tbuckley/cabot-search huggingface dataset:
A CRUK first-in-human phase I trial of a CDC7 Inhibitor, LY3143921 hydrate, in patients with advanced solid tumors.
Authors: Peter F. Gallagher, Victoria Coyle, T.R. Jeffry Evans, Elizabeth Ruth Plummer, Sally Clive, Lesley McGuigan, Patricia Roxburgh, Noor Md Haris, Stefan N. Symeonides, Gregory Naylor, Saira Bashir, Barbara Stanley, Lisa Godfrey, Moira Elliott, Gavin Halbert, Sue Brook, Nicola Dobbs, Richard H. Wilson
Journal: Journal of Clinical Oncology (2019)

TPS3167 Background: CDC7 is a protein with key roles in DNA replication initiation, the intra-S-phase checkpoint and M-phase completion. CDC7 is over-expressed in malignant compared to non-malignant cells, particularly those with TP53 mutations, making it an attractive therapeutic target. LY3143921 hydrate is an orally administered ATP-competitive CDC7 inhibitor. Pre-clinical studies in colorectal cancer (CRC) and squamous non-small cell lung cancer (sqNSCLC) demonstrate favourable anti-cancer activity, particularly in squamous NSCLC and in CRC with TP53 null and missense mutations. We hypothesise that solid tumours mutated in TP53 will be sensitive to LY3143921 therapy. Methods: This is a first-in-human, phase I trial of LY3143921 hydrate (LY3143921) monotherapy given twice daily, continuously on a 21 day schedule until disease progression, patient (pt) withdrawal or unacceptable toxicity (NCT03096054). Eligible pts have histologically proven advanced/metastatic solid tumours for which no further standard therapy exists and WHO PS 0-1. Pts have regular clinical assessment and tumour imaging every 2 cycles. Phase Ia (dose escalation) is recruiting in a 3+3 design following 3 initial single patient cohorts (starting dose 30 mg OD), enriching for patients with malignancies associated with p53 mutations (CRC, sqNSCLC, high grade serous ovarian, squamous cell oesophageal, squamous cell head &amp; neck, urothelial, pancreatic and triple negative breast cancer). Recruitment to cohort 6 (180 mg BD) is ongoing. On determination of the maximum tolerated dose (MTD) and recommended phase II dose and schedule (RP2D), 2 expansion cohorts (≤ 25 pts each) of patients with CRC and sqNSCLC will be evaluated. Primary objectives: assess safety and tolerability of LY3143921, determine MTD and RP2D. Secondary objectives: evaluate preliminary efficacy and PK profile of LY3143921. All pts will have archival tumour tissue retrospectively analysed, while patients in phase Ib will also have pre- and on-treatment tumour biopsies. Evaluation of potential predictive and pharmacodynamic biomarkers including p53 mutations, phosphorylated MCM2, cyclin B1 and molecular subgroups of target tumours will be included. Clinical trial information: NCT03096054.
Characterization of oncologic patient visits at the emergency department (ED) at an Austrian tertiary care center.
