tbuckley/cabot-search huggingface dataset:
BRCA1 tumor expression and clinical outcome in Uruguayan breast cancer patients diagnosed before the age of 40 years.
Authors: Silvina Malvasio, Natalia Camejo, Cecilia Castillo, Nora Artagaveytia, Carina Di Matteo, Benedicta Caserta, Roberto Notejane, Maria Isabel Alonso, Andrea Schiavone, Lucia Beatriz Delgado
Journal: Journal of Clinical Oncology (2019)

e12028 Background: BRCA1 is one of the main susceptibility genes for breast cancer (BC). While BRCA1 mutations are rare in sporadic tumors, loss or reduction of gene expression have been reported in approximately 30-50% of sporadic BCs in the general population. From the molecular point of view, there is no clear characterization of these tumors in young women and we have found no studies reporting the rate of under-expression of BRCA1 in women with sporadic BC under 40 years of age. Objective: to assess the tumor expression of BRCA1 using immunohistochemistry (IHC) and its prognostic value in Uruguayan women diagnosed with BC before the age of 40 years. Methods: IHQ was used to analyze the tumor expression of BRCA1 in paraffin-embedded tumor samples of 40 BC patients diagnosed before the age of 40 between 01/01/2006 and 12/31/2012. The optimization and determination of the BRCA1 protein by IHC was centralized. The antibodies used were anti BRCA1 MS110 monoclonal antibodies against the N-terminal end and GLK-2 against the C-terminal end (amino acids 1839-1863). Expression was considered positive when &gt;10% of the cells had nuclear and/or cytoplasmic labeling. Overall survival (OS) and disease free survival (DFS) were calculated; the curves were developed using the Kaplan-Meier method and the difference in survival was evaluated through the log rank test. Results: the average age of the 40 patients included was 36 years; 8 patients (20%) had significant family history of BC or ovarian cancer. The distribution by stage (S) was as follows: SI: 9 patients (22.5%); SII: 20 patients (50%); SIII: 10 patients (25%), and SIV: 1 patient. Regarding the biological profile: 17 patients (42.5%) were HER2- and ER/PR+, 13 (32.5%) were HER2+ and the remaining 10 patients (25%) were classified as triple negative. The 5-year OS and DFS were 73% and 60% respectively. The expression of BRCA1 with GLK-2 was ≤10% in 16 of the 40 patients included (40%). The 5-year OS and DFS for patients with ≤10% expression was 56% vs. 85% for patients with &gt;10% (p = 0.015) and 40% vs. 72% (p = 0.034) respectively. The expression of BRCA1 by MS110 was ≤10% in 11 of the 40 patients included (27.5%). No statistically significant differences were found in the 5-year OS or DFS based on the expression of this marker. Conclusions: Decreased BRCA1 tumor expression as assessed by IHC using GLK-2 was found in 40% of young patients included and was associated with unfavorable prognosis.
Access to diagnostics and treatment of neuroendocrine tumors (NETs): The difference between patient perception and reality.
Authors: Simone Leyden, Teodora Kolarova, Catherine Bouvier, Martyn E. Caplin, Siobhan Conroy, Philippa Davies, Sugandha Dureja, Massimo Falconi, Piero Ferolla, George A. Fisher, Grace Goldstein, Rodney J. Hicks, Benjamin James Lawrence, Yoshiyuki Majima, David C. Metz, Dermot O'Toole, Philippe B. Ruszniewski, Bertram Wiedenmann, Ron Hollander
Journal: Journal of Clinical Oncology (2019)

