from RCT due to detrimental effects of study participation; (2) drop-outs of patients; (3) physician workload related to RCT; (4) physician benefit related to RCT. Descriptive statistics and chi square tests or Fisher`s exact tests were used to analyze frequencies. Results: Mean age of the 110 patients was 66.2 years (SD = 9.7) with 64% being male (n = 70). Tumor stages were UICC III (n = 40), II (n = 33), I (n = 24), and IV (n = 13). Only 1 out of 110 patients was excluded from the study by the physician due to patient`s psychological burden. Four more patients dropped out of the study due to either lack of motivation, comorbidity, or positive health situation. Workload regarding RCT was rated low by most physicians (33/35 CPs with IG-patients vs. 24/27 CPs with CG-patients; p = .65). In contrast, many physicians reported benefits connected with RCT participation (19/33 CPs with IG-patients vs. 8/27 CPs with CG-patients; p = .03). Conclusions: Data showed that the study is feasible and safe. Thus, the RCT will be continued to the end according to trial protocol.Clinical trial information: NCT02321813 Clinical trial information: NCT02321813.
The clinical utility of prospective molecular characterization in advanced cervical and vulvovaginal cancer.
Authors: Claire Frances Friedman, Mark Donoghue, Malavika Vivek, Carol Aghajanian, Nadeem Abu-Rustum, Karen Anne Cadoo, Rachel N. Grisham, Martee Leigh Hensley, Jason A. Konner, Chrisann Kyi, Mario M. Leitao, Vicky Makker, Roisin Eilish O'Cearbhaill, William P. Tew, Britta Weigelt, Dmitriy Zamarin, Kay J. Park, Barry S. Taylor, David Michael Hyman
Journal: Journal of Clinical Oncology (2018)

5531 Background: The molecular landscape of recurrent cervical and vulvovaginal cancers is undefined. We sought to determine the clinical impact of performing next generation sequencing (NGS) in these patients (pts). Methods: 82 pts consented to an IRB-approved protocol for the prospective sequencing of tumor and matched normal with MSK-IMPACT (NCT01775072), a NGS assay of up to 468 cancer-associated genes. Hotspot mutations were annotated using the OncoKB knowledge base (OncoKB.org). Results: We analyzed 90 samples. There was no significant difference in the incidence of mutations between primary (45%) and metastatic (mets) (55%) specimens. In the 5 pts with paired mets and 2 with matched primary and mets, the molecular profiling was identical in all but one pt that gained a TP53 mutation. We identified likely therapeutically actionable mutations in 44% of pts. Using OncoKB, we found that 8.5% of patients had a level 2B oncogenic alteration (See Table). Other alterations that have a lower level of clinical evidence included mutations in PIK3CA, ERBB2, AKT, and FGFR3 (n = 29, 35%). In this cohort, 32 pts (39%) enrolled in at least one clinical trial, half of which (n = 15) were genotype-matched. Among these pts, 11 (73%) had stable disease or partial responses (PR). Overall, 24% of patients received checkpoint blockade; two patients without evidence of somatic hypermutation achieved a PR. Conclusions: Prospective NGS of cervical and vulvovaginal cancer informs management of patients through the identification of potentially actionable mutations. Age at Dx (med, range) 46 (22-86) Histology (n, %) Cervical Adenosquamous 7 (9%) Cervical Squamous 25(30%) Endocervical Adenocarcinoma 26 (32%) Gastric Type 7 (9%) Other Cervical 8 (10%) Vulvovaginal carcinoma 9 (11%) Sample Type (n, %) Primary 40 (45%) Metastatic 50 (55%) Hotspot Mutations (n, %) OnkoKB Level 2B: Biomarker to an FDA approved drug in another indication BRCA2, ERBB2 amp, KIT 7 (8.5%) OncoKB Level 3B: Biomarker is likely predictive of response to a drug in another indication, but neither FDA approved PI3K, AKT1, ERBB2 mut, FGFR3 29 (35%) OncoKB Level 4: Biomarker is likely predictive of response to a drug, but neither FDA approved BRAF, HRAS, NF1, PTEN 9 (11%)
Primary results from a randomized (1:1), open-label phase II study of talimogene laherparepvec (T) and ipilimumab (I) vs I alone in unresected stage IIIB- IV melanoma.
