tbuckley/cabot-search huggingface dataset:
Delta-radiomics for prediction of pseudoprogression in malignant melanoma treated with immune checkpoint inhibition.
Authors: Lucas Basler, Hubert Gabrys, Sabrina A. Hogan, Marta Bogowicz, Diem Vuong, Martin Huellner, Stephanie Tanadini-Lang, Robert Foerster, Reinhard Dummer, Matthias Guckenberger, Mitchell P. Levesque
Journal: Journal of Clinical Oncology (2019)

9575 Background: Distinguishing progressive disease (PD) from pseudoprogression (PP) in patients treated with immune-checkpoint inhibition (ICI) is challenging and usually requires confirmation follow-up imaging or invasive diagnostic techniques. This project aimed to identify predictive radiomic signatures for PP from CT imaging. Methods: The response to ICI of 105 metastatic melanoma patients with 645 metastases was retrospectively correlated with radiomic signatures (172 total features). All metastatic lesions were delineated at 3 time points: prior to ICI (t0), at 3 (t1) and 6 months (t2). Response was defined individually for each metastasis using RECIST 1.1, comparing baseline t0 to t2. Three prediction models for PP were built: CT radiomics at t0 and t1, as well as the relative difference between both t0 and t1 (delta-radiomics). Results: Median follow-up was 18 months and 2-year OS and PFS were 72% and 25%, respectively. Median OS: not reached, median PFS: 6 months. Response per lesion at t1: 13% complete remission (CR), 19% partial remission (PR), 52% stable disease (SD) and 16% PD. At t2: 16% CR, 31% PR, 38% SD and 15% PD. 106 progressive lesions were identified at t1, of which, 26 changed to SD, 1 to CR and 3 to PR at t2, resulting in 30 PPs (4.7%). Metastasis location significantly influenced response rates but was not associated with PP (p = 0.4). Lung metastases had significantly higher response rates than soft tissue (p &lt; 0.001), liver (p &lt; 0.001) and bone metastases (p = 0.008). Univariate analysis followed by removal of correlated features revealed no significant radiomic features associated with PP at t0. One independent feature was identified at t1 (AUC 0.74), while delta-radiomics was the best performing approach, identifying four independent features (AUC 0.72 to 0.81). A final multivariate delta radiomics logistic regression model was generated and internally validated, achieving an AUC of 0.81 (± 0.11, 10-fold cross-validation). Conclusions: Metastasis location significantly influenced response rates and CT-based delta-radiomics is a promising biomarker for early differentiation between pseudoprogression and true progression in metastatic melanoma patients treated with ICI.
Determinants of early discontinuation of first-line chemotherapy, and associated outcomes among elderly with advanced non-small cell lung cancer.
Authors: Pramit Nadpara
Journal: Journal of Clinical Oncology (2019)

9102 Background: Chemotherapy is the primary treatment modality in elderly with Advanced-NSCLC (Adv-NSCLC), with ASCO/NCCN guideline recommending First-Line Chemotherapy (FL-Chemo) for at least 4 months. The objective of this study was to identify the determinants, and outcomes of early discontinuation of FL-Chemo, in a nationwide sample of elderly patients. Methods: We used NCI’s Surveillance, Epidemiology, and End Results registry linked Medicare (SEER-Medicare) 2007-2014 files. We included patients with NSCLC diagnosis in 2007-2013, age ≥65, AJCC Stage IIIB/IV, receiving only FL-Chemo (Identified using HCPCS/CPT codes), and surviving at least 9 months post-diagnosis. We excluded those with non-continuous Medicare enrollment, or HMO enrollment. Patients receiving 1-3 months (vs. 4-7 months) of FL-Chemo were characterized as those experiencing early discontinuation. Patient’s performance status and comorbidity burden were assessed using previously validated algorithms. Survival was calculated from the diagnosis date to the date of death/study end date. Chi-square test, logistic regression, survivor function, proportional hazards regression, and propensity score–adjusted modeling were conducted. Results: We identified 1,029 patients (meeting inclusion and exclusion criteria) with incident Adv-NSCLC during the study years. Of those, 43.2% patients experienced early discontinuation. Adjusted analysis revealed Age as the only significant factor associated with early FL-Chemo discontinuation, with odds increasing with increase in age (p &lt; 0.035). Other patient factors (non-clinical and clinical factors including performance score, comorbidity) were not associated with early discontinuation in any model. Survival outcomes and mortality risk were poor among those experiencing early discontinuation, however the difference was not statistically significant (p &lt; 0.165). Conclusions: A large proportion of elderly with Adv-NSCLC experience early discontinuation of FL-Chemo. Even after controlling for variability in patient performance score and comorbidity burden, Age remained a key factor associated with early discontinuation, raising a cause for concern. Future studies need to explore the impact of Age along with patient reported Quality of Life on early treatment discontinuation.
Tumor volume, circulating tumor cells, and cfDNA changes during radiotherapy in patients with head and neck cancer.
Authors: Sweet Ping Ng, Carolyn S. Hall, Salyna Meas, Vanessa Nicole Sarli, Carlos Cardenas, Houda Bahig, Baher Elgohari, Amy Catherine Moreno, Heath Devin Skinner, Adam S. Garden, David Ira Rosenthal, William H. Morrison, Jack Phan, Gary Brandon Gunn, Steven J. Frank, Clifton David Fuller, Anthony Lucci
Journal: Journal of Clinical Oncology (2019)