e13524 Background: The aim of this global patient survey was to better understand the needs and expectations of patients with NETs regarding access to diagnostic tools and treatment. Methods: In 2017, an online, questionnaire survey of NET patients/family members, patient advocates and healthcare professionals (HCPs) was conducted. Results: In total, 443 participants from 26 countries responded: 338 patients/families; 35 advocates; 70 HCPs. Following NET diagnosis, many patients use patient association (69%) and HCP (48%) websites to fulfill their informational needs. Patients overestimated the availability of key diagnostic tools and treatments compared to HCPs: Gallium-68-Dotatate PET/CT scan was believed available by 28% of patients vs. 14% of HCPs; fluorodeoxyglucose PET by 77% of patients vs. 64% of HCPs; peptide receptor radionuclide therapy by 58% of patients vs. 23% of HCPs; genetic test/precision medicine by 75% of patients vs. 71% of HCPs; and transplantation by 86% of patients vs. 55% of HCPs. Reasons reported by patients and advocates for unavailability of treatment were: not provided by healthcare system (28% &amp; 67%, respectively); non-referral (19% &amp; 33%, respectively), unable to afford treatment (18% &amp; 57%, respectively); treatment not covered by insurance (17% &amp; 24%, respectively); distance to treatment centre (15% &amp; 48%, respectively). Almost a third (30%) of patients had to travel more than 300 km/186 miles for treatment or consultation with a NET specialist, while 34% of patients did not have access to an MDT and those that did may be in contact with them less than once per year (14%). In contrast, advocates and HCPs believe there is wider availability of MDTs (94% and 70%, respectively). Conclusions: Patients are increasingly well-educated about NETs and often travel considerable distances to obtain specialist treatment. However, there remains considerable disparity in what patients feel is available to them in terms of the latest tools and treatments, compared to what is there in reality. This significant difference in perception needs to be managed delicately by both advocates and healthcare professionals.
Decreased risk of esophageal squamous cell carcinoma among metformin users in a population-based cohort study.
Authors: Qiao-Li Wang
Journal: Journal of Clinical Oncology (2019)

e15507 Background: Metformin, mainly used in the treatment of diabetes, may prevent various types of cancer, but no study has specifically examined its potential influence on the risk of esophageal squamous cell carcinoma, the major histological type of esophageal cancer. The aim of this study was to determine the association between metformin use and esophageal squamous cell carcinoma. Methods: This was a nationwide population-based prospective cohort study conducted in Sweden in 2005-2015. Among 8.4 million participants identified from the Swedish Prescribed Drug Registry, 411,603 (5%) were users of metformin. The metformin users were compared with 10 times as many frequency-matched non-users of metformin (n = 4,116,030) by age and sex. Multivariable cause-specific proportional hazards model was used to calculate hazard ratios (HR) with 95% confidence intervals (CI), adjusted for age, sex, calendar year, place of residence, tobacco smoking, alcohol overconsumption, and use of non-steroidal anti-inflammatory drugs or statins. Results: The incidence rates of esophageal squamous cell carcinoma were 3.5 per 100,000 person-years among the metformin users and 5.3 per 100,000 person-years in the non-users. Metformin users overall were at a decreased risk of esophageal squamous cell carcinoma compared with non-users (adjusted HR 0.68, 95% CI 0.54-0.85). The decrease in risk was more pronounced in new metformin users who were 56 years old when they started their metformin therapy (HR 0.44, 95% CI 0.30-0.65). Conclusions: Metformin therapy may decrease the risk of developing esophageal squamous cell carcinoma.
A population-based study of medical cannabis utilization in patients with cancer in the pre-legalization era.
Authors: Safiya Karim, Jingyu Bu, Ed Jess, Winson Y. Cheung, Marc Kerba
Journal: Journal of Clinical Oncology (2019)

e18297 Background: Between April 1, 2014 and October 17, 2018, access to cannabis for medical purposes was regulated by Health Canada. Surveys have demonstrated that cancer patients use cannabis to manage symptoms and side effects. However, medical cannabis utilization patterns in cancer patients under Health Canada’s regulatory framework have not been well-described. We aimed to determine the proportion of cancer patients who used medical cannabis, timing of use in relation to cancer treatment and sociodemographic factors predicting use in a large Canadian province. Methods: The Alberta Cancer Registry was used to identify all patients age ≥ 18 diagnosed with invasive cancer in the province from April 01, 2014 to December 31, 2016. These cases were linked to records from the College of Physicians and Surgeons of Alberta database which collects data on patients who received authorization to access medical cannabis as well as on physicians that provided the authorization. Authorization was used as a surrogate for medical cannabis utilization. Univariate and multivariate logistic regression models were constructed to determine factors associated with medical cannabis utilization. Results: We identified 41,889 patients between April 1, 2014 and December 31, 2016. Median age at cancer diagnosis was 65 and 50% were female. Among these patients, 1,070 (2.5%) used medical cannabis. Of these patients, 541 (51%) used medical cannabis within 1 year of diagnosis, 248 (52%) within one year of the start of systemic therapy and 128 (41%) within one year of the start of radiation therapy. On multivariate analysis, patients aged 18-29 (OR 12.4, 95% CI 7.8-19.7) and those receiving systemic therapy (OR 2.0, 95% CI 1.7-2.4) were more likely to use medical cannabis (p &lt; 0.001). There were 171 unique physicians who authorized medical cannabis of which only 3.5% (6/171) were oncologists. Conclusions: A small proportion of cancer patients used medical cannabis under Health Canada’s regulatory framework. Utilization was associated with a cancer diagnosis and receiving treatment. Younger patients and those undergoing systemic treatment were predictors of medical cannabis use. Further study is required to understand utilization patterns after cannabis legalization and how to incorporate these findings into patient-centered cancer care.
Protein Delivery into the Cell Cytosol using Non-Viral Nanocarriers
Authors: Yi-Wei Lee, David C. Luther, Jessica A. Kretzmann, Andrew Burden, Taewon Jeon, Shumei Zhai, Vincent M. Rotello
Journal: Theranostics (2019)