Authors: Jason Alan Chesney, Igor Puzanov, Merrick I. Ross, Frances A. Collichio, Mohammed M. Milhem, Lisa Chen, Jenny J. Kim, Claus Garbe, Axel Hauschild, Robert Hans Ingemar Andtbacka
Journal: Journal of Clinical Oncology (2017)

9509 Background: T is a HSV-1-based oncolytic virus designed to selectively replicate in tumors and produce GM-CSF to stimulate antitumor immune responses. I is an anti-CTLA-4 Ab that blocks inhibition of activated T cells. This is the first randomized study to evaluate the addition of an oncolytic virus to a checkpoint inhibitor. Methods: The 1 o endpoint was ORR by immune-related response criteria. Key 2 o endpoints: duration of response, disease control rate (DCR), PFS, OS, and safety. Prior treatment was allowed but not required. Pts had unresected stage IIIB-IV melanoma with measurable/injectable tumor(s) and no evidence of immunosuppression. T was given at approved dosing until no injectable tumors, disease progression (PD), or intolerance. I was started at w6 in T+I and at w1 in I at 3 mg/kg IV q3w x 4. Primary analysis occurred 6 m after last pt enrolled. Results: 198 pts were randomized: 98 T+I; 100 I. Characteristics were similar: 54% stage IIIB-IVM1a, 46% IVM1b/c. Median follow up time was 68 w (T+I) and 58 w (I). ORR was 38.8% (T+I) and 18.0% I, P = 0.002, Odds ratio (OR) 2.9. 89% T+I and 83% I pts remain in response. Unconfirmed visceral lesion response was 35.5% T+I vs 13.6% I. OS is immature. Of 190 pts (safety set: 95 T+I, 95 I), most common adverse events (AEs) for T+I, I (%) were fatigue (59, 42), chills (53, 3), and diarrhea (42, 35). 28% T+I and 18% I pts had gr ≥3 tx-related AE. There were 3 deaths (all unrelated) in T+I: 1 myocardial infarction and 2 PD. Conclusions: The study met the 1 o endpoint. ORR was significantly higher for T+I vs I; responses were not limited to injected lesions. Toxicity of T+I combination was tolerable with no unexpected AEs. Clinical trial information: NCT01740297. [Table: see text]
Antitumor efficacy of CDK 4/6 dual inhibitor, abemaciclib, in an esophageal adenocarcinoma model.
Authors: Ashten N Omstead, Daisuke Matsui, Juliann E Kosovec, Samantha A Martin, Ronan Joseph Kelly, Ali Hussainy Zaidi, Blair Anderson Jobe
Journal: Journal of Clinical Oncology (2017)

e15598 Background: Esophageal adenocarcinoma (EAC) is a leading cause of cancer death, and current treatment options are extremely limited. Cell cycle regulators CDK6 and its homolog, CDK4, are known to be up-regulated in EAC and are associated with poor prognosis. At the molecular level, CDK4 and 6 bind to cyclin D1 and activates E2F transcription factor via phosphorylation of pRb. Up-regulation of this pathway leads to deregulation of the G1 checkpoint, resulting in increased cellular proliferation. Previously, studies have shown progressive up-regulation of CDK6 in pre-neoplastic lesions from Barrett’s esophagus to low-grade and high-grade dysplasia, thus establishing a rational for testing of a CDK4/6 dual inhibitor, Abemaciclib, in an established EAC model. Methods: Esophagojejunostomy was performed on Sprague-Dawley rats to induce gastroduodenojejunal reflux resulting in a sequence of histologic and molecular events that lead to the development esophageal adenocarcinoma. At 36 weeks post operatively, rats were randomized to receive Abemaciclib at 26 mg/kg or placebo (acetate buffer), intraperitoneally once daily for 4 weeks. Drug efficacy was evaluated with magnetic resonance imaging (MRI), endoscopic biopsy, histology, and CDK4/6 pathway expression by RT-PCR. Results: Twelve of 15 (80.0%) treated animals and all of 18 (100%) control animals reached study end-point. All of the treatment group mortality consisted of rats afflicted with moderate peritonitis, diarrhea and weight loss. Mean MRI tumor volume decreased by 93.55% in treatment animals and increased by 108.33% in control animals (P = 0.003). Treatment with Abemaciclib demonstrated tumor volume increase in 0% (control = 66.7%) (P = 0.0003), decrease in 75% (control = 0%) (P = 0.00001), and stable volume in 25% (control = 33.3%) (P = 0.63). EAC prevalence in treatment animals decreased by 50%; whereas, prevalence in control animals increased by 5.6% (P = 0.003). mRNA expression, pre- and post-treatment, demonstrated significant downregulation of CDK4, CDK6, RB1, pRB1 and Cyclin-D. Conclusions: Abemaciclib exhibits potent in vivo antitumor efficacy in a de novo EAC model, providing the rationale for clinical testing.
