tbuckley/cabot-search huggingface dataset:
Preimplantation genetic diagnosis: What do BRCA mutation carriers think?
Authors: Olivia R Khouri, Deanna Gerber, Julia Anne Smith, Leslie R. Boyd
Journal: Journal of Clinical Oncology (2019)

1526 Background: The use of pre-implantation genetic diagnosis (PGD) to select against BRCA mutated embryos for in-vitro fertilization (IVF), introduces complex choices for patients with pathogenic BRCA mutations. We sought to describe the uptake of and attitudes toward this technology in this patient population. Methods: We conducted a prospective survey study at a single institution in New York City affiliated with both a Cancer Center and Fertility Center, to assess attitudes and utilization of PGD. Cancer Center staff distributed surveys to patients with known BRCA mutations between April and August 2018. Survey participation was voluntary and anonymous. Survey data were analyzed using descriptive statistics and two-tailed t tests. Results: 80 survey responses were collected. A majority of the patient population identified as Caucasian (87.5%, 70) and Jewish (52.5%, 42). The survey was distributed to all age groups; however 81% (65) were between 26 and 45 years of age. 63.8% (51) had heard of PGD prior to completing the survey, while 36.3% (29) had not. Only 40% of respondents (32) felt sufficiently educated regarding PGD. 35% (28) patients met with an REI, of whom 6.3% (5) utilized IVF with PGD, and 21.3% (17) plan to use IVF with PGD in the future. 11.3% (9) wish they had known about this technology prior to starting a family, 20% (16) would not have used PGD had they known about it prior to childbearing. Reasons respondents were unlikely to pursue PGD included: cost (38.8%, 31), completed childbearing (25%, 20), medical risk (18.8%, 15), and ethical concerns (16.2%, 13). Patients gave cost estimates for PGD ranging from $500 - $120,000. There was no statistically significant correlation between likelihood of pursuing PGD and parity (p = 0.45), religion (p = 0.78), education level (p = 0.13), number of family members affected by BRCA mutations (p = 0.20) or by cancer (p = 0.11). Conclusions: Overall, a small number of patients with pathogenic BRCA mutations utilize PGD. A minority of survey respondents felt adequately educated about PGD. Reported barriers to uptake were varied, and there was a wide range of cost estimates reported. Our results suggest that increased patient education regarding PGD in BRCA mutation carriers is warranted.
A phase 0 first-in-human study using NU-0129: A gold base spherical nucleic acid (SNA) nanoconjugate targeting BCL2L12 in recurrent glioblastoma patients.
Authors: Priya Kumthekar, Alfred Rademaker, Caroline Ko, Karan Dixit, Margaret A. Schwartz, Adam M. Sonabend, Laura Sharp, Rimas Vincas Lukas, Roger Stupp, Craig Horbinski, Kathleen McCortney, Alexander H. Stegh
Journal: Journal of Clinical Oncology (2019)

3012 Background: Glioblastoma is a difficult to treat tumor with therapeutics limited by their ability to cross the blood brain barrier. SNAs, i.e., gold nanoparticle cores covalently conjugated with a corona of densely packed, highly oriented siRNA oligonucleotides targeted to the GBM oncogene BCL2L12, represent a novel class of blood-brain and blood-tumor barrier-permeable nanomedicinal conjugates, for suppressing gene expression in the tumors of GBM patients. Methods: This is a single-arm, open-label, “window of opportunity” phase 0 first-in-human trial to determine the safety and bioavailability of a novel nanotherapeutic compound, NU-0129. Enrolled patients were treated with intravenous NU-0129 at the dose of 0.04mg/kg. This treatment dosing was considered microdosing defined as 1/50 th the NOAEL (no observed adverse event level) from non-human primate studies. Treatment was followed by tumor resection 8-48 hours later. Primary outcome patient safety and toxicity was monitored weekly for 3 weeks post-infusion. Secondary objectives included biodistribution of NU0129 in tissue, evaluation of pharmacokinetics of NU0129 and the feasibility of NU0129 administration. Exploratory objectives included Bcl2L12 expression and post treatment apoptotic markers as well as progression free survival and overall survival rates. Results: 8 patients were enrolled, treated and subsequently underwent surgical resection. No significant treatment related toxicities were seen. Severe ( &gt; grade 3) adverse events were observed in two patients: hypophosphatemia (one grade 3, one grade 4) and one patient with grade 3 lymphopenia, all were considered as “possibly related” by treating oncologists. In 6 of the 8 patients sufficient tumor tissue was available for analysis of gold accumulation by ICP-MS (inductively coupled plasma-mass spectrometry), and gold accumulation was seen in the tumor tissue of all 6 of these patients. Conclusions: Macrodosing of the nanotherapeutic NU-0129 was well tolerated in glioblastoma patients with no unexpected adverse effects and showed initial evidence of crossing blood brain barrier. Immunohistochemistry for Bcl2L12 expression, apoptotic markers, and PK studies are pending. The demonstration of gold nanoparticles in the tumor tissue validates this approach for drug delivery. Clinical trial information: NCT03020017.
The use of optimal evidence-based chemotherapy (chemo) regimens in physician offices versus hospital outpatient facilities.
Authors: Michael Jordan Fisch, Ying Liu, ANN NGUYEN, John Barron, Ezra Fishman, Gosia Sylwestrzak
Journal: Journal of Clinical Oncology (2019)

