tbuckley/cabot-search huggingface dataset:
Randomised phase II study with cetuximab in combination with 5-FU and cisplatin or carboplatin versus cetuximab in combination with paclitaxel and carboplatin for treatment of patients with relapsed or metastatic squamous cell carcinoma of the head and neck (CETMET trial).
Authors: Signe Friesland, Georgios Tsakonas, Claus Kristensen, Maria Herlestam Calero Moren, Hedda Haugen, Karin Soderstrom, Lena Specht
Journal: Journal of Clinical Oncology (2018)

6032 Background: Platinum-based chemotherapy with cetuximab is the standard of care for relapsed or metastatic squamous cell carcinoma of the head and neck (SCCHN). The aim of this trial was to investigate whether cetuximab and paclitaxel/carboplatin can achieve similar progression free survival (PFS) with less toxicity compared to standard cetuximab and 5-FU/platinum based chemotherapy. Methods: In this multicentre, randomised, controlled, phase 2 trial, 85 patients with relapsed or metastatic SCCHN were randomised in a 1:1 ratio to cetuximab and 5-FU/cisplatin or carboplatin (arm A, n = 42), versus cetuximab and paclitaxel/carboplatin (arm B, n = 43). Patients without disease progression continued with cetuximab maintenance every second week until progression or toxicity. Eligibility criteria included age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, and adequate organ functions. The primary endpoint was to investigate whether PFS in arm B is non-inferior to PFS in arm A using a liberal non-inferiority margin of 1.5 for the PFS hazard ratio (HR). Results: The median age for the whole study population was 60.9 years with a male predominance (69.4%). Clinically significant parameters, such as tumour localization, tumour stage, PS, HPV status and age were well balanced between the two treatment arms. Adverse events ≥ grade 3 were more frequent in arm A than in arm B (60% vs 40%; p = 0.034). Median PFS in arm A was 4.37 months (95% CI: 2.9- 5.9 m) and 6.5 months (95% CI: 4.8-8.2 m) in arm B, (p = 0.064). Median overall survival (OS) was 8.4 months (95% CI: 5.3-11.5 m) in arm A and 10.2 months (95% CI: 5.4-15 m) in arm B (HR = 0.71; 95% CI: 0.43-1.16). PFS HR for arm B was 0.65 (95% CI: 0.41- 1.03) and the predefined non-inferiority criterion was met. Conclusions: Cetuximab and paclitaxel/carboplatin was found to have similar efficacy and less toxicity compared to cetuximab and 5-FU/cisplatin or carboplatin. The experimental arm is easier to administer rendering it a favourable alternative to standard therapy in daily clinical practice. Clinical trial information: NCT01830556.
Organized screening for colorectal cancer in Algeria: First pilot study in North Africa.
Authors: Bouzid Kamel, Mazouzi Chahira
Journal: Journal of Clinical Oncology (2018)

e15697 Background: In Algeria in 2015 colorectal cancer represents the 2nd cause of cancer mortality after lung cancer in men and after breast cancer in women. The increasing CRC incidence and mortality can be reduced by screening and treating adenomas and early cancers. A pilot CRC screening programme using immunochemical faecal occult blood testing (iFOBT) and colonoscopy for test-positives were implemented in Béjaia a northeast district of Algeria. This study aims to evaluate the acceptability, feasibility, validity of screening tests, and scaling-up of screening in Algeria. This report describes the implementation, coverage and performance indicators of this pilot project. Methods: This is a pilot study for colorectal cancer screening with an immunological test of an average risk population aged [50-74] over a 20-month period,A target population aged 50–74 years was informed about and invited to undergo CRC screening by community –clinics . faecal sample collection kits were provided through local primary care units for home sample collection. iFOBT-positive persons were referred for colonoscopy at the Béjaia Univesity hospital, and endoscopic polypectomy/biopsies were performed according to the colonoscopies findings. Those with confirmed CRC received appropriate treatment. Results: Of the 10 000 target population, 2562 (26%) were screened using iFOBT between January 2016 and November 2017. The main issue in the program was accessing people living in study areas due to lack of valid registry system. Of those screened, 156 (6.11%) were found positive; positivity was equitably between men and woman, a rate of 39.4% polyps among the pathological colonoscopies , 6 cancers are found witch corresponding 3.7% of positive tests and a colorectal cancer detection rate of 2.35%. The high false positive rate in our study would be investigated during the next stage through assessment of several kits in Algeria to compare their validity. Conclusions: The successful implementation of the pilot CRC screening with satisfactory process measures indicate the feasibility of scaling-up organized CRC screening through existing health services In Algeria. More work is needed in assessment of kits to be used in the national program.
Detection of AR-V7 using cell-free RNA (cfRNA) in prostate cancer.
Authors: Joshua L. Usher, Kanthi Athreya, Toshiyuki Ishiba, David Samberg, Sadanand Vodala, Mai Dang, Todd Sturdevant, Kathleen Danenberg, Jacek Pinski
Journal: Journal of Clinical Oncology (2016)

