tbuckley/cabot-search huggingface dataset:
Plasma cell free DNA (cfDNA) based somatic aberrations detected in treatment naïve metastatic hormone sensitive prostate cancer (mHSPC), hormonally ablated mHSPC and metastatic castration resistant prostate cancer (mCRPC) states and their impact on survival.
Authors: Manish Kohli, Winston Tan, Tiantian Zheng, Amy Wang, Calvin Wong, Meng-Yao Tan, Shidong Jia, Jianjun Yu
Journal: Journal of Clinical Oncology (2019)

5047 Background: We identified plasma cell free DNA (cfDNA) based copy number variations (CNV); single nucleotide variants (SNVs) &amp; TMPRSS-ERG fusion in four sub states of metastatic prostate cancer (mPCa) and determined the impact on survival. Two mHSPC cohorts included treatment naïve, gp-1 and mHSPC patients (pts) responding to chronic androgen ablation (AA) (gp-2). Two mCRPC cohorts included mHSPC pts with PSA relapse on chronic AA (gp-3) and a clinically progressive mCRPC cohort post AA (gp-4). Methods: Enrollment of mPCa pts was performed from 2009-14 who were followed until 2018. Plasma from collected blood was used for extracting cfDNA. NGS was performed using Illumina HiSeq X for a preselected target panel of 129 genes including DNA damage repair genes. Statistical analyses of genomic aberrations were performed in R 3.5.1 and Cox proportional-hazard models were used for survival analyses. Results: A total of 255 pts were enrolled with 215 having adequate cfDNA that passed NGS QC. Median study follow up was 90.2 (Range:73;99) months. The table highlights pts in each gp with CNV, SNV, fusion events. ARamplification was higher in mCRPC gps3&amp;4 (20/103 pts) compared to 3/106 pts in mHSPC gps1&amp;2 (p &lt; 0.001) and was prognostic for poor survival in mCRPC (p &lt; 0.001;HR:3.34; 95%CI: 1.9-5.76). 54/103 pts in gp3&amp;4 had SNVs in TP53 compared to 34/106 pts in mHSPC gps1&amp;2 (P &lt; 0.01). SNVs in APC, AR, CDK12 and BRIP1 were also increased in gps3&amp;4 (p &lt; 0.01). Gp1 mHSPC pts with SNVs in ATM/ CHEK2 had shorter response to AA (p &lt; 0.001; HR:3.66; 95%: CI:1.81-7.39). Conclusions: Plasma cfDNA based somatic aberrations are detected with increased prevalence in mHSPC to mCRPC states. The ease of specimen collection and the need for molecular profiling in mPCa increases its potential for clinical applications in pt care. [Table: see text]
The practical ethics of medication shortages: Understanding patient preferences for allocation, decision making, and disclosure through narrative inquiry.
Authors: Andrew Hantel, Fay J. Hlubocky, Michael Quinn, Sang Mee Lee, Mark Siegler, Christopher Daugherty
Journal: Journal of Clinical Oncology (2019)

e18323 Background: Hospital medication shortages (HMS) are pervasive throughout the U.S. healthcare system. Current management mechanisms are heterogeneous but routinely include the use of alternatives and the rationing of medications between patients. Little is known about oncology patient preferences for decision-makers, ethical allocation systems, or thresholds for disclosure during HMS. Methods: Oncology patients previously hospitalized for inpatient care within the last 24 months underwent qualitative interviews supplemented with validated instruments measuring: trust (Trust in Oncologist Scale), therapeutic alliance (Human Connection Scale), and shared decision-making (Shared Decision-Making Questionnaire). Qualitative data underwent Framework Analysis for thematic identification. Results: To date, 16 patients have been interviewed: median age 61y (31-77); 44% female; 56% married; 56% &gt; college education; median number of treatment regimens 2 (1-6), days in hospital 18 (3-66), number of hospitalizations 2(1-8). All patients (100%) reported extremely high levels of trust, therapeutic alliance, and shared decision-making with their oncologist. Two patients (13%) reported personal experiences with HMS, 43% reported knowledge of HMS within the U.S., and no patients reported knowledge of local hospital HMS. Framework Analysis revealed that virtually all patients preferred that their oncologist act as the primary decision-maker during allocation/rationing and favored pharmacist and ethicist involvement. Most patients preferred allocation systems that prioritized efficacy, age, and degree of illness. No patients desired the use of a lottery or reciprocity-based decisions. Virtually all patients favored disclosure of shortages if alternatives were used, independent of the level of difference in efficacy/toxicity, and in the case of both chemotherapeutics and supportive medications. Conclusions: Despite ubiquitous HMS in oncology, patients are generally unaware of local HMS and prefer: multi-disciplinary decision-makers during HMS allocation, prioritized allocation schemes, and more frequent HMS disclosure than presently occurs. Study recruitment is ongoing.