6514 Background: The proportion of infused chemo administered in hospital outpatient facilities (HOF) increased from 6% in 2004 to 43% in 2014. The average annual cost for patients receiving chemo was significantly higher in HOFs than in physician offices (POs). One option to explore differences in the quality of care between these two settings is to examine the use of chemo regimens, which, based on their efficacy, toxicity, and costs, have been designated as “on-pathway.” This study compared on-pathway rates among patients receiving infused chemo administered in POs vs. those in HOFs. Methods: Using administrative claims data, we identified 61,496 breast, lung, or colorectal cancer patients receiving chemo from 2013 to 2018. Chemo regimens were considered “on-pathway” when they were on payer's program list of optimal regimens when administered. Generalized linear models examined the association between site of service and on-pathway prescribing rates, and costs of care. Models adjusted for age, sex, year, rural status, cancer type and setting, and comorbidities, with fixed effects for providers. Results: Percentage of infused chemo administered in HOFs increased from 44.2% in 2013 to 54.7% in 2018. After adjustment, on-pathway prescribing rate did not differ significantly between HOFs and POs (50.1%, 95% CI: 48.6%-51.5% vs. 49.8%, 95%CI: 48.3%-51.3%, p = 0.65). 6-month chemo cost ($56,885, 95% CI: $54,364-$59,524 vs $32,240, 95% CI: $30,929-$33,605, p &lt; 0.001) and 6-month medical cost ($114,280, 95% CI: $110,716-$117,960 vs $79,455, 95% CI: $77,089-$81,893, p &lt; 0.001) were significantly higher in HOFs vs. POs. Conclusions: Quality of care as measured by use of optimal chemo regimens was similar in hospital and office setting. Cost continues to be significantly higher in hospital setting. These findings provide a strong basis for site-neutral reimbursement policies.
Factors associated with physician attitude and management of financial toxicity.
Authors: Katrina Fischer, Anne Margaret Walling, John A. Glaspy
Journal: Journal of Clinical Oncology (2019)

e18300 Background: Little is known about the attitudes and knowledge of oncologists who discuss financial toxicity with patients compared with those who do not. We assessed perceptions of the oncologists’ role in discussing out of pocket (OOP) costs and financial stress (FS) to inform quality improvement strategies in the management of financial toxicity. Methods: We surveyed 45 practicing medical oncologists at a large academic medical center in 2019 using Likert scale responses. Questions covered three domains; self-perceived knowledge of financial issues related to care, practice of cost discussions with patients, and perceived ability to navigate toward solutions related to FS. Results: Fifty-three percent of oncologists felt comfortable discussing OOP costs, but only 42.5% discussed FS with patients. Over half (55%) lacked confidence they could help patients experiencing FS from treatment. These providers were less likely to ask about FS than those who were confident (r0.416, p0.004). Perceived knowledge among many was low: 48% felt they had little to no knowledge of OOP treatment costs, 33-37% had little to no understanding of how private or public insurance covers treatment respectively, and 60% reported low knowledge of point of care (POC) resources. Those who ask patients about FS reported higher perceived knowledge of insurance (public r0.47, p &lt; 0.001, private r0.452, p 0.002) and POC resources (r0.392, p 0.007), but not more knowledge of OOP cost. Three factors were associated with increased confidence in the ability to help patients; higher knowledge of POC resources (r 0.379, p 0.01); having changed a treatment because of cost within the past year (r 0.395, p 0.047), and years in practice (r 0.329, p 0.047). Conclusions: Many oncologists lack confidence that they can help patients with financial issues, particularly early on in their career. Providers who lack confidence that they can help their patients appear less likely to ask patients about financial stress. Those who do ask about financial stress report higher self-perceived knowledge of insurance coverage and POC resources. This suggests that quality improvement efforts aimed at improving education and resources for providers to help navigate financial toxicity are needed.
Liver resection in elderly patients over the age of 70 with primary liver cancer: A retrospective analysis.
Authors: Elinor Tan, Charbel Sandroussi
Journal: Journal of Clinical Oncology (2019)

