tbuckley/cabot-search huggingface dataset:
Patient perceptions of stool-based DNA testing across racial groups.
Authors: Lily Huang, Zhengyi Chen, Audrey Lynn, Nathan Devore, Minh-Tri Nguyen, Cheryl L Thompson, Gregory Cooper, Sanford D. Markowitz, Li Li
Journal: Journal of Clinical Oncology (2012)

1569 Background: Despite the widespread acceptance of colonoscopy as the gold standard for Colorectal Cancer (CRC) screening, compliance rates with recommended CRC screening lag far behind screening for breast and cervical cancers. Patients often delay or forgo screening colonoscopy due to associated discomfort, inconvenience, anxiety, and high cost. In addition, recent data have casted doubt on its effectiveness, especially in detecting right-sided colon neoplasia. Stool-based DNA (sDNA) testing is an emerging CRC screening tool that is convenient, noninvasive, and effective in detecting both right and left sided colon cancer. The goal of this study was to evaluate patient attitudes towards sDNA testing, identify preferences in CRC screening tools, and assess racial differences in these attitudes and preferences. Methods: In a colonoscopy-based case-control study, 100 patients of average CRC risk were asked to complete (1) sDNA testing (LabCorp ColoSure test), (2) screening colonoscopy, and (3) a patient satisfaction survey. Results: Eighty patients completed the study, including 55 (69%) White, 22 (27%) African American, and 3 (4%) Others. Overall, patients rated sDNA testing favorably in all preparation and test related features, except for perceived accuracy. Patients reporting a preferred screening method favored sDNA testing (78%) to FOBT (12%) or colonoscopy (10%), and 83% of all patients reported that they are likely to repeat sDNA testing. Non-Caucasians rated sDNA testing less favorably than Caucasians – reporting more discomfort (ANOVA, p&lt;0.004), more anxiety (ANOVA, p&lt;0.001), and less suitability (Chi-Squared, p&lt;0.0035). Of those patients reporting a preferred screening test, 82% of Caucasians and 64% of non-Caucasians selected sDNA testing. Conclusions: Although sDNA testing was ranked less favorably by non-Caucasians, it was well received overall as the preferred CRC screening test, as compared to FOBT and colonoscopy. The differences between racial groups may reflect the generally lower uptake of CRC screening among non-Caucasians, regardless of the test. In conclusion, sDNA testing may be an effective means to increase CRC screening in African Americans, hence preventing CRC and closing the racial disparity gap.
Phase 1 trial of lyso-thermosensitive liposomal doxorubicin (LTLD) and magnetic resonance guided high intensity focused ultrasound (MR-HIFU) for pediatric refractory solid tumors.
Authors: AeRang Kim, Karun Sharma, Pavel Yarmolenko, Haydar Celik, Rosandra N. Kaplan, Jeffrey Dome, Lauren Musso, Nicholas Borys, Ari Partanen, Lizette Warner, Peter C W Kim
Journal: Journal of Clinical Oncology (2017)

TPS10579 Background: Prognosis for children and young adults with refractory solid tumors remains unacceptably poor. Current approaches have reached the limits of maximal dose intensification, and the acute and late side effects of therapy are substantial. MR-HIFU is an innovative therapy that uses an external applicator to focus ultrasound energy inside a tumor non-invasively and without radiation. The resulting heating is precisely controlled and accurately targeted with the aid of MR thermometry and anatomic imaging. The flexibility and control over local heating by MR-HIFU provide an ideal system to be used with LTLD, a novel formulation of liposomal doxorubicin with the unique property of rapid heat-activated release of doxorubicin, an active agent in most pediatric solid tumors. The potential synergistic effects include enhanced permeability of the tumor vasculature, enhanced extravasation of the drug and subsequent high local concentrations of doxorubicin in the targeted tumor, inhibition of DNA repair, and stimulation of immune responses. Methods: This is the first pediatric trial of LTLD with MR-HIFU in refractory solid tumors (NCT02536183). Part A is a phase 1 dose escalation study to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of LTLD combined with MR-HIFU ablation in children. Part B combines LTLD at the MTD/RP2D with MR-HIFU induced mild hyperthermia (MHT) in an expanded cohort. Patients ≤21 (Part A) and ≤30 (Part B) years of age with refractory solid tumors at sites accessible to MR-HIFU, adequate organ function including cardiac function, and prior anthracycline dose of ≤ 450 mg/m 2 are eligible. LTLD is administered intravenously over 30 min followed immediately by MR-HIFU on day 1 of a 21-day cycle. Patients can receive a maximum of 6 cycles (or lifetime of 600 mg/m 2 of cumulative anthracycline) provided treatment is tolerated and have at least stable disease. Secondary objectives evaluate changes in quality of life and pharmacodynamic immune markers in children treated with LTLD and MR-HIFU. Clinical trial information: NCT02536183.
MRI contrast enhancement (CE): Analysis as survival prognostic factor in low grade gliomas (LGG).
Authors: Enrique Alanya Rodríguez, Florian Castet, Jordi Bruna Escuer, Cristina Izquierdo, Giovana Canchari Gonzales, Noemi Vidal Sarro, Carlos Mesia Barroso, Noelia Vilarino, Miguel J. Gil Gil
Journal: Journal of Clinical Oncology (2018)

