tbuckley/cabot-search huggingface dataset:
PRO-105, a phase II open-label study of NUC-1031 in patients with platinum-resistant ovarian cancer.
Authors: Charlie Gourley, Heather J. Dalton, Susana N. Banerjee, Joseph Buscema, Michelle Lockley, Jonathan Krell, Bradley J. Monk
Journal: Journal of Clinical Oncology (2018)

TPS5612 Background: Patients with platinum-resistant ovarian cancer, following ≥3 lines of chemotherapy have limited treatment options. NUC-1031, a phosphoramidate transformation of gemcitabine, is designed to overcome the three key resistance mechanisms associated with gemcitabine: transport, activation and breakdown. By overcoming these resistance mechanisms, NUC-1031 achieves > 200-times higher intracellular concentrations of the active anti-cancer metabolite, dFdCTP, compared to gemcitabine. NUC-1031 was well tolerated and demonstrated anti-tumor activity in ovarian cancer patients (Blagden et al, ASCO 2015; Blagden et al, ESMO 2017). Based on these data, a Phase II dose-confirming study was initiated to investigate NUC-1031 in patients with platinum-resistant ovarian cancer. Methods: PRO-105 is a randomized open-label, two-part clinical study designed to determine the optimal dose of NUC-1031 in patients with platinum-resistant ovarian cancer who have received ≥3 lines of chemotherapy. The primary endpoint is Objective Response Rate at the selected dose level (500 mg/m2 or 750 mg/m2), assessed by a blinded independent central reviewer. Secondary endpoints include duration of response, progression-free survival, overall survival, PK/PD and patient-reported outcomes. In Part I, up to 40 patients will be randomized to NUC-1031 at 500 mg/m2 or 750 mg/m2 on days 1, 8 and 15 of a 28-day cycle. Randomization is stratified for BRCA 1/2 mutation status and number of prior chemotherapy lines. One dose level will be selected for further evaluation in Part II based on safety, PK, dosing intensity and clinical activity. Enrollment will continue in Part II until 44 response evaluable patients are recruited at the selected dose. To date, 22 patients with platinum-resistant ovarian cancer have been randomized into Part I of the study, which is currently recruiting across 15 US and 8 UK sites. Clinical trial information: NCT03146663.
OS4.1 A risk calculator to predict the need for an intervention within a patient’s estimated lifetime for incidentally-found asymptomatic meningiomas
Authors: A I Islim, M Mohan, R Moon, R Kolamunnage-Dona, N Rathi, S J Mills, A R Brodbelt, M D Jenkinson
Journal: Neuro-Oncology (2018)

30% of newly-diagnosed meningiomas are incidental findings. There is no consensus on the optimal management. The aim of this study was to develop a risk calculator to enable identification of patients at risk of active monitoring failure who will require an intervention within their estimated lifetime. Active monitoring failure was defined as: new symptoms, MRI progression (absolute growth rate ≥ 2 cm3/year or absolute growth rate ≥ 1 cm3/year + relative growth rate ≥ 30%/year) or loss of treatment options. A prognostic model was developed using MRI and patient co-morbidity (age-adjusted Charlson index) in a retrospective cohort (2007–2015). 385 patients were included (403 meningiomas). Mean age at diagnosis was 62.6 years (SD= 12.0); 301 (78.2%) were female. Over a median of 36.0 months (range: 3–120), 1688 MRI were performed (mean=4 scans/patient). 44 (10.9%) meningiomas were classed as failed active monitoring; reasons being radiological progression (n=29), new symptom development (n=12), development or worsening of peritumoural oedema (n=12), meningioma volume exceeding 10 cm3 (n=9) and venous sinus invasion (n=7). Nineteen (43.2%) patients had > 1 reason for failing active monitoring. Median time to failure was 33.0 months (range: 5–102). Model parameters were based on statistical and clinical considerations. These included: increasing tumour volume (HR=2.17 [95% CI=1.53–3.09], p<0.001), peritumoural signal change (HR=1.58 [95% CI=0.65–3.85], p=0.313), FLAIR/T2 hyperintense meningiomas (HR=10.6 [95% CI=5.39–21.0], p<0.001) and proximity to critical neurovascular structures (HR=1.38 [95% CI=0.74–2.56], p=0.314). Discriminatory power of the model was excellent (Harrell’s C statistic=0.89). Patients were stratified based on the model into low, medium and high-risk groups. Low-risk patients had non-oedematous, small iso/hypointense meningiomas, distant from neurovascular structures. Rates of active monitoring failure at 5-years were 3%, 28% and 75% respectively. After 5-years of follow-up the probability of failed active monitoring plateaued in all risk groups. Older patients with co-morbidities (age-adjusted Charlson index ≥ 6) were 15-times more likely to die than to receive intervention at 5-years following diagnosis, regardless of risk-group. Most meningiomas remain clinically and radiologically stable. Patients with Charlson index ≥ 6 do not require active monitoring. Low-risk patients require less frequent MRI monitoring. Follow-up beyond 5-years may not be required for all patients. Stratifying follow-up according to risk-group has the potential to reduce the cost of healthcare.
Efficacy and safety of chemotherapy DCX (DOCETAXEL–CISPLATIN–CAPECITABINE) as a perioperative treatment of gastric cancer: A single institution analysis.
Authors: Ismael Macias Declara, Laia Vilà, Alexis Luna, Pere Rebasa, Sandra Montmany, Antoni Malet Munte, Ruth Orellana, Maria Marin Alcala, Paula Ribera Fernandez, Clara MartÃnez Vila, Helena Oliveres, Salvador Navarro, Eugeni Saigí, Carles Pericay
Journal: Journal of Clinical Oncology (2018)

