tbuckley/cabot-search huggingface dataset:
Use of <sup>18</sup>F-HX4 PET/CT to estimate tumor hypoxia enrolled subjects from ongoing Phase 2 trials using tarloxotinib bromide in advanced NSCLC and SCCHN.
Authors: Stephen V. Liu, Danny Rischin, Jess Bell, Jason Valardi, Damien Ferraro, Tillman E. Pearce, Ronald Lee Korn
Journal: Journal of Clinical Oncology (2016)

e23158 Background: Tumor hypoxia is associated with resistance to chemotherapy and radiotherapy. Recurrent/metastatic squamous cell carcinomas of the head and neck & skin (SCCHN/SCCS) and non-small cell lung cancer (NSCLC) tumors can be hypoxic leading to EGFR-TKI resistance. Tarloxotinib bromide (TRLX) is a hypoxia-activated prodrug that releases an irreversible pan-ErbB TKI targeting WT EGFR, mutant EGFR and HER2. Hypoxic tumor targeting with TRLX may lead to greater TKI tumor exposure with less toxicity than current EGFR TKIs. 18F-flortanidazole (18F-HX4) is a new hypoxia PET imaging agent that has the potential to identify and quantify tumor hypoxia with better tumor hypoxia targeting than earlier PET hypoxia agents. However, cross-institutional comparison of PET results without a standardization program can be challenging leading to insufficient or inappropriate conclusions based on PET results. Methods: Two concurrent multicenter Phase 2 trials are investigating the safety and activity of single-agent TRLX in recurrent or recurrent/metastatic SCCHN and SCCS (NCT02449681) or NSCLC (NCT02454842). Subjects have a whole-body18F-HX4 PET/CT scan prior to treatment. PET scanners are prequalified using a phantom harmonization program to ensure consistent image quality and robust 18F-HX4 quantitation for cross-institutional comparison. 18F-HX4 uptake will be quantitated to help correlate tumor 18F-HX4 uptake with measurement-based tumor treatment responses. Results: Up to 4 sites have been qualified with anthropomorphic phantoms to standardize PET scans and avoid poor quantitation of 18F-HX4. Excellent image quality scans in 3 of 4 patients have shown 18F-HX4 tumor uptake with preliminary estimates of tumor hypoxia ranging from 0-21% for hypoxic fractions (% of tumor hypoxia relative to reference tissue) and volumes (volume of hypoxia relative to reference tissue) permitting feasibility of signal detection to be correlated with responses. Conclusions: Multicenter PET studies of 18F-HX4 uptake and tumor response to TRLX is ongoing. Our PET harmonization strategy has shown promising early results in tumor hypoxia visualization. Recruitment is ongoing. Clinical trial information: NCT02449681.
Prognostic factors for mortality in malignant pleural effusion: Is it possible to predict survival?
Authors: Fernando Abrao, Mariana Campello de Oliveira, Geisa Garcia, Igor Abreu, Renata D'Alpino D'Alpino, Rodrigo Afonso Sardenberg, Carolina Marciano, Mariana Belaunde Toledo, Riad N. Younes
Journal: Journal of Clinical Oncology (2017)

e21638 Background: The aim of this study was to identify predictors of overall survival (OS) following palliative pleural procedures in patients with malignant pleural effusion (MPE). Methods: Data was collected from our database between January 2012 and December 2016 including all patients with MPE. All patients were followed-up for at least 30 days after the pleural procedure. We evaluated radiological aspects, biochemical and hematologic parameters as well as clinical features. For OS analysis, patients were divided into two groups. Group I included OS &lt; 30 days and Group II included OS &gt; 30 days. Prognostic factors for OS were identified by univariate analysis, using Fisher's exact for the categorical variables and Student's t-test for the quantitative ones. The cutoff points for any significant continuous variables were determined by the ROC curve. Subsequently, significant variables were entered into a multivariate logistic regression analysis ( p &lt; 0.05). Results: A total of 238 patients were included in the analysis (37,6% males). Median age was 62 year-old (range 24-965) and median follow-up time for surviving patients was 127 days. Median OS was 83 days for therapeutic pleural aspiration (TPA), 353 days for pleurodesis, 135 days for VAT drainages without pleurodesis due to trapped lung and 39 days for indwelling pleural catheter. Regarding primary site, median OS was 170 days for lung (n = 91), 253 days for breast (n = 70), 90 days for gynecological (n = 18), 33 for gastrointestinal (n = 34) and 305 days for others (n = 26). Factors affecting OS in univariate analysis with p &lt; 0.0001 were ECOG, procedure, protein, albumin, neutrophil to lymphocyte ratio(NLR) and hemoglobin, pulmonary infiltrate (p &lt; 0.0438), hematocrit (p &lt; 0.0002), and chemotherapy line (p &lt; 0.0229). In multivariate analysis the following variables were identified as independent prognostic factor: ECOG 3/4 (p &lt; 0.0095), pulmonary infiltrate (p &lt; 0.0011), albumin &lt; 2.5 (p &lt; 0.0325), and hematocrit &lt; 35 (p &lt; 0.0055). Conclusions: Patients with MPE who presented with ECOG 3/4, pulmonary infiltrate, albumin &lt; 2.5 and hematocrit &lt; 35 had shorter OS. The identification of these prognostic factors may assist physicians in choosing the optimal palliative technique.
Referral patterns and attrition rate for germline testing in pancreatic cancer (PC) patients.
Authors: Evan Justin Walker, Julia C. Carnevale, Christina Pedley, Amie Blanco, Salina Chan, Eric Andrew Collisson, Andrew H. Ko
Journal: Journal of Clinical Oncology (2018)