6062 Background: Head and neck (HN) cancer treatment response relies heavily on macroscopic clinical findings. Monitoring of circulating markers during treatment may improve detection of responders versus non-responders during radiotherapy (RT). Our work prospectively describes the changes in gross tumor volume (GTV), circulating tumor cell (CTC), and cell-free DNA (cfDNA) enumeration during RT. Methods: Patients with intact HN squamous cell carcinoma were enrolled in a prospective IRB-approved study. Pre-, after first RT, weekly in-, and post-RT blood samples were collected. Serial pre-, weekly in-, and post-RT magnetic resonance imaging (MRI) was obtained. Serial GTV measurements were recorded. CTC was enumerated using the FDA-approved CellSearch (Menarini Silicon Biosystems) system. Plasma were collected and cfNA from pre-, mid- and post-RT timepoints were isolated using the MagMAX Nucleic Acid Isolation Kit (Thermo Fisher Scientific), and cfDNA were quantified with Qubit high sensitivity dsDNA assay (Invitrogen). Results: 40 patients were eligible for analysis. Median age was 60 years and 36 were males. The median pre-RT GTV was 14.1cc (range 1.3 – 44.9cc). There was a median reduction of 81% in GTV by week 4 (p &lt; 0.0001). Of the 341 samples analyzed for CTC, 146 (43%) had detectable CTC. 7 patients had detectable pre-RT CTCs (1-3/7.5ml blood). There was no correlation between cancer stage, nodal status, and GTV with detection of CTC. After 1 fraction of RT, 14 patients had CTCs detected, including 11 who had no CTC detected prior. All patients had CTC detected at some point during RT except for 2 patients who had none. In week 4, with significant reduction in GTV, 25 (63%) had detectable CTC. 16 and 11 patients had detectable CTC in final week and post-RT timepoints. The cfDNA levels increased during RT, with its highest level in the final week of RT and lowest at post-RT time-point, inversely correlated with GTV. Conclusions: Our study showed that CTCs can be detected during RT, suggesting mobilization into peripheral circulation during RT with unknown viability. cfDNA kinetics during RT correlated with CTC release, and may indicate apoptotic change during RT. Combined cfDNA-CTC as an early marker of treatment response should be investigated further.
IL15 by Continuous Intravenous Infusion to Adult Patients with Solid Tumors in a Phase I Trial Induced Dramatic NK-Cell Subset Expansion
Authors: Kevin C. Conlon, E. Lake Potter, Stefania Pittaluga, Chyi-Chia Richard Lee, Milos D. Miljkovic, Thomas A. Fleisher, Sigrid Dubois, Bonita R. Bryant, Michael Petrus, Liyanage P. Perera, Jennifer Hsu, William D. Figg, Cody J. Peer, Joanna H. Shih, Jason L. Yovandich, Stephen P. Creekmore, Mario Roederer, Thomas A. Waldmann
Journal: Clinical Cancer Research (2019)