e16094 Background: Currently, ECF/ECX is the standard of care for peri-operative oesophagogastric adenocarcinoma (OGA), considering MAGIC trial even though the outcome still remains unsatisfactory with 36% 5-year overall survival (OS). FLOT4 trial proved superior results in OS and progression free survival (PFS) than ECF/ECX. The aim of our study is to check out the paper of taxane in perioperative setting as DCX schedule. Methods: Patients affected by OGA between 2008 to 2016 treated in our hospital with perioperative DCX were analyzed. Demographic, clinical, pathological and treatment characteristics were evaluated. We used the Kaplan-Meier method to generate curves for overall survival and time to progression (TTP). Results: Twenty-three patients were included. The median age at diagnosis was 64.13 years (46-75) and the male/female ratio was 1,3. The prevalence of primary location was antrum 21.7%, cardias Siewert II 4.3%, cardias Siewert III 26.1%, gastric body 43.5, linitis plastica 4.3%. Intestinal Laureen subtype was more common than diffuse subtype (39.1% vs 30.4%). 39.1% patients relapsed after surgery and the most common location was peritoneal (26.1%). Time admitted by surgery was 9.96 days (6-52). Time between end-of-chemotherapy and surgery was 48.3 days and time elapsed between surgery and postoperative chemotherapy was 45.8 days. Median OS data are not reached with current (34.69 months) follow-up, whereas a 65.5 months survival has been obtained with an immature evaluation. The median TTP was 15.79 months. Conclusions: Despite median OS data are still immature, they are superior than those obtained in FLOT4 trial and MAGIC trial. Further follow-up is required for more consistent data.
CRS-207 immunotherapy expressing mesothelin, combined with chemotherapy as treatment for malignant pleural mesothelioma (MPM).
Authors: Raffit Hassan, Evan W. Alley, Hedy L. Kindler, Scott Joseph Antonia, Thierry Marie Jahan, Somayeh Honarmand, Katherine McDougall, Chan C. Whiting, Nitya Nair, Amanda Enstrom, Ed Lemmens, Takahiro Tsujikawa, Sushil Kumar, Lisa M Coussens, Aimee Murphy, Anish Thomas, Dirk G. Brockstedt
Journal: Journal of Clinical Oncology (2016)