Authors: Christoph Minichsdorfer, Bettina Pauzenberger, Anton Laggner, Christoph Zielinski, Thorsten Fuereder
Journal: Journal of Clinical Oncology (2019)

6609 Background: Oncologic patients frequently seek out the ED as first contact point. Besides the rare classic oncologic emergencies other causes are supposed to be more frequent. However, little is known about reasons of patients with active malignancies to consult the ED. Methods: Retrospective data regarding emergency visits of patients with a medical history of active cancer or adjuvant therapy, who were taken by ambulance to the ED in the time period from 01.01.2017 – 31.07.2017, was collected. For OS Kaplan-Meier curves were created and univariate COX proportional hazards model analysis was used and log rank tests were performed. For statistical analysis the chi2-test was used to investigate significant relations between the three months mortality (3MM) and patient characteristics. 3MM was defined as death within 3 month of the first ED consultation. Results: From a total of 1029 patient contacts 743 met the inclusion criteria. In total 552 patients were included. The median age was 67 years (Minimum: 18y; Maximum: 95y). The vast majority of patients (480, 87%) were in a palliative setting. 243 patients (44%) were under active treatment. The biggest group of patients suffered from lung cancer (18%) followed by hematologic malignancies (14%), pancreaticobiliary tumours (11%), breast cancer (8%) and colorectal cancer (7%). In total 111 patient contacts (15%) were treatment associated, 384 patient contacts (52%) were tumor related, the remaining (248, 33%) were unrelated to either. In 533 cases (72%) inpatient treatment was necessary. The average length of stay was 9, 36 days. Furthermore the 3MM was significantly higher in elderly patients &gt; 65y (p = 0,001), palliative patients not undergoing active treatment (p = 0,003) and patients with elevated CRP levels ( &gt; 0,5mg/dl) (p = 0,001) at time of ED contact. In addition in our univariate analysis factors that significantly decreased the OS were age &gt; 65, visceral metastasis and palliative patients without active treatment. Conclusions: The majority of cancer patients in this study were in a palliative setting. Moreover, cancer associated complications posed the most frequent cause for ED consultation. We could identify a higher risk for mortality for elderly patients, patients with visceral metastasis and patients undergoing best supportive care. The results may help to inform both cancer patients and primary care units about frequent complications.
A retrospective analysis of cisplatin dosing strategies when used with radiation on outcomes in head and neck squamous cell carcinoma of the oropharynx.
Authors: Vatche Tchekmedyian, Alan Loh Ho, Lara Dunn, James Vincent Fetten, David G. Pfister, Stephanie Lobaugh, Zhigang Zhang, Jung Kang, Linda Chen, Nadeem Riaz, Sean Matthew McBride, Yao Yu, C. Jillian Tsai, Nancy Y. Lee, Eric Jeffrey Sherman
Journal: Journal of Clinical Oncology (2019)

6079 Background: Cis is the gold standard radiosensitizer for CRT to treat head and neck cancer. Prospective trials have required that cis be administered early in the week (Mon/Tues) to optimize radiosensitization without evidence to support this practice. This retrospective analysis considers the impact of cis day of week (DOW) administration and other variables on OPSCC pt outcomes. Methods: We reviewed OPSCC cases treated with primary CRT at our center. Pts treated with non-cis or induction chemotherapy were excluded. Data collected includes age, DOW (Mon/Tues vs Wed/Thurs/Fri), smoking status, total dose (TD) of cis (≤200mg/m2 vs &gt; 200mg/m2), single dose (SiD) [100mg/m2 x1 day] vs split dose (SpD) [50mg/m2 x2 days] administration, T stage (0-2b vs 2c-3), N stage (0-2b vs 2c-3), overall survival (OS) (from start of RT), local/regional/distant failure, KPS and HPV/p16 status. Univariate Cox proportional hazards regression was used to analyze OS and multivariate Cox proportional hazard model investigated the relationships between OS and cis dosing variables while controlling for other factors. Results: 745 pts with OPSCC were treated with CRT from 7/31/2001-2/7/2014. 459 used cis based regimens and were included. Median age at start of RT was 55. 311 pts (67.8%) received SpD, 124 (27%) received SiD, 8 (1.7%) received weekly cis and 16 (3.5) received mixed cycles. 269 (58.6%) received ≤200mg/m2. 232 (50.5%) were HPV/p16 positive, 40 (8.7%) were negative and 187 (40.7%) were unknown. Median f/u was 7.9yrs (1.8m -18.9yrs). There were 92 (20%) deaths, and 75 (16.4%) recurrences (local/regional and distant) with 44 (9.6%) competing events. In univariate analysis, age, N stage, T stage, KPS and HPV/p16 status were significantly associated with OS, while DOW, TD, and SiD/SpD were not. In multivariate analysis (MVA), none of the associations between cis dosing and OS were significant (although MVA was limited by low number of events and total variables included). Conclusions: This retrospective analysis suggests that the DOW cis is given has no impact upon CRT outcomes for OPSCC pts. SpD cis represents an alternative administration approach.