e14031 Background: LGG are heterogeneous diseases, and factors related to poor prognosis have not been completely determined. MRI CE at follow-up has been related with progression to high grade glioma (HGG), however its role at the time of diagnosis remains less understood. The aim of our study was to determine the prognostic value of CE at the time of diagnosis in patients with histologically proved LGG. Methods: A retrospective longitudinal study was designed. Data from clinical records of all patients with histological diagnosis of LGG from Jan 2006 to Apr 2016 were collected. Diagnostic MRI was re-evaluated to define tumor size, midline compromise (MLC) and CE. IDH1 status by IHC was also determined. Cases with histological evidence of HGG at any follow-up time were excluded. Results: Sixty-six patients (43 astrocytoma, 11 oligoastrocytoma and 12 oligodendroglioma [WHO 2007]) were included for analysis: 24 with CE (36.4%) and 42 without CE (63.6%). No significant differences in clinical and treatment-related variables between groups were found, except for age < 40 (25.0% CE vs. 61.9% non-CE; p = .009). Median follow-up time was 55.4 months. Univariate analysis showed HR 6.33 (95%CI 2.01 – 19.93, p = .0016) for CE; HR 4.73 (95%CI 1.65 – 13.54, p = .0038) when only biopsy (Bp) was performed; and HR 2.73 (95%CI 0.95 – 7.86, p = .063) for Pignatti score (PgS) > 2. Multivariable analysis including CE, PgS, MLC and IDH1 only revealed CE (HR 5.06, 95%CI 1.57 – 16.3, p = .0066) as independent survival prognostic factor. In addition, bivariate analyses were performed: PsG and CE, IDH1 and CE, histopathology and CE. In all of them only CE remained as a significant factor of worse survival (p < .004). Conclusions: Despite the retrospective nature of the study and short follow-up time, CE at the diagnostic MRI in LGG was consistently and significantly associated with greater risk of death, and support the use of MRI CE as an important prognostic factor in the stratification design of LGG trials. OS Univariate Multivariate HR 95%CI p val HR 95%CI p val CE (Yes) 6.33 2.01 – 19.93 0.0016 5.06 1.57 – 16.3 0.0066 No surgery (only Bp) 4.73 1.65 – 13.53 0.0038 3.34 0.76 – 14.68 0.11 PgS > 2 2.73 0.95 – 7.86 0.063 1.41 0.34 – 5.4 0.61 IDH wild type 1.75 0.63 – 4.77 0.28 1.2 0.37 – 3.94 0.76
Phase III study of intraperitoneal/intravenous adjuvant chemotherapy compared intravenous adjuvant chemotherapy in patients with stage III gastric cancer.
Authors: Yang Yang, Juan Du, Jia Wei, Wenxian Guan, Gang Chen, Meng Wang, Lixia Yu, Hanqing Qian, Yan Yang, Baorui Liu
Journal: Journal of Clinical Oncology (2018)