8558 Background: CRS-207 is a live, attenuated Listeria monocytogenes engineered to target mesothelin, a tumor-associated antigen over-expressed in several cancers, including MPM, an aggressive treatment-refractory disease with poor prognosis. CRS-207 activates both innate and adaptive immunity and may act synergistically with chemotherapy to increase the susceptibility of the tumor microenvironment to immune-mediated killing Methods: Eligibility requirements included unresectable, untreated MPM, ECOG 0 or 1, and adequate organ function. Patients received 2 CRS-207 doses 2 weeks apart, 6 cycles of pemetrexed/cisplatin 3 weeks apart, followed by 2 CRS-207 doses 3 weeks apart. Patients continued CRS-207 every 8 weeks if clinically stable. Study objectives included safety, immunogenicity, objective tumor responses, overall survival and tumor marker kinetics. Comprehensive immune profiling included multidimensional IHC, Luminex, flow cytometry and transcriptional analyses Results: 38 patients (89% male; median age 71) have been enrolled and median time on treatment was 8.6 months (mos). The most common CRS-207 related adverse events (AEs) were grades 1/2 fever, chills, hypotension and nausea/vomiting, with no treatment-related serious AEs or deaths. As of Dec. 2015, of 36 evaluable, 94% (34/36) had disease control with 1 complete response (3%), 19 partial responses (53%) and 14 with stable disease (39%); median duration of response was 5.3 mos. Median PFS and OS was 8.4 (95% CI: 7.1 - 10.4) and 20.1 mos (95% CI: 10.9 - N/A), respectively. Preliminary immune analyses reveal substantial CRS-207-mediated immune reprogramming as shown by circulating immune cells and tumor-infiltrating lymphocytes (TILs), serum biomarkers and transcriptional gene signatures Conclusions: CRS-207 was well tolerated and resulted in increased overall response rate and survival than expected with chemotherapy alone. Encouraging anti-tumor responses with overall response rate of 56% and 94% disease control and induction of TILs, circulating effector immune cell subsets and transcription signature following CRS-207 were observed. A global, phase 3, randomized study will be initiated in 2016 Clinical trial information: NCT01675765.
Live tumor cell functional analysis and a xenograft model find co-activated c-Met and ErbB signaling in HER2-negative breast cancer.
Authors: Lance G. Laing, David J Burns, Salmaan Khan, Ian A. MacNeil, Benjamin E. Rich, Sajjad Soltani, Samantha Myhre, Brian Sullivan
Journal: Journal of Clinical Oncology (2018)

e24292 Background: Clinical trials evaluating anti-Met therapies have produced mixed results when subjects are selected for c-Met overexpression or gene amplification. To further elucidate the role of c-Met signaling and its potential involvement with ErbB signaling as a cancer driver, a new assay to identify dynamic multi-pathway signaling dysfunction (CELx MP test) was developed. The current study set out to characterize ErbB family and c-Met function in primary HER2-negative breast tumor cells and evaluate in vivo response to a c-Met inhibitor in breast tumor xenograft models. Methods: Tumor specimens were obtained from 74 HER2- breast cancer patients. Live cell response to ErbB and c-Met agonists with or without antagonist (pertuzumab, neratinib, or tepotinib) was quantified using a 96-well biosensor. Signaling activity above a cut-off value of 250 signaling units was used to identify abnormal EGFR, HER2 and c-Met signaling. HCC1954, a HER2+ cell line with normal HER2 signaling, abnormal EGFR signaling, and abnormal c-Met signaling, as determined by the CELx MP test, was injected into 40 female NSG mice. Mice were treated for 16 days with either Captisol, neratinib, tepotinib or a combination (10 mice/arm). Results: The CELx MP test found abnormal signaling sub-groups as follows: HER2 - 16 of 74 (22%; 95% CI = 14%-32%); c-MET - 31 of 74 (41%; 95% CI = 31%-53%); EGFR – 17 of 74 (23%; CI = 15%-34%). For all samples tested, EGFR and HER2 signaling were each strongly correlated to c-Met signaling levels (r = 0.89 and r = 0.85 respectively). The average amount of c-Met signaling activity inhibited in cell samples increased by 75% when tepotinib was combined with neratinib versus tepotinib alone. In the xenograft study, no significant difference in tumor volume between the control and tepotinib-treated arms after 16 days of treatment was recorded. Tumor volumes after treatment were reduced by 17% in the neratinib arm and by 45% in the tepotinib + neratinib arm. Conclusions: These findings suggest that a sub-group of HER2- breast cancer patients have co-activated abnormal ErbB and c-Met signaling tumors and may respond better to ErbB and c-Met inhibitors combined than c-Met inhibitors alone.
Image Gallery: Wyburn-Mason syndrome with a chronic wound
Authors: J. Dissemond, K. Salva, K. Kröger
Journal: British Journal of Dermatology (2018)