e16613 Background: In prostate cancer (PC), the androgen-receptor isoform that is encoded by the splice variant 7 (AR-V7) is characterized by an absence of the ligand-binding domain that is the target of abiraterone and enzalutamide. Consequently, presence of AR-V7 in prostate cancer has been found to be associated with resistance to these two drug agents. In this study, we analyzed cell-free RNA (cfRNA) released into the bloodstream in order to quantitate AR gene expression and AR-V7 in PC patients. Methods: Blood samples were collected from 13 prostate cancer patients, 6 of whom were treated with androgen ablation agents. Plasma was fractionated from blood samples and nucleic acids were extracted. RNA was reverse-transcribed into cDNA using random primers, and then analyzed by quantitative RT-PCR using appropriate gene-specific primers. AR and AR-V7 were assayed in cDNA samples. Relative AR expression was calculated using beta-actin as a denominator reference gene, and AR expression status was tested for associations with disease status and patients' current therapies. Results: Of the 13 samples tested, a total of 7 had detectable levels of AR expression (53.8%). Of the 7 samples testing positive for AR expression, one also tested positive for AR-V7 (14.3%). Among those with detected levels of AR expression, 5 (71.4%) were metastatic castrate resistant, while the other 2 were hormone naïve. Among the 6 samples with no detectable levels of AR expression, 3 (50%) were metastatic castrate resistant, while the other 3 were hormone naïve. Among those with AR expression detected, 2 (28.6%) were on enzalutamide, 3 (42.9%) were on abiraterone, and the remaining 2 were on no therapy and Lupron injections, respectively. Neither disease status nor current therapies were associated with AR expression (p = 0.1839, Chi-Square). Conclusions: We found a surprisingly high frequency of lack of AR expression among these samples (approaching 50% overall), while AR-V7 frequency was consistent with previous findings. While loss of AR expression might be expected to arise as a means of resistance drugs such as enzalutamide and abiraterone, cancers from hormone-therapy naive patients also lacked AR expression. The mechanism and timing of the loss of AR remains to be investigated.
Natural history of heparin-induced thrombocytopenia (HIT) in the cancer population.
Authors: Myra Pearl Wong, Thein Hlaing Oo, Naveen Garg, Cristhiam Mauricio Rojas Hernandez
Journal: Journal of Clinical Oncology (2016)

e18134 Background: Cancer patients may be at higher risk of HIT-related complications than the general population, yet there is limited data on the epidemiology and natural history of HIT in cancer. The aim of this study was to determine the rates and features of thrombotic complications in patients with cancer and HIT. Methods: Retrospective analysis (2002-2015) was performed of the electronic medical records of adult cancer patients at MD Anderson Cancer Center with suspected HIT in whom HIT antibody and serotonin release assay (SRA) were evaluated. Cases were defined as HIT when results of SRA were positive. All other cases were defined as non-HIT. The study endpoints included: rates of thrombosis at presentation of HIT, rates of recurrent thrombosis and overall survival (OS). Non-parametric statistical procedures were used to determine differences in outcomes with a test significance level of 0.05. Kaplan-Meier curves were used to compare groups for the survival distribution. Results: Among 94 patients, 11 were categorized into the HIT group and 83 into the non-HIT group. The median patient age was 64 (IQR = 54-72) and similar for both groups. Males accounted for 63% of patients. The most common malignancies were hematologic, pulmonary and dermatologic (melanoma). Approximately half of the patients had distant metastatic disease at the time of HIT investigation. The predominant types of thrombosis were venous thromboembolism (VTE) located in the proximal lower limb, upper limb and pulmonary artery. The VTE rate at the time of HIT investigation was significantly higher in the HIT group versus the non-HIT group (82% vs 27% respectively, P = 0.001). VTE recurrence took place in 1/22 patients (4.5%) in the non-HIT group and 2/9 patients (22%) in the HIT group (P = 0.195) The median OS was 4.9 months (95% CI, 1.2 to 8.6) and not different among groups (P = 0.846). Conclusions: Our findings suggest that the occurrence of thrombosis is very common in cancer patients who develop HIT, and the incidence of VTE is increased by several fold when compared with cancer patients without HIT. Our population was composed of ill patients with advanced cancer stages, and HIT did not seem to have an impact on their OS. Additional studies are necessary to confirm our findings.
Number of nodal metastases associated with overall survival in HPV-negative head and neck cancer.
Authors: Doug Farquhar, Trevor Hackman, Maheer Masood, Mark Christian Weissler, Andrew F Olshan, Jared Weiss, Siddharth Sheth
Journal: Journal of Clinical Oncology (2018)