1591 Background: Hereditary predisposition is estimated to account for 10% of all PC cases. Identification of pathogenic germline mutations can inform not only screening recommendations for family members but also, increasingly, treatment selection for pts. However, referral patterns and clinical workflow for germline testing in this disease differ significantly by institution, and many pts may not undergo recommended testing for a variety of reasons. Methods: We performed a retrospective review of all pts diagnosed w/ PC referred to our University of California, San Francisco Clinical Genetics program over a 3-yr period (1/2015 – 10/2017). Medical records were reviewed for demographic, medical/family history, and disease-specific data as well as genetic testing results. If testing did not occur, the reason was documented. Results were categorized as negative, variants of unknown significance (VUS), or established pathogenic mutations. Descriptive statistics included means with standard deviations (SD); associations were analyzed with t-test and Fisher’s Exact Test. Results: ~29% (n = 137) of pts seen at UCSF w/PC dx were referred to Clinical Genetics during this time period. Of these, only 64% attended the appt and 60% ultimately underwent germline testing. Reasons for attrition inc. lack of pt f/u (n = 20), worsening disease severity (n = 11), insurance concerns (n = 7), and logistic/travel difficulties (n = 6). Pathogenic germline mutations were detected in 20% (n = 16) of pts tested [CFTR (n = 4), BRCA2 (n = 3), CHEK2 (n = 2), ATM (n = 2), MLH (n = 1), MUTYH (n = 1), other (n = 3)]; while 48% (n = 39) of pts had ≥1 VUS. Confirmed pathogenic mutations in our cohort were distributed across races/ethnicities, and assoc w/ younger age (mean age 53.3 vs 60.5 y.o.; p = 0.02) and FHx of breast cancer (p = 0.05). Conclusions: PC pts frequently do not undergo genetic counseling/germline testing despite appropriate referrals, highlighting the need to develop streamlined processes to engage more pts in testing, esp those w/ high-risk features such as young age and (+) FHx of cancer. Based on these data, our Center plans to pilot a genetic testing station for all new PC pt visits, incorporating both same-day testing and f/u remote counseling.
The prognostic value of systemic inflammatory factors in patient with metastatic gastric cancer.
Authors: Georgy M. Manikhas, Natalia P. Beliak, Svetlana I. Kutukova, Natalia V. Zhukova, Natalia V. Popova, Sanal Erdniev
Journal: Journal of Clinical Oncology (2017)

