tbuckley/cabot-search huggingface dataset:
Functional imaging as a tool in individualized treatment in advanced thymic epithelial tumors.
Authors: Giovannella Palmieri, Margaret Ottaviano, Silvana Del Vecchio, Sabrina Segreto, Mirella Marino, Vincenzo Damiano
Journal: Journal of Clinical Oncology (2016)

e20105 Background: Thymic epithelial tumors progressed after first line platinum based chemotherapy, represent a very challenge for all clinicians. The decision making for choosing a second line therapy is not defined yet. An useful tool may be represent by functional imaging such as 18 FDG/PET CT scan and 111In-octreotide SPECT (OctreoScan). Here we describe our experience based on the evaluation of OctreoScan positivity and 18FDG uptake value. Methods: Twenty-three patients with diagnosis of advanced thymic epithelial tumor according to Masaoka-Koga stage system (2 pts II; 4 pts IVA; 17 pts IVB stage of disease) were retrospectively included in this monocentric study. Histological diagnosis according WHO 2004 was assessed. A diagnosis of thymic carcinoma (TC) was made in 8 pts, while thymoma was diagnosed in 15 pts (1 pt B1; 1 pt B1/B2; 7 pts B2; 3 pts B2/B3; 3 pts B3). After progressed to first line platinum based chemotherapy, all the cases performed both functional imaging. The decision making of second line therapy was long acting somatostatin analogues (SST) (LAR Octreotide 30 mg/4weeks) plus prednisone (0.2 mg/Kg daily) in OctreoScan positive patients. A second line chemotherapy according the CAP-GEM schedule (capecitabine 650 mg/m2 b.i.d. 14 days; gemcitabine 1000 mg/m2 day 1,8 every 3 weeks) was administered in OctreoScan negative patients. Response rate (RR), median time to progression (TTP) and toxicities were evaluated. Results: Eighteen pts received SST plus PDN with a median TTP of 12 months (3-84). CAP-GEM chemotherapy was administered in five pts, obtaining partial response in 3 pts, and progressive disease in the last two. A median TTP of 9 months (4-18) was reached. All the pts responders to second line therapy showed a low 18FDG uptake at baseline evaluation. Only two pts progressed to CAP-GEM chemotherapy had a baseline high uptake. Conclusions: In our experience, functional imaging performed after first line progression, might be a new tool for choosing the best second line therapy in advanced TETs. We propose an hypothetic algorithm: octreoscan positive pts SST plus PDN; octreoscan negative pts with low 18FDG uptake at PET/CT scan CAP-GEM schedule.
Cyclin-Dependent Kinase 12, Immunity, and Prostate Cancer
Authors: Emmanuel S. Antonarakis
Journal: New England Journal of Medicine (2018)

Somatic inactivating variants in the gene CDK12, encoding cyclin-dependent kinase 12, generate fusion-induced neoantigens in prostate cancer. This finding supports the hypothesis that prostate cancers with variant CDK12 will have a response to checkpoint inhibitor drugs.
A glyco-immune checkpoint: Modulation of the immune micro-environment and induction of stem cell-like properties in breast cancer cells.
Authors: Joy M Burchell, Rosalind Graham, Joyce Taylor-Papadimitriou, Thomas Noll, Richard Beatson
Journal: Journal of Clinical Oncology (2018)