6062 Background: The 8th edition AJCC staging guidelines for HNSCC incorporated the number of positive nodal metastases into the pathologic staging criteria for HPV-positive oropharyngeal HNSCC. However, the number of positive nodes is not used for pathologic staging of HPV-negative HNSCC and may have prognostic significance. In this study, we evaluated whether the number of nodal metastases and other surgical pathology characteristics, including extracapsular extension (ECE), positive surgical margins (PSM), and perineural invasion (PNI), were associated with overall survival (OS) in HPV-negative HNSCC. Methods: Patients were identified from the Carolina Head and Neck Cancer Study (CHANCE). All HPV-negative patients without distance metastasis (M0) who received surgical treatment for their primary tumor were included. The number of positive nodes on surgical pathology was divided into 0, 1-4, and > 4 nodes. T and N stage were based on 8th edition AJCC guidelines. Hazard ratios (HR) were calculated by Cox proportional hazard models. Results: We identified 212 HPV-negative HNSCC patients who received primary surgery with neck dissections; (81 had no positive nodes, 90 had 1-3 positive nodes, and 41 had ≥4 nodes). Number of positive nodes, LVI, and ECE were all associated with 5-year OS in univariate models. In a multivariate model that controlled for T and N staging, the number of positive nodes remained significantly associated with OS (HR 2.8, 95% CI 1.8–4.3 for 1-4 nodes; HR 6.4 95% CI 3.6-11.1 for > 4 nodes). In this model, N-stage as defined by AJCC 8 was no longer significantly associated with survival (HR 1.2, 95% CI 0.5–2.6 for N1 vs. N0, HR 1.1 95% CI 0.5– 2.4 for N2 vs. N0, HR 2.1 95% CI 0.8–5.7 for N3 vs N0). ECE, PSM and LVI were not independently predictive of OS in adjusted models. Conclusions: In this population of HPV-negative HNSCC patients, the number of positive nodes had a stronger association with 5-year OS than N staging based on nodal size and laterality found in AJCC 8. No other pathologic variables were associated with survival after adjusting T and N for stage. Further research is necessary to determine whether the number of positive nodes should replace other criteria in future prognostic staging systems.
Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology
Authors: Jerald P. Radich, Michael Deininger, Camille N. Abboud, Jessica K. Altman, Ellin Berman, Ravi Bhatia, Bhavana Bhatnagar, Peter Curtin, Daniel J. DeAngelo, Jason Gotlib, Gabriela Hobbs, Madan Jagasia, Hagop M. Kantarjian, Lori Maness, Leland Metheny, Joseph O. Moore, Arnel Pallera, Philip Pancari, Mrinal Patnaik, Enkhtsetseg Purev, Michal G. Rose, Neil P. Shah, B. Douglas Smith, David S. Snyder, Kendra L. Sweet, Moshe Talpaz, James Thompson, David T. Yang, Kristina M. Gregory, Hema Sundar
Journal: Journal of the National Comprehensive Cancer Network (2018)

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph), resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor (TKI) therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML (CP-CML). The selection TKI therapy should be based on the risk score, toxicity profile of TKI, patient's age, ability to tolerate therapy, and the presence of comorbid conditions. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CP-CML.
Social media usage within the cancer community of northern New England.
Authors: Lukas P Emery, Bhavina D O Batukbhai, Frederick Lansigan, Nayan Agarwal
Journal: Journal of Clinical Oncology (2018)