Funding sources: no external funding. Conflicts of interest: none to declare. A 39‐year‐old man reported recurrent severe bleeding from a wound on the right cheek (Fig. 1). Due to prior history of Wyburn–Mason syndrome, he had undergone multiple interventional therapies with embolizations using n‐butyl cyanoacrylate. Angiography revealed an angioma extending from the internal carotid artery into the orbit (Fig. 2). Wyburn–Mason syndrome represents a rare phakomatosis characterized by ipsilateral arteriovenous malformations of the brain, eyes and skin with port‐wine stain(s) in the trigeminal or central facial nerve distribution.1 Therapeutic options include embolization, radiation, laser coagulation and surgery.2 Our case report intends to raise clinicians' awareness of chronic wounds as possible sequelae following embolization treatments.
An amplicon-based liquid biopsy for detecting <i>ALK</i> and <i>ROS1</i> fusions and resistance mutations in advanced non-small cell lung cancer (NSCLC) patients.
Authors: Laura Mezquita, Cecile Jovelet, Ludovic Lacroix, David Planchard, Gonzalo Recondo, Emma Pailler, Edouard Auclin, Vincent Plagnol, Karen Howarth, Clive D. Morris, Emma Green, Etienne Rouleau, Claudio Nicotra, Caroline Caramella, Julien Adam, Nathalie Auger, Francoise Farace, Luc Friboulet, Benjamin Besse
Journal: Journal of Clinical Oncology (2018)

9095 Background: Circulating tumor DNA (ctDNA), is a surrogate material for somatic mutation (mut) detection, such as EGFR in NSCLC patients (pts). However, the applicability for the detection of ALK/ROS1 fusions and resistance mut. is poorly described. The aim of this study was to evaluate an amplicon-based ctDNA assay for detecting ALK/ROS1 fusions and mut. in a cohort of ALK/ROS1+ NSCLC pts. Methods: Advanced ALK/ROS1+ NSCLC pts were prospectively enrolled from Dec 2016 to Dec 2017 in our institution. The analysis of ALK/ROS1 mut, EML4-ALK (variant 1,2,3) and ROS1 fusions (with partner genes CD74, SLC34A2, SDC4 and EZR) in ctDNA were performed using InVisionFirst™ Results: 51 pts were included (43 ALK, 8 ROS1); ALK/ROS1 status was confirmed by ALK IHC (26) and FISH (40). The median prior tyrosine kinase inhibitors (TKI) received was 2 (0-4). Blood samples (n = 127) were collected before TKI (n = 9), during (n = 120) or at progression (PD) (n = 25) in 45 pts that received TKI (13 crizotinib, 32 next-gen. TKI) or other therapies (n = 6). Before TKI, ALK/ROS1 ctDNA fusions were detected in 86% of pts (5/6 ALK; 1/1 ROS1). In samples at PD, 64% had fusions detected (15/22 ALK; 1/3 ROS1). Overall, 16 pts had a positive fusion in blood (5 EML4-ALK variant 1-2, 8 variant 3, 2 CD74-ROS1, and 1 SLC34A2-ROS1 (13 ALK, 3 ROS1). By contrast, a minority (13%) of samples collected during clinical response, were positive (8/69 ALK; 2/11 ROS1). ALK mut were detected in 30% of blood samples at PD to TKI (6/17): 17% (1/5) post-crizotinib (G1269A, R1264K, L1196Q, F1164L, C1156Y), and 45% (5/11) post next-gen. TKI (all G1202R), all of them associated with the ALK variant 3. No ROS1 mut were detected. Complex ALK mut were observed in 2 pts variant 3 (post crizotinib and lorlatinib). Other non-ALK mut were found in 47% of samples at PD: TP53 (5), NFE2L2 (4), PTEN (2), KRAS (1) and PI3KCA (1). Complex ALK mut + non-ALK mut were found in 4 (24%) samples; exclusively others non-ALK mut were found in 4 samples. This could explain TKI resistance in 24%. Conclusions: Routine liquid biopsy detects ALK/ROS1 fusions in untreated NSCLC pts and reflects treatment sensitivity in TKI exposed pts. It is also an accurate tool to assess TKI resistance.
New Endometriosis Drug Approved
Authors: Rebecca Voelker
Journal: JAMA (2018)

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TCT-162 Feasibility of Chronic Total Occlusion Recanalization During Balloon Pulmonary Angioplasty
Authors: Sanjum Sethi, Kinjan Parikh, Erika Berman Rosenzweig, Matthew Bacchetta, Alejandro Torres, Philip Green, Khady Fall, Masaru Ishida, Akiko Maehara, Dimitri Karmpaliotis, Ajay Jayant Kirtane
Journal: Journal of the American College of Cardiology (2018)
Potential role of <i>MAD1</i> 1673G&gt;A and <i>ERCC1</i> 8092C&gt;A polymorphisms in the resistance to chemotherapy in advanced ovarian cancer: A pilot study.
Authors: Irwin Alejandro Hernandez Cruz, Diddier Prada, José Díaz-Chávez, Salim Barquet-Munoz, David Francisco Cantu De Leon, Luis Alonso Herrera
Journal: Journal of Clinical Oncology (2017)