The first-in-human clinical trial with human bolus intravenous infusion IL15 (rhIL15) was limited by treatment-associated toxicity. Here, we report toxicity, immunomodulation, and clinical activity of rhIL15 administered as a 10-day continuous intravenous infusion (CIV) to patients with cancers in a phase I trial.Patients received treatment for 10 days with CIV rhIL15 in doses of 0.125, 0.25, 0.5, 1, 2, or 4 μg/kg/day. Correlative laboratory tests included IL15 pharmacokinetic (PK) analyses, and assessment of changes in lymphocyte subset numbers.Twenty-seven patients were treated with rhIL15; 2 μg/kg/day was identified as the MTD. There were eight serious adverse events including two bleeding events, papilledema, uveitis, pneumonitis, duodenal erosions, and two deaths (one due to likely drug-related gastrointestinal ischemia). Evidence of antitumor effects was observed in several patients, but stable disease was the best response noted. Patients in the 2 μg/kg/day group had a 5.8-fold increase in number of circulating CD8+ T cells, 38-fold increase in total NK cells, and 358-fold increase in CD56bright NK cells. Serum IL15 concentrations were markedly lower during the last 3 days of infusion.This phase I trial identified the MTD for CIV rhIL15 and defined a treatment regimen that produced significant expansions of CD8+ T and NK effector cells in circulation and tumor deposits. This regimen has identified several biological features, including dramatic increases in numbers of NK cells, supporting trials of IL15 with anticancer mAbs to increase antibody-dependent cell-mediated cytotoxicity and anticancer efficacy.
Investigating the effect of chemotherapy combined with ketogenic diet on stage IV colon cancer.
Authors: Kenji Furukawa, Kyousuke Shigematsu, Hideo Katsuragawa, Toru Tezuka, Kenichiro Hataji
Journal: Journal of Clinical Oncology (2019)

e15182 Background: The effectiveness of carbohydrate restriction to limiting cancer growth has often been observed in in vitro and in vivo experiments; however, few cases of clinical efficacy have been reported. We examined the clinical effectiveness of chemotherapy with ketogenic diet for advanced cancer treatment. Methods: We administered chemotherapy with a modified medium-chain triglyceride (MCT) ketogenic diet at a ratio of 1.4:1 in 10 patients with stage IV recurrent colon cancer for one year and performed a conversion surgery in five of the cases. We followed-up for the next 3 years, compared the overall survival (OS) of the chemotherapy-only group of the stage IV colon cancer patients, and investigated the factors contributing to an improved OS. Results: Evaluations in the first year revealed a response rate of 21% and disease control rate of 64% for patients in the chemotherapy-only group. Patients in the ketogenic diet-chemotherapy combination group exhibited a response rate of 60%, disease control rate of 70%, and complete response rate of 50% for the five conversion surgeries. The time to conversion surgery was 4.0±0.9 months and the time to postoperative recurrence was 6.2±2.6 months. Regarding the duration of overall survival, there was no significant difference ( p value = 0.98) upon comparing the ketogenic diet group with the chemotherapy-only group (32.5 months and 37.9 months, respectively). However, overall survivals were 50 months, 23.0 months, and 32.5 months for the ketogenic diet-chemotherapy combination response group, ketogenic diet-chemotherapy combination non-response group, and chemotherapy-only group, respectively ( p value = 0.07). The ketogenic diet-chemotherapy combination response group tended to have a longer OS than the chemotherapy-only group. In addition, in the ketogenic diet-chemotherapy combination response group, introduction time was earlier than the ketogenic diet-chemotherapy combination non-response group for 5.7 months, with high serum ketone body levels and low blood sugar levels. Conclusions: Chemotherapy with ketogenic diet resulted in higher response and disease control rates than chemotherapy alone. Additionally, the conversion surgery rate was high and an improved OS could be expected. Therefore, ketogenic diet may be a supportive therapy to chemotherapy. Clinical trial information: 000029527.
Soluble biomarker signature to predict outcome of patients with non-small-cell lung cancer (NSCLC) treated with anti-PD1/PDL1 monoclonal antibodies.
Authors: Javier Garde-Noguera, Eloisa Jantus-Lewintre, Sandra Gallach, Jose Vidal-Martinez, Ana Blasco, Jose Garcia Sanchez, Feiyu Zhang, Francisco Aparisi, Beatriz Honrubia Peris, Lauren Condori Farfan, Susana Torres Martinez, Nuria Piera Molons, J. Murado-Pardo, R. Gisbert-Criado, Silvia Calabuig-Fariñas, Carlos Camps
Journal: Journal of Clinical Oncology (2019)