Protein delivery into cells is a potentially transformative tool for treating "undruggable" targets in diseases associated with protein deficiencies or mutations.The vast majority of these targets are accessed via the cytosol, a challenging prospect for proteins with therapeutic and diagnostic relevance.In this review we will present promising non-viral approaches for intracellular and ultimately cytosolic delivery of proteins using nanocarriers.We will also discuss the mechanistic properties that govern the efficacy of nanocarrier-mediated protein delivery, applications of nanomaterials, and key challenges and opportunities in the use of nanocarriers for intracellular protein delivery.
Angiotensin converting enzyme inhibitors use and development of lung cancer: A systematic review and meta-analysis.
Authors: Waled Bahaj, Anas Albawaliz, Aref Qureini, Omar Khaled Mahmoud Abughanimeh, Moustafa Younis, Mohammad Tahboub, Anas Noman, Aref A Bin Abdulhak
Journal: Journal of Clinical Oncology (2019)

e13093 Background: Angiotensin-converting enzyme inhibitors (ACEIs) are commonly prescribed medications for hypertension and heart failure. Generally, ACEIs are well-tolerated medications with reasonable safety profile making them a favorable choice by many clinicians. However, several studies with conflicting results have signaled an association between ACEIs use and the development of lung cancer. We sought to systematically review the literature and perform the first meta-analysis to study the risk of lung cancer among ACEI users. Methods: We performed a literature review by searching multiple databases. A random effect meta-analysis approach was used to pool the data and relative risk was used to calculate the overall effect estimate. Results: A total of 423 articles were identified but only 6 observational studies were included with a total of 872,220 patients (634,672. ACEIs users). The relative risk of lung cancer development among ACEIs users was 1.02 (CI 0.89-1.16) compared to non-ACEIs users. Conclusions: Current systematic review and meta-analysis show no significant association between ACEIs use and the development of lung cancer. The result of our meta-analysis provides further assurance to the health care providers regarding ACEIs use.
Discovery of a novel natural killer cell line with distinct immunostimulatory and proliferative potential as an alternative platform for cancer immunotherapy
Authors: Hyun Gul Yang, Moon Cheol Kang, Tae Yoon Kim, Injung Hwang, Hyun Tak Jin, Young Chul Sung, Ki-Seong Eom, Sae Won Kim
Journal: Journal for ImmunoTherapy of Cancer (2019)