e15104 Background: Many tumors, including breast cancers, contain infiltrating immune cells that are unable to eliminate the tumor and in many cases, promote tumor progression by adding to the permissive local environment. Tumors have developed a plethora of mechanisms to evade the immune response, including inducing the expression of checkpoint ligands. Siglecs constitute a family of sialic acid binding lectins expressed on immune cells where they are involved in negatively regulating the immune response and like PD-1 contain an ITIM motif in their cytoplasmic tail. Cancers increase their surface sialylation and engage these inhibitory siglecs, mimicking some pathogens, to elicit immune evasion. As a result, siglecs and their interacting glycoproteins on tumor cells have recently been described as important glyco-immune checkpoints. Methods: Primary monocytes from healthy volunteers and macrophages differentiated from these cells were treated with recombinant MUC1 carrying the tumor-associated, sialylated glycan ST. Cells were phenotyped by flow cytometry and the conditioned medium collected and assayed, and placed onto the cancer cells. Results: When MUC1-ST bound to Siglec-9 on monocytes or macrophages a number of factors are secreted that are involved in tumor progression and immune recruitment. Moreover when MUC1-ST bound to Siglec-9 expressed by macrophages or dendritic cells, these ‘educated’ cells displayed reduced CD8 stimulatory capacity. When macrophages were treated with MUC1-ST they developed a tumor-associated macrophage-like phenotype with increased expression of PD-L1, IDO, CD206 and CD163. In addition preliminary data suggests that the factors released by monocytes induce a stem cell-like phenotype in the cancer cells, inducing the formation of mammospheres. Conclusions: This specific glyco-immune checkpoint not only induces immune suppression but also potentially induces tumor growth by the induction of a cancer stem cell like phenotype. Thus Siglec-9 glyco-immune checkpoint is a prime target for the development of novel immunotherapies.
SWOG S1512: A phase II and pilot trial of pembrolizumab in patients with resectable or unresectable desmoplastic melanoma (DM).
Authors: Kari Lynn Kendra, James Moon, Siwen Hu-Lieskovan, William Edgar Carson, Danae Campos, Alistair Cochran, Michael Wu, Antoni Ribas
Journal: Journal of Clinical Oncology (2018)

TPS9608 Background: DM is characterized by high collagenous stroma and a high mutational burden. A retrospective review demonstrated a 70% RR to anti-PD1 -in 60 patients with metastatic melanoma. Surgery for locally advanced DM often results in large resections in exposed areas of the body. Determining the capability of reducing the tumor size and surgical defects is of clinical interest. Evaluating the correlation of T cell infiltrate, TCR clonality, and the impact of pre-existing adaptive immune response with clinical response is of potential predictive interest. Methods: This prospective study evaluates neoadjuvant pembrolizumab in patients with resectable DM (phase 2) and pembrolizumab in patients with unresectable DM (pilot). The primary endpoint of cohort A (resectable DM) is pathologic complete response rate (pCR). Secondary endpoints: ORR at 9 weeks, OS at 9 weeks, and toxicity. The primary endpoint of cohort B (unresectable DM) is CR. Secondary endpoints: PFS and OS. Translational objectives for both cohorts: evaluate the association between mutational load (whole exome sequencing) and pCR, examine relationships between T-cell infiltration and response, and assess the difference in TCR clonality in responders and non-responders. Key eligibility criteria include no prior systemic therapy and adequate organ function. In addition (cohort A) patients must have resectable disease. Cohort A: pembrolizumab 200 mg IV q 3wk x 3, followed by resection. Cohort B: pembrolizumab 200 mg IV q3wk. Blood for correlative studies: prior to initiation of pembrolizumab. For both cohorts, biopsies will occur pretreatment, prior to C2, and at the time of resection (cohort a). Tumor assessments are performed at baseline and at week 9. Cohort B: tumor assessments continue every 9 weeks. Cohort A: if >5 patients demonstrate a pCR, further study is warranted (alpha of 4.6%, power of 90.2%). Cohort B: ≥3 patients demonstrating a CR warrants further study (true CR is 5%, power is 82%). As of January 2018, accrual = 5. Funding: NIH/NCI grant awards U10CA180888 and U10CA180819; and in part by Merck, Sharpe & Dohme, Corp. Clinical trial information: NCT02775851.
Importance of pharmacovigilance in the era of small molecules: Role of pharmacist consultation with ixazomib (IXA) in multiple myeloma (MM).
Authors: Heidi Diann Finnes, Shaji Kumar, Betsy LaPlant, Morie A. Gertz, Francis Buadi, Martha Lacy, Angela Dispenzieri, Kristen Beth McCullough, Julianna A. Merten, Gabriel T. Bartoo, S. Vincent Rajkumar, Prashant Kapoor
Journal: Journal of Clinical Oncology (2016)