The PROPHECY trial: Multicenter prospective trial of circulating tumor cell (CTC) AR-V7 detection in men with mCRPC receiving abiraterone (A) or enzalutamide (E).
Authors: Andrew J. Armstrong, Susan Halabi, Jun Luo, David M. Nanus, Paraskevi Giannakakou, Russell Zelig Szmulewitz, Daniel Costin Danila, Patrick Healy, Monika Anand, Colin Rothwell, John Silberstein, Giuseppe Galletti, Jason Somarelli, Santosh Gupta, Simon Gregory, Howard I. Scher, Ryan Dittamore, Scott T. Tagawa, Emmanuel S. Antonarakis, Daniel J. George
Journal: Journal of Clinical Oncology (2018)

5004 Background: It is unclear if CTC AR-V7 detection is a valid predictive biomarker of clinical efficacy in men with mCRPC receiving A/E or just an indicator of aggressive disease and high tumor burden. Methods: We conducted a multicenter prospective study of circulating biomarkers in men with high-risk mCRPC (PROPHECY, NCT02269982) starting A/E. The primary endpoint was association of baseline AR-V7 with radiographic/clinical progression free survival (PFS), using the Johns Hopkins modified-AdnaTest CTC AR-V7 mRNA assay and the Epic Sciences CTC nuclear AR-V7 protein assay. Overall survival (OS) and PSA decline were key secondary endpoints. Results: We enrolled 118 men with mCRPC starting A/E; 52% had ≥5 Cellsearch CTCs, 36% had prior A/E. On study therapy was A (n = 56), E (n = 59) or both A/E (n = 3). AR-V7 detection by the JHU AR-V7 assay and the Epic AR-V7 assay were independently associated with worse PFS and OS after adjusting for CTC count and established clinical factors (see below table). Concordance between the two AR-V7 assays was 82%. Epic AR-V7 (+) men had more CTC phenotypic heterogeneity: 63% had Shannon Index > 1.5 vs 14% of AR-V7 (-) men; most CTCs in Epic AR-V7 (+) men were AR-V7 (-). We found genetic alterations of aggressive mCRPC in AR-V7 (+) and AR-V7 (-) men including gain of AR, MYCN, and MYC and loss of PTEN, TP53, and DNA repair enzymes in CTCs and ctDNA. Conclusions: We validate AR-V7 detection as an independent CTC-adjusted negative predictive biomarker of short PFS and OS with A/E treatment in men with mCRPC, identify CTC heterogeneity of AR-V7 expression, and highlight the importance of non-AR-V7 drivers of aggressive disease. Clinical trial information: NCT02269982.Outcome AR-V7 (JHU n = 116) (+) n = 28 (24%) / (-) n = 88 (66%) AR-V7 (Epic n = 105) (+) n = 11 (10%) / (-) n = 94 (90%) Median PFS (mo) 3.1 / 7.3 3.1 / 6.0 p-value 0.0003 0.007 HR* (95% CI) 2.4 (1.6-3.8) 2.4 (1.3-4.6) HR˚(95% CI) 2.4 (1.4-3.9) 2.2 (1.0-4.9) Median OS (mo) 11.5 / 25.5 8.4 / 25.5 HR*(95% CI) 3.9 (2.1- 7.3) 4.5 (2.1-9.8) HR˚ (95% CI 4.6 (2.3-9.2) 3.6 (1.5-8.6) ≥ 50% confirmed PSA decline 11% / 28% 0% / 26% Odds Ratio (95% CI) 0.31 (0.09-1.12) Not estimable *univariate, ˚adjusted for Cellsearch CTC enumeration, PSA, Alk Phos, Hgb