e15647 Background: Liver surgery in the elderly remains controversial amidst growing incidence in developed countries. This study compares perioperative outcomes of elderly with non-elderly patients undergoing curative hepatectomy for primary liver malignancies. Methods: 310 patients underwent liver resection for primary tumours between 2000 and 2018. There were 71 elderly (≥70 years) and 239 non-elderly patients ( &lt; 70 years). Survival analyses, stratified according to pathology (Hepatocellular carcinoma (HCC), n = 262 and Cholangiocarcinoma (CC) n = 48), were compared between the elderly and non-elderly group. Multiple regression analyses were performed to evaluate independent predictors of major complications and overall survival. Results: Elderly patients had higher frailty score (modified Frailty Index, mean, 1.14 v 0.51, p &lt; 0.001), more comorbidities (Comorbidities ≥4: 28% v 14%, p = 0.005), had non viral-induced primary liver cancers (Non-Hep B Non-Hep C: 65% v 19%, p &lt; 0.001) with lower AST (p = 0.014) and ALT (p = 0.004) levels. 46% of patients underwent major hepatectomy and were similar between both groups (p = 0.502). The overall complication rate and duration of stay were comparable (p &gt; 0.05). Post-Hepatectomy Liver Failure occurred in 10 (3%) patients with no difference between both groups (p &gt; 0.05). There were 11 (4%) postoperative deaths with higher mortality in the elderly group (8% v 2%, p = 0.011). Multiple logistic regression revealed that MELD ≥11 (OR 2.415, p = 0.480) and a positive surgical margin (OR 2.549, p = 0.024) were independent predictors for major complications. The overall survival (OS) and disease free survival (DFS) for both HCC and CC were similar between elderly and non-elderly group respectively (HCC: 5-yr OS, 62% v 68.5%, p = 0.712; 5-yr DFS, 30.4% v 38.8%, p = 0.323; CC: 5-yr OS, 62.2% v 48.3%, p = 0.919; 5-yr DFS, 43.6% v 28.2%, p = 0.618). Multiple Cox regression revealed that albumin &lt; 40g/L (HR 2.533, p = 0.002) and the presence of vascular invasion (HR 2.417, p = 0.004) were independent predictors of poor survival. Conclusions: Long-term survivals were comparable between the elderly and non-elderly patients following surgical treatment for primary liver cancers. Low albumin and vascular invasion predicted poor survival. Age alone should not be a contraindication to liver surgery. Major complications may be minimised by carefully selecting patient and paying particular attention to the MELD score in elderly patients with primary liver disease. Further prospective studies are required to confirm the findings here.
Subsequent neoplasm risk associated with rare variants in DNA repair and clinical radiation sensitivity syndrome genes: A report from the Childhood Cancer Survivor Study.
Authors: Lindsay M. Morton, Danielle M Karyadi, Steven Hartley, Megan Frone, Joshua N Sampson, Rebecca M. Howell, Joseph Philip Neglia, Michael A. Arnold, Casey L Dagnall, Belynda Hicks, Jones Kristine, Bin Zhu, Wendy M. Leisenring, Yutaka Yasui, Smita Bhatia, Leslie L. Robison, Margaret A. Tucker, Gregory T. Armstrong, Stephen J. Chanock
Journal: Journal of Clinical Oncology (2019)