CENP-U function on TNBC.
Authors: Jin Zhang
Journal: Journal of Clinical Oncology (2019)

e12546 Background: Centromere protein (CENP-U) gene, as an important constitutive kinetochore component, plays significant roles in cell caryomitosis. Our previous research found that about 25 % of transgenic mice with CENP-U amplified had suffered breast cancer in body surface. Also, in highly aggressive breast cancer cell lines, CENP-U presented the highest expression. Furthermore, the CENP-U protein expression obviously increased in human invasive breast carcinoma compared with the normal gland and intra-ductal tissue. Methods: Gene knockdown was accomplished by transient transfection. In addition, cell proliferation was analyzed with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay while cell apoptosis was measured by flow cytometry using an annexin V-FITC apoptosis detection kit. Then, VEGF secretion in the supernatant was detected with an enzyme-linked immunosorbent assay (ELISA). Furthermore,Vascular endothelial markers of nude mouse were discovered by immunohistochemistry. And the signaling activation in the breast cancer cells was accessed by western blot using specific antibodies. Results: The MTT and EdU assay showed that CENP-U promoted the proliferation of the triple negative breast cancer (TNBC) cells while CENP-U downregulated promoted cell apoptosis. Furthermore, the ELISA results revealed that CENP-U significantly promoted the production and secretion of VEGF in TNBC cells. In addition, CENP-U downregulated inhibits tumor growth and angiogenesis in vivo. Importantly, CENP-U targeted HIF-1α,VEGFA, p-AKT and stat3, which were shown by the specific antibodies in the western blot. Conclusions: The results showed that CENP-U influence the proliferation, apoptosis and angiogenesis especially of TNBC cells. But the affected signaling pathways require further study.
Development and external validation of a deep learning model for predicting response to HER2-targeted neoadjuvant therapy from pretreatment breast MRI.
Authors: Manasa Vulchi, Mohammed El Adoui, Nathaniel Braman, Paulette Turk, Maryam Etesami, Stylianos Drisis, Donna Plecha, Mohammed Benjelloun, Anant Madabhushi, Jame Abraham
Journal: Journal of Clinical Oncology (2019)

593 Background: HER2-targeted neoadjuvant chemotherapy (NAC) possesses heterogeneous outcomes and currently lacks clinically-accepted markers of response. A means of predicting which patients will benefit prior to the treatment could reduce toxicity and the delay to effective intervention. Computational analysis of MRI via a deep neural network has shown promise in identifying NAC responders among mixed receptor subtype and treatment regimen cohorts, but faces challenges due to reproducibility across institutions and has not yet been explored in the context of HER2-targeted therapy. Here we present a deep learning approach for predicting response to HER2-targeted NAC from pre-treatment MRI. Methods: 100 HER2+ breast cancer patients who received NAC with docetaxel, carboplatin, trastuzumab, and pertuzumab at Cleveland Clinic (CCF) and had pre-treatment contrast-enhanced MRI’s were included in this analysis. 49 patients achieved pathological complete response (pCR, ypT0/is), while 51 patients retained presence of residual disease following NAC (non-pCR). 