e20685 Background: Immunotherapy with anti-PD1/PDL1 monoclonal antibodies has become the second line standard treatment for most patients diagnosed of advanced Non-Small-Cell lung cancer (NSCLC). The aim of this study is to assess the utility of circulating biomarkers such as sPDL1, sPDL2, sCD137, sIDO, sTIM3, sCD28, sCD27, sCTLA4, sHVEM, sLAG3, sCD80 and sGITR for predicting efficacy of immunotherapy with anti-PD1/PDL1 therapies. Methods: Blood samples were collected before treatment from 50 NSCLC patients who received anti PD1/PDL1 therapies (second line). Plasma biomarkers´ levels were measured by Multiplex bead-based assays. Continuous variables were categorized using the median as a cut-off. Non parametric test were used for correlations between analytical variables and clinical-pathological parameters and response rate analysis. For survival analysis (progression free survival-PFS and overall survival-OS) Kaplan Meier curves and long-rank test were performed. Results: 50 patients met inclusion criteria. Biomarkers associated with better outcome in terms of Response Rate or PFS were sPDL1, sIDO, sCD137 and sGITR. Median plasma levels of sPDL1, sCD137, sIDO and sGITR were 80.5, 168.7, 64.92s and 114.43 ng/ml respectively. ORR was higher in patients with high levels of CD137 (75 vs 25%, p = 0.28), GITR (83.3 vs 16.7%, p = 0.009) and sPDL1 (66.7 vs 33.3%, p = 0.07). Median PFS was significantly higher for patients with high sPDL1 levels (NR vs 3 months, p = 0.017), and there was a favourable trend for patients with higher serum levels of CD137 (NR vs 5.07, p = 0.11), sIDO (NR vs 5.57 months, p = 0.08); and sGITR (14.33 vs 5.57 months, p = 0.16). Combination of these biomarkers allowed the identification of three groups: group1 (0-1 positive biomarker), group2 (2 positive biomarkers) and group 3 (3 or 4 positive biomarkers), with significant differences in ORR (8.3 vs 25 vs 66.7%, p = 0.01), PFS (median 3.2, 1.1 and NR months, p = 0.01) and OS (median 2.3, 5.0 and NR months, p = 0.02). Conclusions: Circulating immune markers can be reliable detected in plasma of advanced NSCLC patients. In patients treated with anti-PD1 antibodies. sCD137, sIDO, sGITR and sPDL1 seem to be related to the degree of response or PFS. Combination of these biomarkers might be helpful to predict efficacy of immunotherapy treatment.
The impact of gastric acid suppressive agents on pazopanib exposure.
Authors: Floor Lubberman, Hans Gelderblom, Paul Hamberg, Walter Vervenne, Carla M.L.- Van Herpen, Nielka P. Van Erp
Journal: Journal of Clinical Oncology (2019)

e16076 Background: Pazopanib has been registered for advanced soft tissue sarcoma (STS) and metastatic renal cell carcinoma (mRCC). The uptake of pazopanib is 40% reduced when a proton pump inhibitor is concomitantly used. Nevertheless, still a large group of cancer patients need a form of gastric acid suppressive agents (GAS, e.g. proton pump inhibitors or H2-anagonists) due to gastrointestinal adverse events. Recently, it was demonstrated that the use of pazopanib with GAS resulted in shorter overall survival and progression free survival in patients with STS. In order to limit the effect of GAS on pazopanib absorption, the advice is to take the GAS 1 hour after pazopanib. In that way the pazopanib is dosed at the lowest gastric pH value. However, the effect of this most optimal controlled intake on pazopanib absorption is unknown. Therefore, we investigated whether this controlled intake algorithm affects pazopanib exposure. Methods: In the DIET study, pazopanib trough concentrations (C trough ) were measured at predefined moments. In this study a total of 80 patients with mRCC and STS were included. The concomitant use of GAS was recorded and taken according the intake algorithm. Patients were subdivided into two groups (with GAS or without GAS). Results: Of the 80 patients, 22 patients were treated with pazopanib in combination with GAS. In patients treated with pazopanib without GAS the geometric mean(GM) pazopanib C trough level was 29.1 mg/L (95% CI 26.4 -31.8) compared to 22.4 mg/L (95% CI 18.0-27.8) (p = 0.01) in those treated with GAS. Conclusions: Patient who use pazopanib with controlled intake of GAS had a 23% lower pazopanib exposure. Therefore, we advice that in patients, who are unable to quit their GAS agent, pazopanib trough concentrations should be monitored in order to prevent shorter treatment benefit. Clinical trial information: NCT02138526.
Comparison of Cinematic Rendering and Computed Tomography for Speed and Comprehension of Surgical Anatomy
Authors: Moustafa Elshafei, Johannes Binder, Justus Baecker, Maximilian Brunner, Michael Uder, Georg F. Weber, Robert Grützmann, Christian Krautz
Journal: JAMA Surgery (2019)