Open versus Endovascular Repair of Abdominal Aortic Aneurysm
Authors: Frank A. Lederle, Tassos C. Kyriakides, Kevin T. Stroupe, Julie A. Freischlag, Frank T. Padberg, Jon S. Matsumura, Zhiping Huo, Gary R. Johnson
Journal: New England Journal of Medicine (2019)

Elective endovascular repair of an abdominal aortic aneurysm results in lower perioperative mortality than traditional open repair, but after 4 years this survival advantage is not seen; in addition, results of two European trials have shown worse long-term outcomes with endovascular repair than with open repair. Long-term results of a study we conducted more than a decade ago to compare endovascular repair with open repair are unknown.We randomly assigned patients with asymptomatic abdominal aortic aneurysms to either endovascular repair or open repair of the aneurysm. All the patients were candidates for either procedure. Patients were followed for up to 14 years.A total of 881 patients underwent randomization: 444 were assigned to endovascular repair and 437 to open repair. The primary outcome was all-cause mortality. A total of 302 patients (68.0%) in the endovascular-repair group and 306 (70.0%) in the open-repair group died (hazard ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.13). During the first 4 years of follow-up, overall survival appeared to be higher with endovascular repair than with open repair; from year 4 through year 8, overall survival was higher in the open-repair group; and after 8 years, overall survival was once again higher in the endovascular-repair group (hazard ratio for death, 0.94; 95% CI, 0.74 to 1.18). None of these trends were significant. There were 12 aneurysm-related deaths (2.7%) in the endovascular-repair group and 16 (3.7%) in the open-repair group (between-group difference, -1.0 percentage point; 95% CI, -3.3 to 1.4); most deaths occurred during the perioperative period. Aneurysm rupture occurred in 7 patients (1.6%) in the endovascular-repair group, and rupture of a thoracic aneurysm occurred in 1 patient (0.2%) in the open-repair group (between-group difference, 1.3 percentage points; 95% CI, 0.1 to 2.6). Death from chronic obstructive lung disease was just over 50% more common with open repair (5.4% of patients in the endovascular-repair group and 8.2% in the open-repair group died from chronic obstructive lung disease; between-group difference, -2.8 percentage points; 95% CI, -6.2 to 0.5). More patients in the endovascular-repair group underwent secondary procedures.Long-term overall survival was similar among patients who underwent endovascular repair and those who underwent open repair. A difference between groups was noted in the number of patients who underwent secondary therapeutic procedures. Our results were not consistent with the findings of worse performance of endovascular repair with respect to long-term survival that was seen in the two European trials. (Funded by the Department of Veteran Affairs Office of Research and Development; OVER ClinicalTrials.gov number, NCT00094575.).
Genomic alteration features of six cancers and their correlation with clinical characters using the next generation sequencing.
Authors: Qian Dong, Haiying Yang, Da Jiang
Journal: Journal of Clinical Oncology (2019)

e13130 Background: Next-generation sequencing (NGS) examination based on liquid biopsy has been agreed as a kind of routine diagnostic tool in cancer field and may provide new sights about oncogenesis mechanisms. This study aimed to observe the genomic alteration features of common cancers and their correlation with clinical characters. Methods: We enrolled 39 subjects (38 subjects with cancer and 1 healthy subject) and administrated mutation examination using a panel including 38 genes, which targeted 6 cancer types. For each subject, the genomic DNA was extracted and NGS was performed. Results: All patients were found to carry at least one alteration among the 38 genes. PSM2 showed a highest mutation rate, with 77% subjects carrying mutations in this gene. Besides, MSH2 and STK11, etc. exhibited a high mutation rate. Overall 17 genes were found to contain known pathogenic or outcome-unknown mutations, among which 15 had outcome-unknown mutations and 5 had recognized pathogenic mutations. RAD50 had a highest frequency of outcome-unknown mutations, and secondly MLH1 and MRE11A. The clinical characters including sex, metastasis/recurrence, and family cancer history had relationships with mutation types. Conclusions: Genomic DNA sequencing is a feasible and minimally invasive approach in cancer genetic analysis and a promising tool in prediction of cancer onset and prognosis. A large amount of variations are associated with sex, family history and cancer types, and may decide metastasis/recurrence outcomes. Those who have a family history of cancer are recommended to receive NGS examination.