85 patients were used to train a convolutional neural network to predict pCR based on pre- and post-contrast MRI images, and the model design was optimized based on performance within a 15 patient internal validation cohort. An external, held-out testing dataset consisting of 28 patients (16 pCR, 12 non-pCR) imaged and treated at University Hospitals (UH) Cleveland Medical Center was used to validate the performance of the model. Performance was assessed by area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. A multivariable model incorporating age, hormone receptor status, stage, and tumor size was developed and similarly evaluated. Results: The neural network was able to predict the response to HER2-targeted NAC in the internal validation cohort (AUC = 0.93) as well as in an independent cohort from a separate institution (AUC = 0.85). This model offered superior performance compared to a multivariate clinical model, which achieved AUC = 0.67 and AUC = 0.52, in internal validation and external held-out testing cohorts, respectively. Conclusions: Deep learning analysis of contrast-enhanced MRI could be used to better target anti-HER2 therapy by pre-treatment prediction of response.[Table: see text]
Immunological impact of canerpaturev (C-REV, formerly HF10), an oncolytic viral immunotherapy, with or without ipilimumab (Ipi) for advanced solid tumor patients (pts).
Authors: Takayuki Nakayama, Makiko Yamashita, Toshihiro Suzuki, Manami Shimomura, Tetsuya Nakatsura, Kazunori Aoki, Noboru Yamamoto, Naoya Yamazaki, Taiki Isei, Hisashi Uhara, Yoshio Kiyohara, Hiroshi Uchi, Hiroshi Saruta, Takashi Inozume, Maki Tanaka, Shigehisa Kitano
Journal: Journal of Clinical Oncology (2019)

2610 Background: C-REV, an oncolytic, spontaneous mutant of Herpes Simplex Virus type 1 (HSV-1), is a cancer immunotherapy agent that combine direct tumor cell killing with immune modulation. A phase I study for solid tumors with cutaneous and/or superficial lesions treated with C-REV monotherapy and a phase II study for unresectable or metastatic melanoma treated with C-REV and Ipi combination therapy were conducted. Immune status of cancer pts before and after administration of C-REV with/without Ipi has been unclear. Methods: A phase I study (n = 6) included solid tumor pts with cutaneous and/or superficial lesions treated with C-REV monotherapy (1 x 10 6 and 1 x 10 7 TCID 50 /mL/dose; 4 injections q2-4wk). In phase II study (n = 28), C-REV (1 x 10 7 TCID 50 /mL/dose; 4 injections q1wk; then up to 15 injections q3wk) was injected into each tumor for advanced melanoma pts. Four Ipi infusions (3 mg/kg) were administered at q3wk. Immune-monitoring was conducted before and after treatment in tumor microenvironment usingpaired biopsy samples by multiplex immunohistochemistry (mIHC) and in peripheral blood by flow cytometry (FCM). Results: In the phase I study, significant infiltrations of CD8 + and CD4 + T cells were observed at tumor local site statistically in three pts (60%) among five pts. In the phase II study, FCM of peripheral blood (n = 10) showed that the responders (irSD, n = 7, 70%) tend to express the higher levels of ICOS on CD4 + T cells as a pharmacodynamic biomarker of ipi monotherapy reported previously (Ng Tang D, et al. Cancer Immunol Res. 2013) and lower levels of PD-L1 on monocyte after two months of treatment. Moreover, mIHC analysis of paired tumor biopsy samples (n = 11) revealed that five pts (45%) among 11 pts were confirmed persistent infection of C-REV at the injected site by qPCR. Disease control rate of pts with the virus DNA detected on Days 85/169 was higher than that without it (100% [n = 5, irPR; 1, irSD; 4] vs. 33% [n = 6, irSD; 2, irPD; 4]). Furthermore, median OS of pts with or without the DNA detected was 342 or 251 days respectively. Conclusions: Our results suggest C-REV injection in the tumor local site have potential to enhance systemic immune response of Ipi. Clinical trial information: NCT03153085.