10028 Background: Radiotherapy for childhood cancer is associated with strikingly elevated risk for developing subsequent neoplasms (SNs). Whether mutations in DNA repair and radiation sensitivity genes modulate SN risks is largely unknown. Methods: We conducted whole-exome sequencing in 5105 long-term childhood cancer survivors of European descent (mean follow-up = 32.7 years). SnpEff and ClinVar identified potentially damaging rare variants in 476 DNA repair or radiation sensitivity genes. Conditional logistic regression assessed SN risk associated with these variants aggregated by gene or pathway (N = 155 with ≥5 carriers). Controls were matched on sex, childhood cancer type and diagnosis age, radiation dose to the SN site, and survival. Exact p-values were calculated by permutation. Analyses used all survivors or subsets stratified on radiation dose. Results: A total of 1108 (21.7%) survivors developed at least one SN type known to be related to ionizing radiation exposure (e.g., breast cancer, basal cell carcinoma, meningioma, thyroid cancer, sarcoma). Radiation-related SN risk was associated with homologous recombination (HR) gene variants for SN sites that received &gt; 0- &lt; 10 Gy (20.9% cases, 11.0% controls; odds ratio [OR] = 2.20, 95% confidence interval [CI] 1.52-3.18; P = 1.41x10 -4 ), most notably for FANCM (3.1% cases, 0.5% controls; OR = 9.91, 95%CI 3.73-26.4; P = 2.85x10 -4 ). For radiation-related SNs at sites with higher doses (≥10 Gy), associations were not observed for the HR pathway (14.4% cases, 12.4% controls, P = 0.17) but were observed for two individual genes implicated in double-strand DNA break repair, EXO1 (1.8% cases, 0.4% controls; OR = 6.50, 95%CI 3.49-12.1; P = 7.43x10 -4 ) and NEIL3 (0% cases, 1.0% controls; P = 3.23x10 -4 ). Conclusions: In this discovery study, we identified dose-specific novel associations between SN risk after radiotherapy for childhood cancer and potentially damaging rare variants in genes involved in double-strand DNA break repair, particularly HR. If replicated, these results could impact long-term screening of childhood cancer survivors and risk-benefit assessments of treatment approaches.
Protamine sulfate may prevent infections by pathogens that require heparan sulfate proteoglycan interactions, including high- and low-risk Human Papillomaviruses and <i>Chlamydia trachomatis.</i>.
Authors: Ricardo Gomez, Jesse Young, Michelle Ozbun
Journal: Journal of Clinical Oncology (2019)

e13065 Background: Human papillomaviruses (HPVs) are the most common pathogens of the reproductive tract with 80% of the population acquiring an infection at least once in their lifetime. Globally, high-risk (oncogenic) HPVs cause 630,000 new cancer cases per year and are responsible for 99% of cervical cancers. Regardless of available screening and preventive measures, cervical cancer is the fourth most common malignancy in women worldwide causing more than 445,000 new cases and 270,000 deaths annually. Like many pathogens of the reproductive tract, initiation of HPV infections require attachment to negatively-charged heparan sulfate proteoglycans (HSPG) present in the extracellular matrix and plasma membrane of host cells. To better define the role of HSPGs in HPV infections, we used protamine sulfate (PrS), a polycationic peptide that is FDA approved to neutralize heparin. Structural similarities between HSPGs and heparin allow PrS to bind HSPGs preventing HPV-HSPG interactions and infection. In order to further evaluate proof of concept for PrS we expanded our investigation to Chlamydia trachomatis, another genital tract pathogen whose mechanism of infection has been reported to rely on HSPGs. Methods: High and low risk HPV viruses were used in prophylactic and post exposure cell-based assays and a preclinical prophylactic mouse vaginal challenge model to evaluate the effects of PrS on infection. Chlamydia trachomatis serovar L2 was also used in prophylactic cell-based assays to evaluate the effects of PrS on infection. Results: A single dose prophylactic application of PrS reduced infection by high- and low-risk HPV genotypes by up to 95% in vitro (p-value &lt; 0.001) in a dose response manner and 60% in vivo (p-value 0.05). In addition, post-HPV exposure PrS treatment significantly decreased infection. PrS showed the greatest effectiveness in the first two hours after HPV exposure. In line with our data on HPV, Chlamydia trachomatis infection showed a statistically significant decrease in cells pretreated with PrS (p-value 0.05). Conclusions: Inhibition of attachment by PrS presents a unique opportunity to provide a new cheap prophylactic modality for HPV infection, which would reduce cervical cancer global burden.
Targeting the p300/CBP interactome through blockage of the CH1-domain triggers tumor regression in AR-positive and AR-negative xenograft models of castration-resistant prostate cancer (CRPC).
Authors: Valentino Cattori, Bernd Hentsch, Ulrich Kessler
Journal: Journal of Clinical Oncology (2019)