Human natural killer (NK) cell lines serve as an attractive source for adoptive immunotherapy, but NK-92 remains the only cell line being assessed in the clinic. Here, we established a novel NK cell line, NK101, from a patient with extra-nodal natural killer/T-cell lymphoma and examined its phenotypic, genomic and functional characteristics. Single cell suspensions from lymphoma tissue were expanded with anti-NKp46/anti-CD2-coated beads in the presence of IL-2. A continuously growing CD56+ cell clone was selected and designated as NK101. Flow cytometry and RNA sequencing were used to characterize phenotypic and genomic features of NK101. In vitro cytotoxicity and IFN-γ/TNF-α secretion were measured by flow cytometry-based cytotoxicity assay and enzyme-linked immunosorbent assay, respectively, after direct co-culture with tumor cells. Immunomodulatory potential of NK101 was assessed in an indirect co-culture system using conditioned medium. Finally, in vivo antitumor efficacy was evaluated in an immunocompetent, syngeneic 4T1 mammary tumor model. NK101 displayed features of CD56dimCD62L+ intermediate stage NK subset with the potential to simultaneously act as a cytokine producer and a cytotoxic effector. Comparative analysis of NK101 and NK-92 revealed that NK101 expressed lower levels of perforin and granzyme B that correlated with weaker cytotoxicity, but produced higher levels of pro-inflammatory cytokines including IFN-γ and TNF-α. Contrarily, NK-92 produced greater amounts of anti-inflammatory cytokines, IL-1 receptor antagonist and IL-10. Genome-wide analysis revealed that genes associated with positive regulation of leukocyte proliferation were overexpressed in NK101, while those with opposite function were highly enriched in NK-92. The consequence of such expressional and functional discrepancies was well-represented in (i) indirect co-culture system where conditioned medium derived from NK101 induced greater proliferation of human peripheral blood mononuclear cells and (ii) immunocompetent 4T1 tumor model where peritumoral injections of NK101 displayed stronger anti-tumor activities by inducing higher tumor-specific immune responses. In a manufacturing context, NK101 not only required shorter recovery time after thawing, but also exhibited faster growth profile than NK-92, yielding more than 200-fold higher cell numbers after 20-day culture. NK101 is a unique NK cell line bearing strong immunostimulatory potential and substantial scalability, providing an attractive source for adoptive cancer immunotherapy.
Pamiparib, an investigational PARP inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) and a circulating tumor cell (CTC) homologous recombination deficiency (HRD) phenotype or <i>BRCA</i> defects: A trial in progress.
Authors: Simon Chowdhury, Joaquin Mateo, Mitchell Gross, Andrew J. Armstrong, Marcia Cruz-Correa, Josep M. Piulats, Jean-Yves Blay, Miao Li, Delcia Rivas, Luis Quintero, Henry Castro, Andong Nkobena, Mitch Raponi, Robert Pelham, Mark Landers, Robert B. Montgomery
Journal: Journal of Clinical Oncology (2019)

TPS5086 Background: Men with mCRPC who have a BRCA1/2 mutation ( BRCA1/2 mut ) or mutations in other genes resulting in HRD have a poor prognosis. A novel liquid biopsy test (EPIC Sciences) identifies CTCs with an HRD phenotype. Preliminary studies showed that these men may respond to treatment with a PARP inhibitor. Pamiparib, an investigational PARP1/2 inhibitor, has shown brain penetration and potent PARP–DNA complex trapping in nonclinical studies. In early phase clinical studies (NCT02361723; NCT03333915), pamiparib was generally well tolerated and showed preliminary antitumor activity; 60 mg orally twice daily (BID) was established as the recommended investigational dose. Methods: This open-label, global, phase 2 study (NCT03712930) evaluates the antitumor activity and safety/tolerability of pamiparib in mCRPC patients (pts) with CTC-HRD, assessed by the CTC-HRD assay, or deleterious germline/somatic mutations in BRCA1/2. Patients must have progressed on/after ≥1 androgen receptor-targeted therapy, received ≥1 taxane-based therapy, and have prostate-specific antigen (PSA) progression per PCWG3 criteria. Four cohorts of pts will receive pamiparib 60 mg BID in 28-day cycles. Cohort 1 will include ~50 pts with CTC-HRD + +/- BRCA1/2 mut mCRPC with measurable metastatic disease; Cohort 2 will include ~30 pts with CTC-HRD + +/- BRCA1/2 mut mCRPC with bone-only disease; Cohorts 3 &amp; 4 will include ~20 pts with CTC-HRD -/unk + BRCA1/2 mut mCRPC with measurable metastatic disease (Cohort 3), or bone-only disease (Cohort 4). Disease status will be assessed every 8 wks for 24 wks, then every 12 wks; PSA levels will be tested every 4 wks. Co-primary endpoints are radiographic ORR assessed by IRC (pts with measurable disease) and confirmed PSA response rate per PCWG3 criteria (pts +/- measurable disease). Secondary endpoints include ORR, time to PSA response/progression, duration of PSA response, time to symptomatic skeletal event, radiographic progression-free survival, overall survival, and safety. As of 05 December 2018, this study is actively enrolling. Clinical trial information: NCT03712930.
Measuring on-treatment genome-wide tumor copy number alterations in cell-free DNA (cfDNA) in plasma is highly prognostic in metastatic breast cancer.
Authors: Adriana Aguilar, Josiane Lafleur, Susie Brousse, Cristiano Ferrario, Graham McLennan, Taylor J. Jensen, Kelly Kimberly, Mark Basik
Journal: Journal of Clinical Oncology (2019)