Abstract 318: Potential Primary Prevention Implantable Cardioverter-Defibrillator Patients Lack Understanding, Want More Information and Are Willing to Reconsider Implant Refusal
Authors: Narendra Singh, Erin Hall, Essy Lucas, Sandeep Chandra, David Song, Linda Yan, David Suh, Anthony Dorsey, Suresh Ramamurthy
Journal: Circulation (2012)

Background: Underutilization of ICD’s for primary prevention of sudden cardiac death has been previously reported in our practice. Factors leading to acceptance or refusal of device implant have not been well studied. Method: Prospective standardized interview and use of a 1-10 rating scale of randomly selected heart failure (HF) pts in a suburban outpatient cardiology practice. Results: Of the 533 HF pts identified with an ejection fraction of &lt;35%, we randomly interviewed 50. Of these 54% were Caucasian (C), 36% African American (AA), 10% Asian (A). 29 pts (58%) accepted an ICD and 21 pts (42%) refused, the “no ICD” group. The mean age was 62+11 yrs, The mean EF was 24+7%. No significant differences in patient demographics, cardiac risk factors, HF medications or baseline labwork was seen. Comparing ICD pts to no ICD pts - in both groups understanding of HF was poor, 4.5 on a scale of 1-10. The no ICD pts had less understanding of ICD purpose p&lt;0.0003 , were less likely to have been given written ICD information (71 vs 38%, p=0.02) and were less likely to recall a recent discussion on the topic of ICD’s (52%). In both groups quality of life was more important than quantity 7.7+3 out of 10. Although 93% were Christian, religious belief (3.3+3 out of 10) and cultural values (3.2+3 out of 10) did not play a major role in decision making. Both group felt they had great access to health care resources and physicians (8.5+2 out of 10). Only 2 (7%) of ICD pts would not accept an ICD again, while 18 no ICD (86%) pts would now reconsider implant, p&lt;0.001 Women were less likely to be married 26 vs 63%, p=0.02. A pts were younger than C, 56 vs 66 yrs, p=0.04. AA pts had less understanding of low EF vs C, p=0.02 and trended towards having less access to best medications p=0.1. Conclusions: Our qualitative study suggest that underutilization of ICD’s for primary prevention of SCD may in part be related to limited communication and poor understanding of HF, sudden death, and the devices. Furthermore the majority of pts initially refusing a device are willing to reconsider implant. These findings, with further validation, offers a potential approach to improving ICD underutilization in these high risk patients.
TIVO-3: Subgroup analysis of progression-free survival of tivozanib compared to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC).
Authors: Camillo Porta, Elena Verzoni, Bernard Escudier, Sumanta K. Pal, Michael B. Atkins, Thomas E. Hutson, Michael N. Needle, David F. McDermott, Brian I. Rini
Journal: Journal of Clinical Oncology (2019)

4572 Background: Tivozanib (T) is a biochemically potent and highly selective VEGF tyrosine kinase receptor inhibitor in clinical development in RCC. The TIVO-3 trial in 3 rd and 4 th line subjects with metastatic (m) RCC showed a median progression free survival (mPFS) of 5.6 months (mos) for T compared to 3.9 mos for sorafenib (S) (p = 0.017, HR = 0.73). Methods: Subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI other than S or T, were stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized in a 1:1 ratio to T or S. The primary objective was to compare PFS by blinded independent radiological review. Pre-specified subgroups included prior treatment, IMDC prognostic group, and demographic characteristics. Results: Tivozanib demonstrated PFS benefit in all subgroups including men, women, patients over 65, and under 65. The hazard ratio was the same for patients enrolled in North America and the EU. Patients with ECOG performance status (PS) of 0 had a lower HR than patients with ECOG PS of 1. There was an increase in HR from IMDC favorable vs IMDC intermediate vs IMDC poor. PFS favored tivozanib in patients who had two prior lines of therapy, those treated with three prior lines, those with a prior checkpoint inhibitor, or with two prior VEGFR TKIs. Conclusions: Tivozanib improved PFS vs. sorafenib across several subgroups in TIVO-3. Patients with favorable and intermediate IMDC risk and ECOG PS 0 seemed to derive the most benefit. Patients treated with a prior checkpoint inhibitor or two VEGFR-TKIs had a longer PFS than patients treated on sorafenib. Clinical trial information: NCT02627963. [Table: see text]
The incidence of microscopic adnexal metastatic disease in women with presumed early stage endometrial cancer.