3105 Background: In advanced prostate cancer, the paralog transcription co-activators p300/CBP are often highly expressed and have been associated with disease progression and poor prognosis. While several inhibitors of the bromo- and histone acetyltransferase domains of p300/CBP have been described, past efforts to develop drug-like ligands of other regions of this attractive target have been unsuccessful. Methods: A rationally designed small molecule modulator of the CH1-domain of p300/CBP was tested in a panel of prostate cancer cell lines, followed by cell cycle analysis and beta-galactosidase staining. Inhibition of the p300-dependent androgen receptor (AR) related transcriptional response was determined in a luciferase reporter assay and by qPCR analysis of expression of downstream genes like prostate-specific antigen (PSA), transmembrane protease-serine 2 (TMPRSS2) and prostein (SLC45A3). In vivo effects were evaluated in cell line- and patient-derived xenograft models of CRPC. Results: Selective blockage of the CH1 domain of p300/CBP results in sustainable anti-proliferative effects in AR-positive and AR-negative prostate cancer cells inducing apoptosis and/or senescence. Transcriptome and gene expression analyses revealed the downregulation of various drivers of cell cycle progression as well as decreased expression of hormone-induced, AR-regulated genes. In enzalutamide-resistant xenograft models of CRPC, oral administration of the compound triggered tumor regression/eradication at well tolerated doses. Serum PSA levels were strongly decreased in treated animals. Conclusions: Simultaneous inhibition of both, AR-signaling and downregulation of p300/CBP activity, may cause profound and long lasting antitumoral effects in patients with advanced prostate cancer. Future clinical investigation of this novel oral small molecule agent is warranted.
High Diagnostic Performance of Short Magnetic Resonance Imaging Protocols for Prostate Cancer Detection in Biopsy-naïve Men: The Next Step in Magnetic Resonance Imaging Accessibility
Authors: Marloes van der Leest, Bas Israël, Erik Bastiaan Cornel, Patrik Zámecnik, Ivo G. Schoots, Hans van der Lelij, Anwar R. Padhani, Maroeska Rovers, Inge van Oort, Michiel Sedelaar, Christina Hulsbergen-van de Kaa, Gerjon Hannink, Jeroen Veltman, Jelle Barentsz
Journal: European Urology (2019)

To make magnetic resonance imaging (MRI) more accessible to men at risk of high-grade prostate cancer (PCa), there is a need for quicker, simpler, and less costly MRI protocols. To compare the diagnostic performance of monoplanar ("fast" biparametric MRI [bp-MRI]) and triplanar noncontrast bp-MRI with that of the current contrast-enhanced multiparametric MRI (mp-MRI) in the detection of high-grade PCa in biopsy-naïve men. A prospective, multireader, head-to-head study included 626 biopsy-naïve men, between February 2015 and February 2018. Men underwent prebiopsy contrast-enhanced mp-MRI. Prior to biopsy, two blinded expert readers subsequently assessed "fast" bp-MRI, bp-MRI, and mp-MRI. Thereafter, systematic transrectal ultrasound-guided biopsies (SBs) were performed. Men with suspicious mp-MRI (Prostate Imaging Reporting and Data System 3–5 lesions) also underwent MR-in-bore biopsy (MRGB). Primary outcome was the diagnostic performance of each protocol for the detection of high-grade PCa. Secondary outcomes included the difference in biopsy avoidance, detection of low-grade PCa, acquisition times, decision curve analyses, inter-reader agreement, and direct costs. Results from combined MRGB and SB were used as the reference standard. High-grade PCa was defined as grade ≥2. Sensitivity for high-grade PCa for all protocols was 95% (180/190; 95% confidence interval [CI]: 91–97%). Specificity was 65% (285/436; 95% CI: 61–70%) for "fast" bp-MRI and 69% (299/436; 95% CI: 64–73%) for bp-MRI and mp-MRI. With fast bp-MRI, 0.96% (6/626) more low-grade PCa was detected. Biopsy could be avoided in 47% for the fast bp-MRI and in 49% for the bp-MRI and mp-MRI protocols. Fast bp-MRI and bp-MRI can be performed in 8 and 13 min, respectively, instead of 16 min at lower direct costs. Inter-reader agreement was 90% for fast bp-MRI protocol and 93% for bp-MRI protocol. A main limitation is the generalizability of these results in less experienced centers. Short MRI protocols can improve prostate MRI accessibility at a lower direct cost. For fast bp-MRI, this is at the cost of ∼2% more biopsies and ∼1% more overdetection of low-grade PCa. In order to implement this technique in nonexpert, low-volume, lower-field-strength scanners, further prospective studies have to be performed. We compared the value of three different magnetic resonance imaging (MRI) protocols for the detection of prostate cancer in men with elevated prostate-specific antigen levels. Our results show that, when used in expert centers, shorter MRI protocols do not compromise the detection of harmful disease. This increases MRI capacity at lower direct costs.