8058 Background: IXA is an oral proteasome inhibitor recently approved for MM. Due to IXA’s Cytochrome P450 CYP3A4 and 1A2 metabolism, clinical trials of IXA excluded pts on 3A4 and 1A2 strong inhibitors and inducers. We examined the role of pharmacist review of potential drug-drug interactions (DDIs) in patients (pts) initiating IXA. Methods: Clinical trial pts receiving IXA between 1/2012 and 12/2015 for relapsed MM (NCT01415882; IXA, dexamethasone) and newly diagnosed MM (NCT01864018; IXA, dexamethasone, cyclophosphamide) were included. A pharmacist medication review for DDI was performed prior to IXA initiation. Baseline characteristics, concomitant medications, and toxicities were recorded. Results: Ninety-seven pts were included; 1 pt was excluded due to use of clarithromycin, a strong CYP3A4 inhibitor. Median age was 69 years (41-88) and 57% were male. The median number of concomitant medications was 9 (1-23). Four (4%) pts had potential CYP-mediated DDIs. One pt was on a strong CYP3A4 inducer (primidone for essential tremor). This pt was switched to propranolol and achieved a partial response to IXA-based therapy. Three pts were on diltiazem, a moderate 3A4 inhibitor. It was discontinued in 1 pt, switched to amlodipine in another, and the third continued diltiazem with IXA and developed grade 2 neuropathy, anorexia, confusion and fatigue. No pts were on strong or moderate 1A2 inhibitors or inducers. Forty-six (47%) pts were on drugs known to cause thrombocytopenia or increased bleeding risk. Because IXA causes thrombocytopenia, providers were alerted to these interactions for closer monitoring. Three pts (3%) had bleeding on IXA plus aspirin (gastrointestinal hemorrhage), clopidogrel (epistaxis) and ibuprofen (hematuria) respectively. At a median follow-up of 15.1 (0.8-40.8) months, 29 (30%) pts remain on IXA. Conclusions: The IXA label now allows concurrent use of CYP3A4 inhibitors but continues to prohibit strong CYP3A4 inducers. Our study highlights the importance of a pharmacist consultation to identify potential DDI, toxicity risks, and to offer alternative medication recommendations prior to initiating IXA in routine practice.
The efficacy and safety of nedaplatin single therapy in 30 patients with platinum-resistant ovarian cancer.
Authors: Yuka Kasamatsu, Munetaka Takekuma, Nobuhiro Kado, Emi Yoshioka, Shiho Kuji, Aki Tanaka, Nobutaka Takahashi, Masakazu Abe, Yasuyuki Hirashima
Journal: Journal of Clinical Oncology (2017)

e17075 Background: This study aimed to investigate the efficacy and safety of Nedaplatin single therapy for patients with platinum-resistant ovarian, tubal and primary peritoneal cancer after completing standard chemotherapy. Methods: From September 2002 to August 2016, 30 patients who were diagnosed with platinum-resistant ovarian cancer, were treated with Nedaplatin single therapy after completing all standard chemotherapy at our institution. Nedaplatin (80-100mg/m 2 ) was adiministered intravenously on day 1 of a 28 day cycle. We retrospectively investigated the response rate, toxicities, and survival based on the use of Nedaplatin single therapy. Results: The median age was 58.5 years (23-76). The median number of prior chemotherapy regimen was 3 (1-7). The median platinum-free interval between the final use of platinum analogues and starting Nedaplatin single therapy was 9.4 months (0.9-54.9). Among 22 patients who had measurable disease, 8 (36.4%) responded partially to Nedaplatin single therapy. Seven patients (23.3%) experienced hematological toxicities of Grade 3/4. Six patients (20.0%) experienced non-hematological toxicities Grade 2. No treatment-related death occurred. The median progression-free survival was 3.2 months (0-23.3), and over all survival was 9.2 months (1.1-56.4) after treatment with Nedaplatin single therapy. Age (&lt;70 years, p=0.017) and platinum-free interval (&lt;6 months, p=0.013) were the prognosis factors for survival in univariate analyses. Conclusions: Nedaplatin single therapy seemed to be an effective and safe chemotherapy regimen for platinum-resistant ovarian cancer after completing standard chemotherapy.
Abstract 16405: Prevention of HeartMate II Pump Thrombosis - Recommendations and Preliminary Observations From the PREVENT Study
Authors: Sitaramesh Emani, Mary Keebler, John M Ransom, Ahmet Kilic, Gregory Egnacyzk, Robert Gallegos, Paul Mather, John Stulak, Igor Gregoric, Jason Katz, Charles T Klodell, Nir Uriel, John B O’Connell, David Farrar, Kartik Sundareswaran, Simon Maltais
Journal: Circulation (2015)