Authors: Wafa Khadraoui, Christina Tierney, Sophie Chung, Masoud Azodi, Elena Ratner, Gulden Menderes
Journal: Journal of Clinical Oncology (2019)

e17128 Background: The standard surgical staging for endometrial cancer has been established as a total laparoscopic hysterectomy,bilateral salpingo-oopherectomy and lymphadenectomies. However, ovarian removal can have significant consequences in pre- and peri-menopausal women, which comprise 25% newly diagnosed endometrial cancer. The potential ramifications of premature surgical menopause are clinically important. The goal of this study is to determine the incidence of microscopic adnexal metastatic disease in younger patients with presumed early stage endometrial cancer. Methods: From January 2005 through December 2010, 57 women who were 52 years old or younger with presumed early stage endometrial cancer were identified from our institutional database. Inclusion criteria included (1) FIGO grade 1 endometrioid endometrial cancer on endometrial biopsy, or (2) FIGO grade 1 endometrioid endometrial cancer on frozen section specimen with &lt; 50% myometrial invasion, no evidence of metastatic disease on pre-operative imaging, and no grossly visible metastatic disease in the peritoneal cavity during the staging surgery. Results: Of these 57 patients, four (7%) had lymphovascular space invasion, 20 (35%) had lower uterine segment involvement, 26 (45%) had superficial myometrial invasion or no residual carcinoma, while three (5%) unexpectedly had 50% or greater myometrial invasion on final pathology. Half of our patient population (50%) received vaginal brachytherapy. Of the 57 patients, one (1.8%) had microscopic adnexal involvement in a fallopian tube which upstaged her to stage IIIA disease. Pathological risk factors for advanced stage included LVI, lower uterine segment disease, and 50% myometrial invasion. Conclusions: After a thorough pre-operative evaluation and intra-operative exploration, preservation of the ovaries appears to be a safe and viable option for younger women who are diagnosed with presumed early stage disease. We suggest that ovarian preservation should be discussed on an individual basis in pre- peri-menopausal patients who meet the above-mentioned strict eligibility criteria.
Incidence patterns of early onset colon cancer by race and stage in the US.
Authors: Nishi Shah, Ana Acuna-Villaorduna, Sanjay Goel
Journal: Journal of Clinical Oncology (2019)

e18168 Background: Several studies show that incidence of colorectal cancer is increasing among young individuals. However, information on incidence of early onset colon cancer by race and stage is lacking. Methods: We analyzed incidence of colon cancer using National Program of Cancer Registries database which covers 99% of the US population. We identified colon cancer using ICD-O-3 code 8000-9049, 9056-9139, 9141-9589, along with the variable for site from cecum to sigmoid colon for years 2001 to 2015. SEER*Stat was used to calculate age-adjusted rates, trends and annual percent change. Results: Age adjusted incidence rate for colon is 31.2 cases per 100,000 among the entire population. Incidence in the age group of 15-39 years, 40-49 years, 50-59 years, 60-69 years, 70-79 years, 80+ years is 2.4, 14.3, 39.8, 86, 165.8, 232.3 per 100,000 respectively. The distribution of colon cancer by race for age groups is listed in table. When evaluating the incidence trend in each race for early onset colon cancer, the trend shows a rise in whites for both age groups (Annual Percent Change [APC] 3.4%, 1.5% for 15-39 years, 40-49 years of age respectively, p &lt; 0.05). The trend in blacks on the other hand shows a rise of 1.2% (p &lt; 0.05) in 15-39 years of age and a small but statistically significant decrease in incidence in 40-49 years of 0.5% (p &lt; 0.05). In Asian Pacific Islanders (API) and American-Indians or Alaskan Natives (AI), the trend is not significant for either age groups. In the age groups above 50 years, the trend shows a decrease in incidence of colon cancer in all races. The rise in incidence for colon cancer in 15-39 years age group appears higher in localized disease as compared to metastatic disease (6.5% vs 2.8% for localized vs distant site of disease). Conclusions: This study highlights differences in incidence of early onset colon cancer among young patients by race and stage. Although there have been more cases of early onset colon cancers in blacks, the rise in incidence is higher in whites. With colonoscopy, there has been decrease in incidence of colon cancer for patients &gt; 50 years for all races and stages. [Table: see text]
Retrospective analysis of patients with sentinel lymph node (SLN) positive melanoma (MEL) who received adjuvant nivolumab (NIVO) without completion lymph node dissection (CLND).