e18839 Background: Social media (SM) has changed how patients and caregivers experience cancer. This quality improvement project aims to evaluate and understand the SM experience in a rural northern New England (NNE) cancer community, and design SM content for patient education, support, and engagement. Methods: We surveyed patients/caregivers (PC) and healthcare providers (HP) across three NNE cancer centers using a survey measuring access and usage of SM. PC surveys were offered to patients in the waiting area. HP surveys were given to NNE providers and solicited via e-Mail. Surveys were done on paper or online with SurveyMonkey. Results: 190 PCs and 103 HPs were surveyed. Most had access to the internet (89% PC, 99% HP) and owned mobile devices (67% PC, 99% HP). iPhone was the most common mobile device (57% PC, 75% HP). Few responders utilize cancer-related apps (24% PC, 28% HP). 68% of PCs prefer phone communication over ePortals/e-Mail (36%) and less than half have interest in a secure text messaging system (48% PC, 44% HP). Personal SM use was high (70% PC, 92% HP); cancer or work-related use was less (27% PC, 18% HP) due to concerns over privacy (66%) and liability (64%). Both groups preferred Facebook (FB) for personal use (57% PC, 80% HP). Among HPs, LinkedIn (71%) was favored over FB (50%) and Twitter (21%) for professional use. 65% of PCs would like to see increased cancer-related SM content from their institution, but only a minority have visited the homepage (40%) or FB page (3%). Conclusions: Lack of electronic connectivity can isolate patient populations hindering information sharing. Compared to HPs, PCs had less access to the internet and mobile devices. This may reflect the socioeconomic status of patients in rural communities. In our area, FB is the most commonly used SM platform, favored over other sites such as YouTube and Twitter. PCs would like to see an increase in cancer-related content from their cancer center, however, the utilization of current platforms is low. There is an opportunity to utilize SM to engage the cancer community in NNE. Enhancing SM visibility by streaming FB Live, promoting “Like us on FB”, and forming FB interest groups may improve engagement. By understanding the voice of the customer, cancer centers can tailor their SM content.
The CDK4/6 inhibitor G1T28 to protect immune cells and fibroblasts from chemotherapy and radiation-induced toxicity in vitro and to maintain efficacy of chemotherapy in SCLC Rb-deficient cells.
Authors: Irene Guijarro, Warren Denning, Renata Ferrarotto, Alissa Poteete, Uma Giri, John E. Bisi, Jessica A. Sorrentino, Patrick J. Roberts, Jay Copeland Strum, Rajesh K. Malik, Emily Roarty, John Heymach
Journal: Journal of Clinical Oncology (2016)

e20099 Background: Small cell lung cancer (SCLC) is an aggressive form of lung cancer characterized by loss of the tumor suppressor Rb. Chemotherapy and radiation remain the standard of care for SCLC patients but produces severe myelosuppression. Cyclin dependent kinases 4 and 6 (CDK4/6) phosphorylate the Rb protein promoting proliferation by allowing cells to progress through S phase. We hypothesize that CDK4/6 inhibition produces a G1 cell cycle arrest of Rb wild type immune cells and fibroblasts resulting in resistance to chemotherapy/radiation damage without diminishing the therapeutic effect in SCLC Rb-deficient tumors Methods: In vitro sensitivity to G1T28 was measured in Rb deficient SCLC cell lines, chimeric antigen receptor-T (CAR-T) cells, PBMCs and Rb/p53 mutant mouse SCLC cells alone and exposure to 5-Fluorouracil (5FU), topotecan, etoposide, cisplatin, temozolomide or PARP inhibitor. H2AX and caspase 3/7 were measured in radiated HS68 human fibroblasts treated with G1T28 Results: CDK4/6 inhibition by G1T28 does not affect viability of Rb deficient SCLC cells (H128 H524 H526 H69 and H209) and does not antagonize the cytotoxic effect when combined with 5FU, topotecan, etoposide, cisplatin, temozolomide or PARPi. Moreover in some cases it enhances cell killing of temozolomide, etoposide, cisplatin or PARPi. Rb/p53 mutant mouse SCLC cells are very sensitive to 5FU, topotecan, etoposide and cisplatin and the addition of G1T28 do not affect the cytotoxic effect. G1T28 reduces cytotoxicity of human PBMCs and CAR-T cells induced by cisplatin and etoposide by 9, 11% and 24, 21% respectively. G1T28 decreases H2AX and caspase 3/7 activities of radiated HS68 cells in vitro Conclusions: G1T28-mediated CDK4/6 inhibition protects human PBMCs, CAR-T cells and fibroblasts from cytotoxic chemotherapy and radiation while not antagonizing the intended antitumor efficacy in Rb-deficient SCLC cells. CDK4/6 inhibition may enhance immunotherapy efficacy by preserving immune cells from chemotherapy/radiation in Rb-deficient SCLC. Clinical trials testing G1T28 combination regimens in SCLC are currently in progress
P04.28 Effect of fibroblast activation protein-expressing stromal cells from human glioblastomas on glioma and endothelial cells
Authors: P Busek, E Balaziova, R Mateu, P Vymola, K Vlasicova, A Sedo
Journal: Neuro-Oncology (2018)