Introduction and hypothesis: Recent data have indicated an increase in the rate of early, confirmed pump thrombosis of the HeartMate II (HMII) left ventricular assist device. Factors related to this increase were not known, but one of the hypotheses was change in clinical management over time. The PREVENT ( PREVEN tion of Heartmate II Pump T hrombosis through Clinical Management) study was designed to evaluate the impact of clinical practices developed to reduce the risk of HMII pump thrombosis. Methods: PREVENT is a prospective, multi-center, single-arm, non-randomized study of up to 300 patients at up to 25 sites. Patient and pump management, including implant technique, anticoagulation, and pump settings are guided by protocol (Table 1). Primary endpoint is incidence of confirmed pump thrombosis at 3 months, with a total follow-up of 6 months. Presented here are the preliminary results from the first 100 subjects enrolled. Results: Median age was 61 years [25-79], 87% were male, and 79% were destination therapy. At implant, 9% were in INTERMACS Profile1, 68% Profiles 2-3, and 22% Profiles 4-7. Preliminary analysis of 90-day outcomes demonstrated an incidence of 1% for confirmed and 2% for suspected thrombosis with a 38% incidence of INTERMACS-defined bleeding. Adherence to the protocol recommendations was as follows: 91% of the pumps were anchored, 97% of the patients were bridged with heparin, median pump speed at 1 month was 9190 [range: 8400-10000], with 93% of the patients having a pump speed &gt; 8600, and 78% of the patients having pump speeds &gt; 9000. Median INR per patient was 2.2 [IQR: 2.0-2.4]. Overall Kaplan-Meier survival was 93%. Conclusions: Preliminary results are encouraging and suggest good adherence to the PREVENT protocol and low rates of pump thrombosis without a resultant increase in bleeding complications. Overall survival after HM II implantation remains excellent.
A novel, open-access data commons for improved disease management in patients (pts) with Merkel cell carcinoma (MCC).
Authors: Zhen Su, Monica M. Bertagnolli, A. Oliver Sartor, Catherine E. Symonds, Hao Zhang, Martin J. Murphy
Journal: Journal of Clinical Oncology (2018)

e21544 Background: MCC, also known as neuroendocrine carcinoma of the skin, is an extremely rare and aggressive skin cancer with poor prognosis and high unmet clinical need. The incidence of MCC in the US in 2008 was 1,500 cases; for metastatic disease, the 5-year survival was 18%. Recent study reports of durable responses to checkpoint inhibitors show promising outcomes and recent regulatory approval of Bavencio (avelumab) provides the first approved treatment option with durable response outcomes for pts with metastatic MCC; The rarity of this tumor type and the limitations on data access make it difficult to quantitatively measure pt care and outcomes for metastatic disease treatment in a real-world setting. Methods: We propose a novel pt-centric approach to establish an open-access prospective pt registry for MCC. Our objective is to collect pt-level data to gain insight into and determine effectiveness of real-world disease treatment paradigms, outcomes and management for these underserved pts. The goal of the MCC registry is to provide a common data source on disease management, adverse events, and patient outcomes. To accommodate disparate data sources, we propose a hybrid approach to collect and integrate pt-level data. Combining an EHR integration platform, bespoke data collection, and pt-driven mobile data entry, we can capture pt-level MCC data from rural community settings and larger specialist centers. This will provide much-needed breadth and depth to the MCC pt data available for research. We will leverage the existing Project Data Sphere platform to house the registry. Results: Launched in 2014, ProjectDataSphere.org hosts data from oncology clinical trials (i.e., industry, academic, and government data providers) for ≈120,000 pt lives. On average, data for > 2,500 additional pt lives are added monthly, and all de-identified data are available to the research community on the advanced SAS-based platform. Conclusions: We aim to formalize the registry and begin enrolling pts at the end of 2018. We are open to and invite collaboration with data providers, researchers and clinicians to effectively establish this novel and valuable platform as a resource for the MCC community.
Functional profiling of oncogenic mutations in lung cancer patients (NCT02274025): Interim results.
Authors: Gabi Tarcic, Nir Peled, Zohar Barbash, Oded Edelheit, Michael Vidne, Mordechai R. Kramer
Journal: Journal of Clinical Oncology (2016)