1097 Background: The clinical management of metastatic breast cancer depends on the measurement of tumor response to successive drugs by serial imaging and changes in blood tumor markers, which remain the standard of care despite poor sensitivity and specificity. Highly sensitive and specific cfDNA secreted from the tumor can detect the changes in tumor-specific aberrations that have been shown to be associated with patient response in the metastatic setting. However, most approaches require prior sequencing of the tumor to target specific known mutations. Methods: Using low coverage genomic sequencing, a genomic instability number (GIN) was measured in cfDNA based on the detection of genome-wide tumor-specific DNA copy number alterations for 27 patients with metastatic breast cancer. The GIN value and its variation from baseline before treatment, as well as within 10 days and 3 weeks after start of therapy were compared with tumor response, progression free survival (PFS) and overall survival (OS) of the patients. Patients were followed for a median of 22 months and we used a previously published GIN threshold at 170 for high vs low GIN values. Sequencing was performed blinded to the clinical results. Results: Baseline GIN values were not associated with tumor response at 3or 6 months, but showed a trend towards lower OS with higher GIN (p = 0.12). GIN values fell by an average of 28% in responders (stable disease or response) and 23% in those with progression (p = 0.85), but remained lower at 3 weeks only in the responders. High GIN values within 10 days and 3 weeks were associated with markedly worse OS (p = 0.014 and p = 0.009 respectively) and those at 3 weeks with worse PFS (p = 0.017). Hence the median survival of patients with high GIN at 10 days or 3 weeks was 12 months vs not reached for those with low GIN. The percentage drop of GIN at 10 days but not at 3 weeks was significantly associated with PFS (p = 0.016). Conclusions: These results demonstrate that GIN values of cfDNA measured at early on-treatment time points can predict PFS and OS with a high degree of accuracy. These findings deserve further study in a larger cohort but hold the promise of early prediction of clinical outcomes in a tumor-independent genome-wide approach.
Navigating care to reduce emergency room (ER) visits in cancer patients using opioids.
Authors: Carlos Frederico Pinto, Fernanda Navarro Loiola, Stela Maris Coelho, Michele Felix, Laura Gomes, Henrique Zanoni Fernandes
Journal: Journal of Clinical Oncology (2019)

e18265 Background: Pain is the most frequent and one of the most important cancer related symptom with significant impact in quality of life. It is also the most frequent reason (27% of visits) for a patient to go to an ER and 53% can be prevented with adequate care (Panattoni, JCO 35, 2017 suppl; abstr 6505). Methods: In 2015 IOV developed a patient centered Navigation System based on Kanban (board and visual signals - KNS) for managing treatment plan of our patients that was very successful. In 2016 with support of an educational grant from QTP-ASCO we extended this system to manage pain and other cancer or treatment related symptoms. This study addresses only pain management and ER visits between dec16 and dec18 for a total of 187 patients using opioids. We measured the proportional reduction of ER visits related to pain to the total ER visits in three successive periods: development of the NKS (dec15-jul16), pilot phase (aug16-oct17) and as an adopted best practice (oct17-dec18). The pain KNS comprises a set of standardized procedures and successive checks for patients using opioids based on three procedures: (a) standardized prescription and use of analgesics using WHO’s Pain Ladder; (b) standardized follow up in 24 and 48 hours, 1, 2 and 4 weeks; and (c) manage side effects of opioids or other emerging problem (constipation, confusion, etc). Any patient initiating opioid use is included in the KNS until opioid is discontinued. Once pain is adequately controlled, the frequency of checks become wider up to once a month if no toxicity is identified. Any new condition will restart the 24-48 hours loop. The KNS is managed by oncology nurses using phone or video calls, messaging, and appointments; Mon-Sat from 6AM to 10PM. Results: The KNS managed a median of 132 patients per month during 29 months (aug16 to dec18). Pain represented 20% of ER visits (33.65 UCL and 6.7 LCL); in pilot phase 15% of ER visits (27.34 UCL and 3.70 LCL); and now 4% of ER visits ( 8.46 UCL and 0 LCL), an 80% reduction in pain related ER visits. ER visits represents patients with uncontrolled pain and not effectively managed by the KNS. Conclusions: The development of a simple visual system to manage cancer patients with pain resulted in 80% reduction of ER visits and adequate pain control in our practice.