Fibroblast activation protein (FAP) is a protease selectively expressed in a number of extracranial cancers especially in cancer associated fibroblasts (CAF). CAF play an important role in the pathogenesis of malignant tumors through extracellular matrix remodeling, secretion of growth factors and cytokines, and promotion of angiogenesis and intratumoral immunosuppression. Glioblastomas (GBMs) have a unique composition of the tumor microenvironment and whether CAF are present in these tumors remains controversial. We have recently shown that FAP is upregulated in a subgroup of GBMs and is expressed in both cancer and stromal cells. The role of FAP+ stromal cells in GBM is however unknown. FAP positive stromal cells were isolated using magnetic activated cell sorting (MACS), and cultured in pericyte media. Expression of FAP and other phenotypic markers was assessed by immunocytochemistry. Conditioned media were prepared and used as a chemoattractant in a transwell migration assay. Cell growth was analyzed using the XTT assay, angiogenesis was evaluated using a 3D angiogenesis assay in type I collagen gel. A cytokine array was used to analyze soluble mediators released by FAP+ stromal cells. FAP+ stromal cells were isolated from several human GBMs and characteristically expressed mesenchymal (TE-7, PDGFR, SMA), but not endothelial (vWF) or glial (GFAP) markers. Conditioned media from these FAP+ cells enhanced the migration of glioma and endothelial cells and enhanced endothelial sprouting in a 3D angiogenesis assay. Part of the conditioned media had a mild growth promoting effect on endothelial and glioma cells. Using cytokine arrays, we identified several chemokines, growth factors and angiogenic factors produced by these FAP+ stromal cells. Our data demonstrate that FAP+ mesenchymal cells analogous to cancer associated fibroblasts participate on multidirectional interactions among cell subpopulations in human glioblastomas mediated, at least in part, by soluble factors. These FAP+ stromal cells may contribute to the invasive growth and neoangiogenesis in glioblastoma. Ministry of Health of CR grant 15-31379A, Progres Q28/1LFUK and grant LM2015064 of the EATRIS-CZ.
βIV-Spectrin regulates STAT3 targeting to tune cardiac response to pressure overload
Authors: Sathya D. Unudurthi, Drew Nassal, Amara Greer-Short, Nehal Patel, Taylor Howard, Xianyao Xu, Birce Onal, Tony Satroplus, Deborah Hong, Cemantha Lane, Alyssa Dalic, Sara N. Koenig, Adam C. Lehnig, Lisa A. Baer, Hassan Musa, Kristin I. Stanford, Sakima Smith, Peter J. Mohler, Thomas J. Hund
Journal: Journal of Clinical Investigation (2018)

Heart failure (HF) remains a major source of morbidity and mortality in the US. The multifunctional Ca2+/calmodulin-dependent kinase II (CaMKII) has emerged as a critical regulator of cardiac hypertrophy and failure, although the mechanisms remain unclear. Previous studies have established that the cytoskeletal protein βIV-spectrin coordinates local CaMKII signaling. Here, we sought to determine the role of a spectrin-CaMKII complex in maladaptive remodeling in HF. Chronic pressure overload (6 weeks of transaortic constriction [TAC]) induced a decrease in cardiac function in WT mice but not in animals expressing truncated βIV-spectrin lacking spectrin-CaMKII interaction (qv3J mice). Underlying the observed differences in function was an unexpected differential regulation of STAT3-related genes in qv3J TAC hearts. In vitro experiments demonstrated that βIV-spectrin serves as a target for CaMKII phosphorylation, which regulates its stability. Cardiac-specific βIV-spectrin–KO (βIV-cKO) mice showed STAT3 dysregulation, fibrosis, and decreased cardiac function at baseline, similar to what was observed with TAC in WT mice. STAT3 inhibition restored normal cardiac structure and function in βIV-cKO and WT TAC hearts. Our studies identify a spectrin-based complex essential for regulation of the cardiac response to chronic pressure overload. We anticipate that strategies targeting the new spectrin-based “statosome” will be effective at suppressing maladaptive remodeling in response to chronic stress.