e20066 Background: A major advancement in the treatment of lung cancer patients is the use of EGFR inhibitors, which have shown clinical efficacy. Additionally, there are several FDA approved inhibitors of EGFR that can be used. One of the major issues in this respect is the use of the different drugs, and prediction of response. To address this issue we have initiated an observational trial to functionally profile patient EGFR mutations as well as collect clinical outcome data. The functional analysis was done using the NovellusDx Precision Cancer Analysis system (PCAS), which monitors the activity of signaling pathways by means of a transfected cell-based assay. A major advantage of this system is its capacity to identify oncogenic activity of mutations as well as their response to different types of drugs Methods: On trial, pts that are suspected to have lung cancer and are eligible for biopsy or surgical intervention were included. All samples were taken before the start of treatment. Of these, the mutational status of EGFR was verified by NGS. Patients positive for mutations were then analyzed using PCAS for their activity and their response to the targeted therapy used in the clinic were measured. Clinical response was observed by cross-sectional imaging Results: In the 23 pts enrolled so far, 4 (17%) were identified with an alteration in EGFR. These patients were treated with EGFR inhibitors (Tarceva, Gefitinib or Gilotrif). The clinical responses varied, and 2 of the patients, underwent additional EGFR therapy (Gilotrif or Tagrisso) after disease progression. All treatment decision were at physician’s choice only. When profiling the activity level of these mutations, the PCAS successfully identified the oncogenic mutations as well as their sensitivity and resistance to the different drugs used Conclusions: This study shows the importance of functional profiling of mutations, specifically in the case of multiple treatment options. We show that the activity profiles of the identified EGFR mutations vary, and that their sensitivity to different targeted therapies also differs. Importantly, the different sensitivities were also predictive of the resistance seen in the clinical outcome of the patients Clinical trial information: NCT02274025.
Cancer genomics at the edge of public health and precision medicine in Belgium: A national perspective.
Authors: Marc Van den Bulcke
Journal: Journal of Clinical Oncology (2018)

e18543 Background: Cancer pathology is strongly driven by genetic modifications in the genome DNA what invoked the development of integrated technology in assessing cancer preventive and curative strategies. Through better understanding and integrating information on the role of the genome in disease and adaptation to environmental factors novel approaches are envisaged. The latter is generally designated as ‘personalized’ or ‘precision’ medicine, the former when studied at the population level as ‘Public Health Genomics’ (PHG). Methods: Integrating both PHG and ‘Precision medicine’ into an overall healthcare approach from a national perspective is a challenge. A societal debate on ethical and legal aspects on these topics is being organized. Preventive strategies e.g. through stratified genetic screening is a first challenge tackled through a feasibility assessment. The implementation of genomics in standard medical care for the whole population is currently introduced through a national pilot study Finally, integrating the population dimension into the genomics paradigm is envisaged through the collection of genomic information from participants of the national health survey initiative. Results: We are rolling out a national pilot for the use of Next-Generation Sequencing testing in routine diagnostics in advanced cancers. A centralized documentation system has been developed linked to the national cancer registry, allowing monitoring and evaluating the effectiveness. We are assessing in practice stratified genetic screening in breast cancer through the Horizon 2020 research program of the EC. Finally, the national health survey 2018 will serve as a representative baseline of genomic variability in the Belgian population. Conclusions: Integrating genomics as a counterstone of the national health care system (HCS) in Belgium is a novel paradigm requiring a shift in societal thinking. The success of implementing such novel paradigm can only be obtained through mutual support by policy makers, citizens/patients, the healthcare professionals at large and industrial partners. A societal debate on ethical and legal aspects when integrating genomics in public health and medical care is essential.