e15505 Background: Inflammation seems to be significant factor in carcinogenesis and tumor progression of numerous cancers. Blood calculated neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP), lactate dehydrogenase (LDH), international normalized ratio (INR) can be evaluated as systemic inflammation markers and prognostic biomarker for many aims: survival outcomes, lymph node metastasis and recurrence, treatment responses in a variety of cancers. The purpose of this study was to investigate baseline associations between blood test parameters (NLR, PLR, LDH, CRP, INR) and their prognostic biomarker role for patient with metastatic gastric cancer, undergoing first-line chemotherapy Methods: Potential baseline inflammatory markers (platelets, neutrophils, lymphocytes, the platelet-lymphocyte ratio, the neutrophil-lymphocyte ratio, the serum C-reactive protein [CRP], the serum LDH, INR) were retrospectively analyzed in 32 patients with metastatic gastric cancer, IV stage (median of age – 60,50). Multivariate analyses were used to identify prognostic factors for overall survival (OS). Baseline values were compared with tumor characteristic and median survival times (MSTs). Results: Multivariate analysis identified due to Cox proportional-hazards regression showed significant longest OS in patients with: localization of primary tumor in antral part of gastric (HR 0,45, 95% CI 0,25-0,80, p = 0,0065); low baseline’s level of WBC (HR 1,17, 95% CI 1.02 - 1,35, p = 0,0219); low baseline’s level of neutrophil (HR 1,18, 95% CI 1.02 - 1,34, p = 0,0251). Level of LDH, CRP, INR didn’t show significant ratio for this cohort of patient. Peritoneum metastatic also didn’t significant affect on OS in patient with metastatic gastric cancer. Patients with low baseline’s platelet to lymphocyte ratio (HR 1,004, 95% CI 1,0009-1,0072, p = 0,0125) and low (from 0 to 3,0) neutrophil to lymphocyte ratio (HR 1,81, 95% CI 1,09-2,99, p = 0,0212) had a significantly longest OS time. Conclusions: Inflammatory markers can predict overall survival in stage IV gastric cancer. Simple and useful.
Does para-aortic irradiation reduce the risk of distant metastasis in cervical cancer? A systematic review and meta-analysis of randomized clinical trials.
Authors: Lucas Gomes Sapienza, Maria Jose Leite Gomes, Vinicius Fernando Calsavara, Mario M. Leitao, Glauco Baiocchi
Journal: Journal of Clinical Oncology (2016)

e17013 Background: To evaluate the impact of the extension of radiotherapy field cranially towards para-aortic lymph nodes (EF-RT) in advanced cervical cancer. Methods: A systematic search of data-bases (PubMed, CENTRAL, Clinical Trials) was performed and included studies published before November 2015 without language restrictions published since 1960. The randomized clinical trials (RCT) were further analyzed. All patients should have pelvic radiotherapy and the same systemic therapy in both arms. Primary end-points were loco-regional failure, incidence of distant metastasis, para-aortic failure and cancer related death. Mantel-Haenszel method was used in the meta-analysis. The risk of bias analysis was carried out with the seven-domain methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions V5.1.0. A review of the treatment technique and toxicity was also performed. Results: 1309 studies were evaluated with only four RCT meeting inclusion criteria. A total of 506 patients allocated to standard pelvic irradiation and 494 to EF-RT. The risk of bias rate was nearly 80%. EF-RT reduced the para-aortic failure by 0.35 (0.19-0.64; p < 0.01) and incidence of other distant metastasis by 0.69 (0.50-0.96; p = 0.03). The OR for loco-regional failure and cancer related death were 1.06 (0.80-1.42; p = 0.67) and 0.68 (0.45-1.01; p = 0.06), respectively. The radiotherapy technique was conventional in 3 studies and conformational in 1 study. In total, 10 events of grade 5 toxicity (death) occurred, 4 in pelvic radiation and 6 in EF-RT, with an OR of 2.12 (0.71-6.27; p = 0.18). Conclusions: EF-RT targeting para-aortic lymphatic chain reduces distant metastasis events. The impact on survival is unclear. Studies addressing the role of EF-RT using modern radiation techniques should be conducted.
The clinical significance of autophagy in patients with non small cell lung cancer.
Authors: Nariyasu Nakashima, Dage Liu, Takayuki Nakano, Xia Zhang, Tetsuhiko Go, Yoshiyuki Kakehi, Hiroyasu Yokomise
Journal: Journal of Clinical Oncology (2018)