4067 Background: Peritoneal metastasis is detected as any part of the metastasis/recurrence pattern in most stage III patients after radical surgery and appears to be the most life-threatening type of metastasis in patients with advanced gastric cancer. Previous studies have suggested that the molecular detection of cancer-specific carcinoembryonic antigen (CEA) mRNA levels in the peritoneal lavage has superior value for postoperative peritoneal recurrence in patients with advanced gastric cancer. The efficacy of intraperitoneal (IP) chemotherapy has been shown in gastric cancer patients with peritoneal metastasis. Methods: Eligibility criteria included pathologically confirmed stage III gastric adenocarcinoma after radical surgery, and no prior chemotherapy. Patients were first divided into CEA-positive group and CEA-negative group according to the CEA mRNA lever in the peritoneal lavage, and then in each group patients were randomized 1:1 to intraperitoneal (IP) arm and intravenous (IV) arm. Patients in IP arm received 2 cycles intraperitoneal docetaxel with oral S-1 and 4 cycles intravenous docetaxel with oral S-1, while patients in IV arm received 6 cycles intravenous docetaxel with oral S-1. The primary endpoint was 1-year disease-free survival rate (1-year DFS rate). Secondary endpoints were disease-free survival, overall survival, and safety. Result: Between April 2015 and June 2016, 161 patients were enrolled and 158 patients included in the efficacy analysis. 65 patients had positive CEA mRNA in peritoneal lavage and 93 had negative CEA mRNA. Baseline patient characteristics were balanced between IP arm and IV arm in both CEA-positive group and CEA-negative group. The 1-year DFS rate for CEA-positive group and CEA-negative group were 41% and 89%, respectively (p < 0.01). In CEA-negative group, the 1-year DFS rate for IP arm and IV arm were 86% and 89%, respective (P = 0.720). In CEA-positive group, the 1-year DFS rate for IP arm and IV arm were 66% and 41%, respective (P = 0.035). Both regimens were tolerable. Conclusion: The primary analysis showed the statistical superiority and clinical efficacy of the multi-route (intraperitoneal/intravenous/oral) regimen for patients with positive CEA mRNA in peritoneal lavage. It suggested clinical efficacy. Clinical trial information: ChiCTR-IPR-15006202.
Biomarker study for trastuzumab continuation beyond progression in a randomized phase II trial of weekly paclitaxel±trastuzumab in patients with HER2-positive advanced gastric or gastro-esophageal junction cancer refractory to trastuzumab combined with fluoropyrimidine and platinum (WJOG7112G).
Authors: Yasutaka Sukawa, Akitaka Makiyama, Taito Esaki, Gen Hirano, Masato Komoda, Tomomi Kashiwada, Junji Kawada, Ayumu Hosokawa, Takashi Tsuda, Akihito Tsuji, Toshikazu Moriwaki, Hiroaki Tanioka, Kimio Yonesaka, Kazuto Nishio, Katsuhiko Nosho, Kentaro Yamazaki, Shuichi Hironaka, Narikazu Boku, Ichinosuke Hyodo, Kei Muro
Journal: Journal of Clinical Oncology (2018)

4029 Background: WJOG7112G study, comparing paclitaxel plus trastuzumab (PT; n = 44) with paclitaxel alone (P; n = 45), did not demonstrate survival benefit of trastuzumab continuation beyond progression (TBP) in HER2-positive gastric or gastro-esophageal junction cancer. As a collaborative study, we analyzed biomarkers possibly associating with TBP efficacy. Methods: We prospectively collected tumor tissues and serum samples after progression of prior chemotherapy from patients enrolled into the WJOG7112G trial. HER2 status in tumor tissues was examined by immunohistochemitory (IHC) and fluorescent in situ hybridization (FISH). HER2 amplification in serum cell-free DNA (cfHER2amp) was assessed by droplet PCR. Serum level of neuregulin-1 (NRG1), a ligand of HER3 and an activator of HER2 heterodimerization, was measured by ELISA. Results: Tumor tissues and serum samples were collected from 18 (P; n = 10, PT; n = 8) and 68 (P; n = 33, PT; n = 35) patients, respectively. IHC 3+, 2+, and FISH positive tumors were 3 (17%), 3 (17%), and 8 (44%), respectively. All IHC 3+ and 2+ tumors were FISH positive except 1 unevaluable tumor. cfHER2amp was positive in 41 (60%) patients (P; n = 21, PT; n = 20). There was no benefit of TBP in progression free survival (PFS) regardless of cfHER2amp (+) and (-) [hazard ratio (HR) 0.93, 95% CI 0.49 - 1.76, and HR 0.81, 95% CI 0.36 - 1.85, respectively]. Serum NRG1 was detectable in 16 (24%) patients, and significantly associated with shorter survival in patients treated with PT (median PFS; 2.6 and 3.8 months, log-rank test p = 0.045, median OS; 7.4 and 10.9 months, p = 0.013). Conclusions: Two third of patients lost tumor HER2-positivity after the progression of prior trastuzumab-containing chemotherapy. Serum cfHER2amp was not associated with the efficacy of TBP. NRG1 might be a resistant marker to TBP in HER2 positive gastric or gastro-esophageal cancer. Clinical trial information: UMIN000009297.
A randomized phase II study of weekly paclitaxel ± trastuzumab in patients with HER2-positive advanced gastric or gastro-esophageal junction cancer refractory to trastuzumab combined with fluoropyrimidine and platinum: WJOG7112G (T-ACT).
Authors: Akitaka Makiyama, Kosuke Sagara, Junji Kawada, Tomomi Kashiwada, Ayumu Hosokawa, Yoshiki Horie, Hironaga Satake, Yoshiyuki Yamamoto, Hiroaki Tanioka, Katsunori Shinozaki, Kazuhiro Nishikawa, Keita Uchino, Yasutaka Sukawa, Takeharu Yamanaka, Kentaro Yamazaki, Shuichi Hironaka, Narikazu Boku, Ichinosuke Hyodo, Taito Esaki, Kei Muro
Journal: Journal of Clinical Oncology (2018)