Three-dimensional (3-D) volume rendering has been shown to improve visualization in general surgery. Cinematic rendering (CR), a novel 3-D visualization technology for postprocessing of computed tomographaphy (CT) images, provides photorealistic images with the potential to improve visualization of anatomic details.To determine the value of CR for the comprehension of the surgical anatomy.This preclinical, randomized, 2-sequence crossover study was conducted from February to November 1, 2018, at University Hospital of Erlangen, Germany. The 40 patient cases were evaluated by 18 resident and attending surgeons using a prepared set of CT and CR images. The patient cases were randomized to 2 assessment sequences (CR-CT and CT-CR). During each assessment period, participants answered 1 question per case that addressed crucial issues of anatomic understanding, preoperative planning, and intraoperative strategies. After a washout period of 2 weeks, case evaluations were crossed over to the respective second image modality.The primary outcome measure was the correctness of answers. Secondary outcome was the time needed to answer.The mean (SD) interperiod differences for the percentage of correct answers in the CR-CT sequence (8.5% [7.0%]) differed significantly from those in the CT-CR sequence (-13.1% [6.3%]) (P < .001). The mean (SD) interperiod differences for the time spent to answer the questions in the CR-CT sequence (-18.3 [76.9] seconds) also differed significantly from those in the CT-CR sequence (52.4 [88.5] seconds) (P < .001). Subgroup analysis revealed that residents as well as attending physicians benefitted from CR visualization. Analysis of the case assessment questionnaire showed that CR added significant value to the comprehension of the surgical anatomy (overall mean [SD] score, 4.53 [0.75]). No carryover or period effects were observed.The visualization with CR allowed a more correct and faster comprehension of the surgical anatomy compared with conventional CT imaging, independent of level of surgeon experience. Therefore, CR may assist general surgeons with preoperative preparation and intraoperative guidance.
EUDARIO/ENGOTov-48: A European multicenter randomised phase II trial on the combination of the HSP90 inhibitor ganetespib with carboplatin followed by maintenance treatment with niraparib (+/- ganetespib) compared to platinum-based combination-chemotherapy followed by niraparib in relapsed platinum-sensitive ovarian cancer patients.
Authors: Nicole Concin, Domenica Lorusso, Ioana Braicu, Isabelle Laure Ray-Coquard, Florence Joly, Philipp Harter, Pauline Wimberger, Jean-Pierre Lotz, Alain G Zeimet, Giovanni Scambia, Barbara Schmalfeldt, Claudio Zamagni, Francesco Raspagliesi, Alexander Mustea, Hanno Ulmer, Daniela Kramer, Matthias Dobbelstein, Eric Pujade-Lauraine, Jalid Sehouli, Ignace Vergote
Journal: Journal of Clinical Oncology (2019)

TPS5605 Background: Carboplatin (C) mainly acts by forming interstrand crosslinks (ICL) within the DNA double helix, which can only be removed by the Fanconi Anemia (FA) pathway. HSP90 inhibitors destabilise a number of HSP90 client proteins, such as those governing the FA DNA repair pathway and the G2/M checkpoint (e.g. Chk1 and Wee1). Kramer et al. (Cell Death Differ, 2017) showed that the HSP90 inhibitor Ganetespib (G) virtually eliminates a functional FA DNA repair complex, therewith preventing the repair of DNA ICL in vitro and vivo. In parallel, G abrogated Chk1 and Wee1 expression and circumvented a G2/M arrest. Consequently, cells with unrepaired DNA damage rushed into mitosis, which resulted in massive tumour cell death. Furthermore, HSP90 inhibition has been shown to reduce the amount of BRCA1 in the cell therewith broadening sensitivity towards PARPi and preventing acquired PARP resistance. Our trial approach is tested in ovarian carcinomas with a mutant p53 background. EUDARIO (EUDRACT 017-004058-40) is funded by the European Commission (FP7 project GANNET53). Methods: Eligible patients have relapsed platinum-sensitive ovarian cancer, no limits in prior lines, high-grade (but clear cell) histology or carcinosarcoma, disease measurable or evaluable according to RECIST 1.1. Patients are randomised into 3 treatment arms (1:1:1), a) control arm: C+Gemcitabine or C+Paclitaxel (q3w, 6 cycles, investigator`s choice) followed by Niraparib, b+c) 2 experimental arms: C (AUC5, d1) + G (150mg/m 2 , d1) q3w 6 cycles followed by either Niraparib alone (arm b) or by Niraparib+G (arm c; G at 100mg/m 2 weekly, limited to 9 months). Niraparib (200/300mg/day) is given in case of SD, PR or CR after platinum-based treatment until disease progression. The main analysis will combine both experimental arms b+c and jointly compare them against arm a using log-rank test. Primary endpoint is PFS, secondary endpoints are PFS2, TFST, TSST, safety, ORR, PRO, OS. The first patient was dosed in January 2019. Clinical trial information: NCT03783949.