e24268 Background: Autophagy is the major intracellular degradation system by which unnecessary or dysfunctional components are delivered to and degraded in the lysosome. It is an important mechanism in keeping the homeostasis in eukaryote. Recently, autophagy was reported to play an important role in cancer, both in protecting against cancer as well as in potentially contributing to the growth of cancer. The role of autophagy in non-small cell lung cancer (NSCLC) has not been well clarified. We constructed the present study to investigate the clinical significance of autophagy. Methods: Tumor tissues from 67 patients underwent operation with NSCLC were analyzed. The status of autophagy was evaluated by the intratumoral expressions of the autophagy marker p62 with immunohistochemistry. The percent of p62 dot-like stained tumor cell was scored. A sample was classified as an autophagy-high tumor if > 20% of the tumor cells were positively stained, as this has been shown to be significantly related to patient survival. The Ki-67 proliferation index was also investigated by immunohistochemistry. Results: The percentage of autophagy tumor cells varied greatly (median = 10.0%; mean±SD = 23.8±26.8%) in the NSCLC tumors. Among the 67 NSCLCs, 23 tumors (34.3%) were autophagy-high. Autophagy tumor cell was significantly higher in T2 tumor than in T1 (35.3±27.7% vs. 17.7±24.5%, P = 0.0097). No significant relation was observed between the autophagy status and the other patient variables. Regarding to the tumor proliferation, the Ki-67 index was significantly higher in the autophagy-high tumors than that in autophagy-low tumors (24.0±22.1% vs. 13.6±15.3%, P = 0.0291). Furthermore, the 5-year survival rate for patients with autophagy-high tumor was significantly worse than that for patients with low autophagy-low tumors (54.3% vs. 90.9%, P = 0.0005). A Cox regression analyses also demonstrated autophagy status to be a significant prognostic factor (hazard ratio, 6.180; P = 0.0021). Conclusions: The high expression of autophagy evaluated by p62 was associated with the tumor proliferation in NSCLC. The autophagy status can be used as a poor prognosis in NSCLCs.
Identification of clinical variables and biomarkers of hypercoagulability for VTE risk evaluation in ambulatory patients with lung adenocarcinoma on chemotherapy: The ROADMAP study.
Authors: Grigoris Gerotziafas, Paraskey Boura, Andriani Charpidou, Ioannis Gkiozos, Ilias Evmorfiadis, Patrick Van Dreden, Aurelie Rousseau, Rabiatou Sangare, Annette K Larsen, Konstantinos N. Syrigos, Ismail Elalany
Journal: Journal of Clinical Oncology (2016)

e23073 Background: In ambulatory patients with lung adenocarcinoma (LA) the risk of VTE increases during chemotherapy (CTx). The identification of clinically relevant biomarkers of hypercoagulability (BH) and clinical variables could lead to better evaluation of VTE risk. The prospective longitudinal non interventional study ROADMAP, was designed to identify the most relevant related risk factors of VTE in ambulatory patients with LA on CTx. Methods: Patients were included and followed up at 3, 6 and 12 months. Documented symptomatic VTE was the end-point of the study. Blood samples were collected at inclusion and assessed for BH (Table). Assays and reagents were from Stago (France). A Clinical Research Form was completed by patients' interview at inclusion. Univariate analysis was done. Results: The study included 150 patients (mean age 65 years, 73% male). The LA diagnosis was done within 6 months before inclusion in 70% of them and 90% had advanced or metastatic disease at inclusion. In 85% of patients the ECOG performance status was < 3. In one year follow up 12 symptomatic VTE episodes occurred (8%), 75% of which occurred within the 3 months from inclusion. The univariate analysis identified the odds ratio for each variable as shown in the table. Conclusions: The ROADMAP study reveals that the Mean Rate index (MRI) and the Procoagulant Phospholipid clotting time (PPL-ct) are the BH related with the risk of VTE in ambulatory patients with LA. Their combination with the clinically relevant variables of patients and cancer related VTE risk may build a RAM specific for this group of cancer patients. Odds Ratio (95% CI) Biomarkers Tissue factor activity (TFa) 0.991 (0.91 - 1.079) D-Dimers 0.917 (0.634 - 1.325) * Fibrin Monomers 0.983 (0.929 - 1.041) PPL-ct 1.058 (1.008 - 1.144) * Lag-time 0.603 (0.294 - 1.235) MRI 1.016 (1.003 - 1.032) * Peak 1.006 (0.997 - 1.016) ETP 1 ttPeak 0.522 (0.307 - 0.887) Clinical variables Recent hospitalization within the last month before assessment 4.274 (0.946 – 1.333)* Time since diagnosis of the cancer 4.679 (0.443 – 29.4) * Cancer progression 4.114 (1.014 - 16.692)* *p < 0.05
Time to deterioration (TTD) in health-related quality of life (HRQoL) with carfilzomib plus dexamethasone (Kd56) versus bortezomib plus dexamethasone (Vd) in the ENDEAVOR trial.
Authors: Katja Weisel, Heinz Ludwig, Meletios A. Dimopoulos, Martin Kaiser, Roman Hajek, Joseph Mikhael, Kim Cocks, Sumeet Panjabi
Journal: Journal of Clinical Oncology (2018)