4011 Background: Trastuzumab (Tmab) is a key drug for HER2-positive breast and gastric or gastro-esophageal junction (G/GEJ) cancer. While continuous use of Tmab beyond progression (TBP) showed a benefit in HER2-positive metastatic breast cancer, it has not been studied in HER2-positive G/GEJ cancer. We compared weekly paclitaxel alone (P) with weekly paclitaxel plus Tmab (PT) in patients (pts) with HER2-positive advanced G/GEJ cancer progressing during Tmab-containing therapy. Methods: Pts with HER2-positive advanced G/GEJ cancer progressing during first-line chemotherapy with Tmab + fluoropyrimidine + platinum were enrolled, and randomized to receive either P (80mg/m2, day1, 8, 15, q4w) or PT (P + initial Tmab 8mg/kg followed by 6mg/kg, q3w). The primary endpoint was progression-free survival (PFS). Major secondary endpoints included overall survival (OS), response rate, safety, and translational biomarker research. A total of 69 events was required to achieve 80% power for one-sided log rank test with 10% significance level, expecting median PFS of P and PT arms was 3 and 5 months, respectively. Results: From December 2012 to October 2016, 91 pts were randomized to P (n = 45) or PT (n = 44) arms. Median PFS was 3.19 (95% CI 2.86-3.48) and 3.68 (95% CI 2.76 to 4.53) months in the P and PT arms, respectively (HR = 0.91, 95% CI 0.67-1.22, p = 0.33). Median OS was 9.95 months in the P arm and 10.2 months in the PT arm (HR = 1.23, 95% CI 0.75-1.99, p = 0.20). In the P and PT arms, the overall response rates were 31.6 and 33.3% (p = 1.00), and the disease control rates were 71.1 and 61.5% (p = 0.47), respectively. PT treatment was associated with longer PFS in pts whose interval between the last Tmab administration and the randomization ≥30 days (HR = 0.45, 95% CI 0.21-0.96), but not in pts < 30 days (HR = 1.40, 95%CI 0.82-2.37). Safety was comparable between the arms. HER2-positivity of tumor tissues obtained from 16 pts before the study entry was lost in 69%. Conclusions: TBP strategy failed to improve PFS in pts with HER2-positive advanced G/GEJ cancer. Clinical trial information: UMIN000009297.
Short telomere syndromes cause a primary T cell immunodeficiency
Authors: Christa L. Wagner, Vidya Sagar Hanumanthu, C. Conover Talbot, Roshini S. Abraham, David Hamm, Dustin L. Gable, Christopher G. Kanakry, Carolyn D. Applegate, Janet Siliciano, J. Brooks Jackson, Stephen Desiderio, Jonathan K. Alder, Leo Luznik, Mary Armanios
Journal: Journal of Clinical Investigation (2018)

The mechanisms that drive T cell aging are not understood. We report that children and adult telomerase mutation carriers with short telomere length (TL) develop a T cell immunodeficiency that can manifest in the absence of bone marrow failure and causes life-threatening opportunistic infections. Mutation carriers shared T cell-aging phenotypes seen in adults 5 decades older, including depleted naive T cells, increased apoptosis, and restricted T cell repertoire. T cell receptor excision circles (TRECs) were also undetectable or low, suggesting that newborn screening may identify individuals with germline telomere maintenance defects. Telomerase-null mice with short TL showed defects throughout T cell development, including increased apoptosis of stimulated thymocytes, their intrathymic precursors, in addition to depleted hematopoietic reserves. When we examined the transcriptional programs of T cells from telomerase mutation carriers, we found they diverged from older adults with normal TL. Short telomere T cells upregulated DNA damage and intrinsic apoptosis pathways, while older adult T cells upregulated extrinsic apoptosis pathways and programmed cell death 1 (PD-1) expression. T cells from mice with short TL also showed an active DNA-damage response, in contrast with old WT mice, despite their shared propensity to apoptosis. Our data suggest there are TL-dependent and TL-independent mechanisms that differentially contribute to distinct molecular programs of T cell apoptosis with aging.
Correlation of QNBC immune and basal signature to targeted therapies and race.
Authors: Raymond Wesley Hughley, Windy Marie Dean-Colomb, Shweta Tripathi, Melissa Davis, Clayton Clopton Yates
Journal: Journal of Clinical Oncology (2017)