Absolute lymphocyte count in patients with glioblastoma treated with temozolomide chemoradiation.
Authors: Anas Saeed Bamashmos, Assad Ali, Addison Barnett, Soumya Sagar, Lisa A. Rybicki, Gene H. Barnett, Alireza Mohammad Mohammadi, Lilyana Angelov, Samuel T. Chao, Erin Sennett Murphy, John H. Suh, Jennifer S. Yu, David M. Peereboom, Glen Stevens, Manmeet Singh Ahluwalia, Wei (Auston) Wei
Journal: Journal of Clinical Oncology (2019)

e13564 Background: Standard glioblastoma (GBM) management includes radiotherapy, chemotherapy, and steroids; all of which can result in immunosuppression and a low absolute lymphocyte count (ALC). Previous literature identified an association between low CD4 and worse progression free survival (PFS) and overall survival (OS). There remains a lack of research addressing predictors of immunosuppression in patients with GBM. The primary objective of this study is to identify the degree of immunosuppression, measured by ALC, in GBM patients receiving concurrent temozolomide chemoradiation (CRT). Secondary objectives include associations between ALC, PFS, and OS, and whether there are any predictors of immunosuppression in patients with GBM. Methods: We retrospectively reviewed 231 newly diagnosed GBM patients who underwent surgery followed by standard of care CRT. We also analyzed the association between ALC and age, sex, MGMT methylation status, and extent of surgical resection. ALC was collected at the time of surgery, CRT start date, and two, four, six, and ten weeks post-CRT start date. Common Terminology Criteria for Adverse Events (CTCAE) protocol version 5.0 was then used to grade low ALC as grade 0, 1, 2, 3, or 4. Results: Of the 231 patients analyzed, 139 were males, 74 underwent gross total resection of the tumor, 129 patients were less than 65 years, and 79 (42.5%) were MGMT methylated. 37 patients had grade 3-4 low ALC. In a univariate analysis, grade 3-4 low ALC at 4 weeks (±14 days) post-CRT start was associated with higher mortality (HR 1.54, P = 0.028) but had no significant association with PFS (HR 1.22, P = 0.29). Logistic regression analysis was used to identify risk factors for grade 3-4 low ALC and its association with survival. None of the risk factors that we tested such as age, gender, type of surgery, or molecular markers including MGMT, IDH, or EGFR were associated with low ALC. Conclusions: Our study demonstrated that patients with ALC grade 3 or 4 at 4 weeks (±14 days) of CRT had a significantly higher mortality (HR 1.54, P = 0.028) but had no significant association with PFS (HR 1.22, P = 0.29).
Phase II study: Induction chemotherapy &amp; transoral surgery as definitive treatment (Tx) for locally advanced oropharyngeal squamous cell carcinoma (OPSCC): An update and retrospective review of non-study patients.