e20011 Background: In ENDEAVOR, Kd56 demonstrated superiority over Vd with improvements of 9.3 and 7.6 months in progression-free and overall survival and higher global health status/quality of life scores. We compared differences in TTD between Kd56 and Vd across the The European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire-Core 30-item module (QLQ-C30), the MM module (QLQ-MY20), and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity subscales (FACT/GOG-Ntx). Methods: TTD events were recorded as a worsening of ≥10 points for each subscale from baseline. Patients were censored if they progressed or died prior to event, or the day after baseline if additional assessments were not made, or at last visit for patients without an event. TTD was compared using Cox proportional hazards models accounting for stratification factors. Results: In contrast to the Kd56 arm, the Vd group experienced a more rapid deterioration (median: 113 vs 85 days) in GHS/QoL (HR: 0.77; 95% CI 0.65 to 0.92). Compared to the Kd56 group, the Vd group also reported a more rapid deterioration in physical function (median: 169 vs 114 days; HR: 0.82; 95% CI 0.68 to 0.99), cognitive function (median: 142 vs 113 days; HR: 0.83; 95% CI: 0.69 to 1.00), nausea/vomiting (537 vs 251 days; HR: 0.78; 95% CI 0.62 to 0.98;), insomnia (111 vs 85 days; HR: 0.80; 95% CI: 0.67 to 0.95), appetite loss (337 vs 166 days; HR: 0.66; 95% CI: 0.54 to 0.81), constipation (NR vs 141 days; HR: 0.47; 95% CI: 0.038 to 0.59), diarrhea (309 vs 169 days; HR: 0.71; 95% CI: 0.58 to 0.88), and side effects (196 vs 113 days; HR: 0.65; 95% CI 0.54 to 0.78). TTD in neurotoxicity symptoms was also more rapid in the Vd group (FACT/GOG-Ntx: 11.1 vs 5.5 months; HR: 0.69; 95% CI 0.56 to 0.85). No TTD differences were observed for other subscales. Conclusions: Compared with Kd56, patients treated with Vd experienced a more rapid deterioration in GHS/QOL, physical and cognitive function, side-effects, and neurotoxicity symptoms. Kd56 offers superior outcomes that lead to improved and prolonged HRQoL compared with Vd in patients with ≥1 prior therapy. Clinical trial information: NCT01568866.
Comprehensive genetic analysis of microsatellite instability-high colorectal cancers.
Authors: Kazuhito Sato, Masahito Kawazu, Yoko Yamamoto, Hiroyuki Mano
Journal: Journal of Clinical Oncology (2018)

e13536 Background: Patients with microsatellite instability-high colorectal cancers (MSI-H CRCs), which have been heretofore conventionally divided into hereditary (Lynch syndrome, LS) and sporadic categories, have poor post-relapse prognosis according to consensus molecular subtyping. Fusion kinases exist in less than 2% of all CRCs and do not seem to cluster in a subtype of the disease. In response to reports of some MSI-H CRCs’ resistance to immune checkpoint blockade, we sought to identify a therapeutic target. Methods: MSI testing was done on approximately 2,800 resected colorectal tumors; whole-exome sequencing, transcriptome sequencing, and methylation array were done on 149 out of 162 tumors showing MSI in BAT25 and BAT26 loci. Results: Males accounted for 47% (68/146). Sporadic MSI-H CRCs were further classifiable into somatic mismatch repair (MMR) gene mutation (Lynch-like, LL) or MLH1 methylated (MM) types. Methylation of other MMR genes (MSH2/MSH6/PMS2) was not detected. The mutational and clinicopathological properties of 26 LL CRCs more closely resembled those of 24 LS-associated tumors than those of 99 MM CRCs. There were significant differences between LS/LL and MM groups in age, location, number of insertions/deletions, recurrent mutations of KRAS/APC and BRAF/RNF43, and loss of heterozygosity of the locus encompassing TGFBR2 and MLH1. However, a gene mutation associated with the number of tumor-infiltrating CD8+ cells was recurrent (20%) in each category. Clinically actionable fusion kinases were detected in 11/19 (58%) MM MSI-H CRCs lacking KRAS/BRAF oncogenes. A 3T3 transformation assay confirmed the tumorigenicity of identified fusion kinases; small-molecule inhibitors that suppress the activity of the kinases significantly attenuated malignant transformation of 3T3 cells. In another cohort, we also validated a cost-effective strategy for detecting fusion kinases. Patients in the MM category including fusion kinases had worse post-relapse prognoses than did LS/LL patients. Conclusions: This integrated molecular characterization provides a foundation for developing target therapy and immune checkpoint blockade-based MSI-H CRC precision medicine.
TCT-479 Novel Approach for Left Atrial Appendage Occlusion: A Feasibility Study of Catheter-Delivered Expandable Foam
Authors: Gilberto Melnick, Marco Ferrone, Nicolas Isaza, Gerard Conditt, Genghua Yi, Yanping Cheng, Chung Yeh, Landon Nsah, Juan Granada, Grzegorz Kaluza
Journal: Journal of the American College of Cardiology (2018)