e17045 Background: Ovarian cancer (OC) is the most lethal gynecological cancer and 70% of cases are in advanced stages at diagnosis. The standard treatment for those stages is optimal cytoreduction plus chemotherapy based on carboplatin-paclitaxel. Nevertheless, 60%-70% of patients will progress after diagnosis, becoming resistant in some point of the disease. There are no biomarkers to predict response to chemotherapy in OC. Some polymorphisms, including MAD1 1673G &gt; A and ERCC1 8092C &gt; A have shown potential to predict chemoresistance in other tumors. Thus, we explored the role of these polymorphisms in the resistance to chemotherapy in advanced OC. Methods: We genotypified 89 OC patients samples, and also determined the mRNA expression for both genes by RT-PCR. We compared distributions using chi-squared test and determined differences in overall survival and free-relapse survival using Kaplan-Meier curves and log-rank test. Results: Most of cases were IIIC stage (35.48%), papillary histological subtype (32.26%), highly differentiated (67.74%), and 35.48% tumors with recurrence. Distribution for MAD1 genotype was 35.48% for wild-type (WT), 32.26% for heterozygous (HT), and 32.26% for homozygous polymorphic condition (Poly). For ERCC1, we found a distribution of 25.81% for WT, 51.61% for HT, and 22.58% for Poly. When comparing distributions, we found statistically significant differences between sensitive vs. resistant tumors ( p= 0.02), with lack of the WT condition for ERCC1 in sensitive tumors. When analyzing haplotypes in regard to platinum-sensitivity, we also found statistical differences in the distribution of haplotypes ( p = 0.02). No association between genotypes and expression was observed. Remarkably, we found a lower free-relapse survival in the presence of at least one WT allele for the MAD1 polymorphism (p = 0.021, log-rank test). Conclusions: In this pilot study, we have found that ERCC1 8092C &gt; A polymorphism, as well as haplotypes for these two genes, could be associated with chemoresistance. MAD1 1673G &gt; A polymorphism could play also a role in recurrence in advanced OC.
Plasma cell-free DNA for noninvasive molecular profiling in high-risk stage 4 neuroblastoma.
Authors: Prachi Kothari, Julie Yang, Michael F. Berger, Neerav Narendra Shukla, Shakeel Modak, Dana Tsui
Journal: Journal of Clinical Oncology (2018)

10554 Background: Cell-free DNA (cfDNA) allows real-time molecular analysis of solid tumors. Neuroblastoma, the most common extracranial pediatric solid tumor, is known to have a higher mutational burden at relapse. In this study, we evaluate the value of cfDNA profiling in a cohort of 21 high-risk stage 4 neuroblastoma (NB) patients. Methods: Plasma cfDNA samples were collected near diagnosis or at time of relapse from 21 patients. FISH analysis confirmed 5/21 patients were MYCN amplified. Tumor mutational profiles are known from targeted NGS analysis in 19/21 patients. Plasma cfDNA was analyzed by MSK-IMPACT (468 genes panel) to profile somatic mutations, and shallow whole genome sequencing (sWGS) to look for MYCN amplification. We also evaluated the utility of sWGS to assess tumor-derived mutant allele fractions (MAF) in cfDNA using genomewide z-scores (GWZ). Matched control samples were used to filter germline variants. Results: We detected somatic mutations in tumor tissue and cfDNA of 17/19 and 12/21 patients, respectively. These included recurrent drivers such as ALK and ATRX. In 5 patients with MYCN-amplified NB, sWGS sequencing confirmed the same finding in 4. The patients with a GWZ above 2.5 at the time of blood draw were associated with a decreased overall survival. In 1 patient, longitudinal samples were collected after 1 cycle of chemotherapy and pre-/post-surgery, the GWZ decreased as the patient responded to therapy. Two patients with GWZ > 5 (MAF~10%) were selected for WES to perform more comprehensive analysis. WES revealed FGFR1, ARID1A and FOXP1 mutations which have been reported in relapsed high-risk NB patients. Mutational signature analysis using WES data from cfDNA also revealed signature 18 that has previously been reported predominantly in neuroblastoma. Conclusions: This study shows the utility of cfDNA analysis through multiple platforms to noninvasively profile the genetic heterogeneity of neuroblastoma, reveal somatic copy number alterations and monitor response to therapy. These findings call for cfDNA analysis to be incorporated in clinical trial to further evaluate its utility for clinical management of NB patients.