Authors: Robert S. Siegel, Punam Thakkar, Nader Sadeghi, Joseph Goodman, Arjun Joshi, Anonglack Vongpachith
Journal: Journal of Clinical Oncology (2020)

e18549 Background: The standard of care for OPSCC includes chemoradiation (CRT) or surgery with adjuvant radiation (RT). However, RT is associated with significant life long morbidity. We assessed the efficacy of a two-drug induction regimen, followed by transoral robotic assisted surgery (TORS) &amp; neck dissection for locally advanced OPSCC. Methods: This is an IRB approved single-arm phase II study for untreated stage III or IVA (AJCC 7 th edition) OPSCC patients (pts) with an ECOG &lt; 2 and GFR &gt; 50 cc. Induction cisplatin 75 mg/m2 and docetaxel 75 mg/m2 was administered every 21 days for 3 cycles. Patients then underwent TORS and neck dissection(s). At post-op visits, flexible laryngoscopy, blood tests, and imaging with PET/CT and/or MRI were done. Short and long term toxicity, progression-free survival, overall survival, and quality of life (QOL) were evaluated in all pts. Results: Twenty oropharyngeal pts were treated, 19 were male, 17 were Caucasian, and 19 were HPV+. Median age at dx was 57. Three pts were stage III, and 17 were stage IVA. Pathologic CR at the primary site occurred in 15 pts and CR among LN neck dissections occurred in 13 pts. Four pts were given dose-reduced chemo and 1 pt was changed to carboplatin per protocol because of renal dysfunction. Pre vs post tx QOL scores did not change. At a mean follow-up of 40.7 months (range 13 to 55), 18 pts are alive and NED. Three pts recurred a mean of 2.2 mos after surgery, and were treated with salvage CRT. Two pts died of metastatic disease, the third is alive and well. All 3 pts had positive LN (9 LN, 3 LN and 1 LN) at surgery. A fourth pt had 12 pos LN and received radiation. He has not recurred. A retrospective review of an additional 20 twenty pts treated in the same way, were also reviewed for efficacy. Mean age was 61.5. Two pts died of metastatic disease. Twenty pts have been followed for &gt; 13 mos (17 are alive and well, 2 died, and 1 LFU), and their mean follow-up is 43.5 mos. Conclusions: Cisplatin + docetaxel followed by TORS &amp; neck dissection(s) appears to be an effective model for the definitive treatment for OPSCC, while avoiding the adverse effects of RT. Clinical trial information: NCT02760667.
Impact of travel time on healthcare costs and resource utilization by phase of care for older cancer patients.
Authors: Gabrielle Betty Rocque, Courtney Williams, Harold D. Miller, Andres Azuero, Stephanie B. Wheeler, Maria Pisu, Olivia Margaret Hull, Rodney Paul Rocconi, Kelly Kenzik
Journal: Journal of Clinical Oncology (2019)

6560 Background: Closures of hospitals and clinics may have unintended consequences, including increasing patient travel time. Increased patient travel time to healthcare facilities has the potential to adversely impact patient outcomes. Limited data exist on the impact of travel time on healthcare costs and resource utilization. Methods: This retrospective cohort study from 2012-2015 evaluated drive time to cancer care site for Medicare beneficiaries age ≥ 65 in the Southeastern US. The primary outcome was Medicare spending by phase of care (initial, survivorship, end of life [EOL]). Secondary outcomes included resource utilization measured by hospitalization rates, hospitalization sites, intensive care unit (ICU) admissions, and chemotherapy-related hospitalization rates. Hierarchical linear models with patients clustered within cancer care site and adjusted for pertinent covariates were used to determine the effects of drive time on average monthly phase-specific Medicare spending. Results: Median drive time was 32 minutes (IQR 18-59) for the 23,382 included Medicare beneficiaries, with 24% of patients driving &gt; 1 hour to their cancer care site. During the initial phase of care, Medicare spending was 14% higher for patients traveling &gt; 1 hour than those traveling ≤ 30 minutes.Hospitalizationrates were 4-13% higher for patients traveling &gt; 1 hour vs. ≤ 30 minutes in the initial (61 vs. 54), survivorship (27 vs. 26), and EOL (310 vs. 86) phases of care (all p &lt; .05). The majority of patients traveling &gt; 1 hour were hospitalized at a local hospital rather than at their cancer care site, whereas the converse was true for patients traveling ≤ 30 minutes. Conclusions: As healthcare locations close, patients living farther from treatment sites may experience more limited access to care, and healthcare spending could increase for Medicare.