e14537 Background: Triple Negative Breast Cancer has been identified as one of the most aggressive breast cancer subtypes. We previously identified a subtype of TNBC, which lacks the androgen receptor (AR), which we coined quadriple negative breast cancer (QNBC). We have shown that women with QNBC have a worse prognosis compared to those with just TNBC. Additionally, we have noted that African American (AA) women with TNBC have a greater chance of having QNBC (28%) and a higher rate of disease progression (25%) vs Caucasian Americans (CA). We also found these QNBC patients have a unique immune signature that correlates to the more aggressive basal subtype. Here, we explore individual genes and their correlation to race and immune therapies. Methods: We analyzed mRNA expression in 925 tumors from CA or AA women from The Cancer Genome Atlas. Samples were dichotomized as positive or negative using mean gene expression cutoff. Gene expression comparisons among groups were determined using standard t-tests, ANOVA, and odds ratios with a significance threshold alpha of 0.05. Therapy targets were selected from the list of significantly differentiated genes. Boxplots and heatmaps were made using R packages. Cumulative Incidence plots for time to progression were constructed using XLStats and Grays test for significance. Results: QNBC CA have higher expression of PDCD4 (p &lt; .001), CD46 ( p &lt; .001), CD3EAP ( p = .04) and CD84 ( p = .07) compared to QNBC AA. CD47 ( p = .63) and PD1 (p = .96) express no significant differences in race. QNBC AA show higher expression of NFKB ( p &lt; .001), CCL2 ( p &lt; .001), and IL12 ( p &lt; .001) compared to QNBC CAs. Interestingly, QNBCs with high expressions of CD47 ( p = .04) have poor prognosis. Thus, QNBC patients with low expression of CD46 (p = .025), PDCD4 ( p &lt; .001), and CD3EAP ( p &lt; .001) have poor prognosis and overall survival. Conclusions: Current immune targeted therapies like CD47 and PD1 looks favorable for treatment in some QNBC patients. Race appears to effect other major therapy target gene expressions in the QNBC immune basal signature as well. This may imply that QNBC AA and CA have different immune response which may explain racial progression differences. Assessment of immune markers may contribute to more accurate prognosis.
Neurogliovascular dysfunction in a model of repeated traumatic brain injury
Authors: Conner Adams, Paolo Bazzigaluppi, Tina L. Beckett, Jossana Bishay, Iliya Weisspapir, Adrienne Dorr, James R. Mester, Joe Steinman, Lydiane Hirschler, Jan M. Warnking, Emmanuel L. Barbier, JoAnne McLaurin, John G. Sled, Bojana Stefanovic
Journal: Theranostics (2018)

Traumatic brain injury (TBI) research has focused on moderate to severe injuries as their outcomes are significantly worse than those of a mild TBI (mTBI).However, recent epidemiological evidence has indicated that a series of even mild TBIs greatly increases the risk of neurodegenerative and psychiatric disorders.Neuropathological studies of repeated TBI have identified changes in neuronal ionic concentrations, axonal injury, and cytoskeletal damage as important determinants of later life neurological and mood compromise; yet, there is a paucity of data on the contribution of neurogliovascular dysfunction to the progression of repeated TBI and alterations of brain function in the intervening period.Methods: Here, we established a mouse model of repeated TBI induced via three electromagnetically actuated impacts delivered to the intact skull at three-day intervals and determined the long-term deficits in neurogliovascular functioning in Thy1-ChR2 mice.Two weeks post the third impact, cerebral blood flow and cerebrovascular reactivity were measured with arterial spin labelling magnetic resonance imaging.Neuronal function was investigated through bilateral intracranial electrophysiological responses to optogenetic photostimulation.Vascular density of the site of impacts was measured with in vivo two photon fluorescence microscopy.Pathological analysis of neuronal survival and astrogliosis was performed via NeuN and GFAP immunofluorescence.Results: Cerebral blood flow and cerebrovascular reactivity were decreased by 50±16% and 70±20%, respectively, in the TBI cohort relative to sham-treated animals.Concomitantly, electrophysiological recordings revealed a 97±1% attenuation in peri-contusional neuronal reactivity relative to sham.Peri-contusional vascular volume was increased by 33±2% relative to sham-treated mice.Pathological analysis of the peri-contusional cortex demonstrated astrogliosis, but no changes in neuronal survival. Conclusion:This work provides the first in-situ characterization of the long-term deficits of the neurogliovascular unit following repeated TBI.The findings will help guide the development of diagnostic markers as well as therapeutics targeting neurogliovascular dysfunction.