Authors: Zeynep Eroglu, Nalan Babacan, Kenneth F. Grossmann, Joseph Markowitz, Andrew Scott Brohl, Jennifer Cisneros, Wayne Cruse, Michael Harrington, Ricardo Jorge Gonzalez, Amod Sarnaik, Jonathan S. Zager, Vernon K. Sondak, Nikhil I. Khushalani
Journal: Journal of Clinical Oncology (2019)

9590 Background: Until recently, most patients (pts) with SLN+ MEL underwent CLND, a procedure mandated in published trials of adjuvant anti-PD-1 therapy to date. Following MSLT-II, this practice has dramatically changed with most pts now undergoing surveillance or adjuvant therapy without CLND. In addition, pts with in-transit/satellite MEL were excluded or not reported in these prior adjuvant studies. Our aim was to explore real-world outcomes of adjuvant NIVO in these pts. Methods: We carried out a single center retrospective analysis of stage 3 MEL pts who received adjuvant NIVO. Results: 32 pts with SLN+ MEL who did not undergo a CLND and started adjuvant NIVO within 3 months of surgery were included. Median age was 60 (26-77); per AJCC v7, 12 pts had Stage 3A, 11 stage 3B, and 9 pts had Stage 3C MEL. One was acral MEL; 18 had an ulcerated primary. 6 pts had BRAF-mutant MEL, 20 had BRAF-WT, and 6 unknown. NIVO treatment was 240 mg Q2wks or 480 mg Q4wks, up to one year. 21 pts developed grade 1/2 immune-related adverse events (irAEs), and 1 pt stopped NIVO due to toxicity (fatigue). With median follow-up of 7 months, only 1 pt had a recurrence, which was in the in SLN+ nodal basin; pt was rendered disease-free with surgery. The relapse-free rate (RFS) rate at 1 year was 95% (95% CI, 71-100). Of 21 pts with in-transit/satellite recurrent MEL (median age 68 [29-84]) who started adjuvant NIVO (no prior drug treatment), 5 had BRAF-mutant MEL, 14 BRAF-WT, 2 unknown; two were acral-lentiginous. 3 pts had recurrences: 2 regional and 1 distant mets, treated with surgery, TVEC, or BRAF-targeted therapy. Median follow-up was 8 months from NIVO start; 1-year RFS was 72% (95% CI 32-91). 15 pts developed irAEs; in 12, these were grade 1-2 and in 3, were grade 3 that led to discontinuation. Conclusions: While preliminary, these findings suggest that adjuvant anti-PD-1 therapy may be effective in SLN+ pts who forego CLND prior to adjuvant treatment, as 1-year RFS rate appears similar to rates in the published adjuvant anti-PD-1 trials that mandated CLND. This therapy may be similarly effective in pts with resected in-transit/satellite stage 3 melanoma. Further follow-up will be presented.