CDK4/6 plus aromatase inhibitor-induced alopecia in breast cancer patients.
Authors: Donald Chan, Azael David Freites Martinez, Shari Beth Goldfarb, Shanu Modi, Devika Gajria, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2019)

e12537 Background: Cyclin-dependent kinase (CDK) 4 and 6 inhibitors are a novel therapy for metastatic breast cancer, and have shown to double the risk of alopecia. This study analyzed CDK4/6 plus aromatase inhibitor-induced alopecia (CDKIA), its impact on quality of life (QoL), and response to topical dermatologic therapy. Methods: The study analyzed a retrospective cohort of breast cancer patients diagnosed with CDKIA, evaluating clinical features, QoL, and response to therapy. CDKIA was also compared with endocrine-therapy induced alopecia (EIA). Results: 39 female CDKIA patients (median age 62 years [range 34-81]) were included, and 36 (92%) had standardized clinical images. CDKIA was most commonly attributed to a CDK inhibitor and letrozole in 23 patients (59%). CDKIA was similar to androgenetic alopecia (AGA) in every patient. Compared to EIA, CDKIA took less time to develop, was more severe, was associated with diffuse alopecia more frequently, and consisted of more vellus hairs on trichoscopy (Table). The Hairdex questionnaire, an alopecia-specific QoL survey, showed that CDKIA patients experienced worse QoL than EIA patients ( P &lt; 0.05) and were most affected emotionally ( P &lt; 0.01). There was a moderate to significant alopecia improvement in 11 of 13 CDKIA patients (85%) after treatment with topical minoxidil. Conclusions: CDKIA was clinically similar to AGA in association with diffuse alopecia. Patients with CDKIA had a negative emotional impact on appearance-based QoL. However, topical minoxidil may improve the severity of CDKIA. Baseline characteristics of CDKIA and EIA patients. [Table: see text]
Incidence of second primary neoplasms among cancer survivors in the United States, 2000 through 2015.
Authors: Eric Adjei Boakye, Wiley D Jenkins, Nosayaba Osazuwa-Peters, Maggie Wang, Min Jee Lee, Betty Chen, Edem S. Agamah, Arun Sharma
Journal: Journal of Clinical Oncology (2019)

1586 Background: The number of cancer survivors in the United States is projected to exceed 20 million by 2024. Survivors are at risk of developing a second primary neoplasm (SPN) – a leading cause of survivor death. We described the risk of developing a SPN among survivors of common cancers (smoking-related vs non-smoking-related) in the United States. Methods: We identified patients aged ≥18 years who were diagnosed with a primary cancer from the 10 sites with highest survival rates and stratified as smoking-related (urinary bladder, kidney &amp; renal pelvis, uterine cervix, oral cavity &amp; pharynx, and colon &amp; rectum) and non-smoking related (prostate, thyroid, breast, corpus &amp; uterus, and non-Hodgkin lymphoma) from Surveillance, Epidemiology, and End Results (2000-2015). SPN was defined as the first subsequent primary cancer occurring ≥2 months after first cancer diagnosis. Excess SPN risk was quantified using standardized incidence ratios (SIRs) stratified by sex. Results: A cohort of 2,908,349 patients (50.1% female) was identified and 260,267 (9.0%) developed SPN (7.6% of females and 10.3% of males). All index cancer sites were associated with a significant increase in SPN risk for females and males (except prostate cancer). Index smoking-related cancers (SIR range 1.20 – 2.17 for females and 1.12 – 1.91 for males) had higher increased risk of SPN than non-smoking-related cancers (SIR range 1.08 – 1.39 for females and 0.55 – 1.38 for males) relative to the general population. Conclusions: Nearly 10% of cancer survivors developed an SPN, and those with smoking-related cancers had higher risk. Given the increasing number of cancer survivors and importance of SPN as a cause of cancer death, these findings can improve secondary prevention and surveillance guidelines. [Table: see text]