tbuckley/cabot-search huggingface dataset:
Cancer associated thrombosis in patients taking direct oral anticoagulants (DOACs): Retrospective review of a single institutional series.
Authors: Sophia Angelov, Andrew Peter Dean
Journal: Journal of Clinical Oncology (2017)

e14080 Background: Venous thromboembolism (VTE) is a common and often serious complication for patients with malignancy. Even though low molecular weight heparin (LMWH) is recommended as first line therapy for initial and long term anticoagulation, patient choice may demand oral anticoagulants. This retrospective review illustrates the repeated observation of recurrent thromboembolic disease in patients taking the new class of oral anticoagulant, DOAC. Methods: The pharmacy database at our institution was searched to identify oncology patients who had received a prescription for a DOAC (rivaroxaban or apixiban). Sixtyfive patients were identified and case records were then examined for evidence of venous thromboembolism. Results: Five seperate episodes of recurrent venous thromboembolism were identified in four patients in our cohort., one patient having two seperate episodes of pulmonary embolus. All were on recommended therapeutic doses of DOAC at the time of thromboembolic event. Two patients experienced proven pulmonary embolus on CT pulmonary angiography (1 twice), one lower limb deep vein thrombosis and one upper limb deep vein thrombosis. Conclusions: This retrosepctive review reinforces the clinical guidelines stated by the Cochrane review and ASCO that LMWH should always be first line for the initial and continuation treatment of a VTE. The guidelines did not focus on the suboptimal anticoagulation aspect of the newer oral anticoagulants but more on the safety issues. Research has been mainly focused on comparing LMWH with unfractionated heparin (UFH) or oral warfarin. Comparisons between DOAC versus Warfarin as an oral form of therapy have also been made. In the available published literature, there is a paucity of research comparing DOACs to LMWH. We have identified four patients out of sixtyfive treated with therapeutic doses of DOAC who developed subsequent thromboembolism. This is additional supportive evidence that newer oral anticoagulant agents may not be efficacious in malignancy driven VTE and that LMWH should remain the standard of care. Patients specifically requesting DOAC for cancer associated VTE should be made aware of this data.
Correlation of next generation sequencing (NGS) of urine with tumor and plasma in patients with non-muscle invasive bladder cancer (NMIBC).
Authors: Chris Raymond, Alexandria Lahdya, Jenny Hernandez, Kavita Garg, Samantha Henderson, Funda Vakar-Lopez, Mark Li, Robert B. Montgomery, Jonathan Lawrence Wright
Journal: Journal of Clinical Oncology (2017)

e16002 Background: The current standard-of-care surveillance protocols for post-treatment NMIBC patients involve invasive procedures that result in poor patient compliance. Detection of recurrent NMIBC tumor DNA in plasma or urine would provide a less invasive alternative, and here we examine the feasibility of this approach by performing targeted NGS on tumor, plasma, and urine samples from NMIBC patients. Methods: 5 patients with untreated NMIBC (histology: Ta(n = 3), T1(n = 2)) have been analyzed to date. Urine and plasma samples were taken just prior to tumor resection. Samples were analyzed using a capture panel that includes common mutations found in &gt; 80% of NMIBC patients. Coverage includes the promoter region of the TERT gene, the entire coding regions of KDM6A and FGFR3, and copy number variation in PD-L1 and JAK2. Results: Mutations were observed in all tumor samples, with the TERT -124C &gt; T promoter mutation found in 4 patients (AF:16-84%) and the TERT -146C &gt; T promoter mutation found in the other (AF:19%). Deleterious mutations were found in KDM6A for 4 patients, and FGFR3 activating mutations were found in 2 patients. Amplification of FGFR3 was seen in one sample. When the 4 matched pairs of urine and tumor samples were examined, all of the called mutations in tumor were also found in urine at similar allele frequencies. This includes the detection of gene copy alterations. No such mutations were observed in plasma samples despite extensive sequencing ( &gt; 2000 unique read coverage). Conclusions: These data show that canonical NMIBC mutations are readily detectable in urine and correlate well with tumor, suggesting that NMIBC tumors shed prolifically into urine, and indicate that further investigation of NGS sequencing of urine as a means of detecting NMIBC recurrence is warranted.
A calculator for adhering to guidelines on conditioning regimen dose adjustments in obese patients undergoing HSCT.
Authors: Alejandro Ramon Carvajal, Mark Curtis, Kimberly Loftus, Todd F. Roberts
Journal: Journal of Clinical Oncology (2016)

e14022 Background: In 2014, ASBMT released Guidelines on Conditioning Chemotherapy Dose Adjustments in Obese Patients(BBMT 20 (2014)). Previously, all drugs within a regimen were adjusted only when a patient was > 125% above ideal body weight. Now, each drug within a regimen can be dosed based on different patient metrics (i.e. Adjusted Body Weight vs Actual Body Weight).The dosing calculations can be complex and are susceptible to human error. In order to improve patient safety and adhere to the new guidelines, a dosing calculator was developed to best support these practices. Methods: The calculator, built using Microsoft Excel, and formulated to adhere to the obesity dosing guidelines, was validated by testing against calculations not using the calculator to ensure accuracy. We then retrospectively reviewed 109 patients who received bone marrow transplants at Roger Williams Medical Center from 2010 through 2014. Transplants were categorized into its separate preparative regimens. Each drug within the specific conditioning regimens was evaluated to see if there was a dosing variance ( > 5%) when compared to the doses calculated using the calculator. Results: We found that 74 of the 109 transplants (68%) had dosing variances. The majority of the variances were a result of the weight metric (actual, adjusted40 or adjusted25) used in the previous dosing scheme calculation. Additionally, 133 of 219 total chemotherapy drug doses calculated using the previous dosing scheme (61%) were found to be incorrectly dosed. Of the incorrectly dosed drugs, 50 out of 133 (38%) were dosed too high, while the other 83 out 133 (62%) were dosed too low. Conclusions: When using our conditioning regimen calculator, we found that 68% of transplants over the past 4 years at our institution were incorrectly dosed based on the ASBMT guidelines for chemotherapy dosing in obese patients. The majority of these differences were a result of using the incorrect weight metric for obese patients when dosing for each drug within each regimen. Using the dosing calculator improves adherence to the latest ASBMT Guidelines and supports patient safety. Evaluation is ongoing to determine if these dosing variances had any effect on survivable outcomes.
Expression of miRNA and occurrence of distant metastases in patients with Hürthle cell carcinoma.
Authors: Nikola Besic, Rok Petric, Barbara Gazic, Katja Goricar, Vita Dolzan
Journal: Journal of Clinical Oncology (2016)

e17554 Background: Hürthle cell thyroid carcinoma (HCTC) is a rare type of thyroid carcinoma which accounts for around 3% of all thyroid malignancies. According to the World Health Organization classification, HCTC is considered an oxyphilic variant of follicular thyroid carcinoma, but genomic dissection of HCTC revealed a unique class of thyroid malignancy distinct from papillary and follicular carcinoma. In the present study, we investigated if expression of miRNAs of interest is associated with occurrence of metastases in patients with HCTC. Methods: In 39 patients with HCTC ( 22 with non-metastatic and 17 with metastatic disease), the expression levels of six miRNAs (miR-138, miR-183, miR-221, miR-222, miR-768-3p, miR-885-5p) and U6 snRNA as endogenous control were determined in FFPE samples of primary tumor and normal thyroid tissue using TaqMan miRNA assays. Results: In patients with HCTC, miR-138 and miR-768-3p were downregulated in tumor samples compared to normal tissue (p = 0.013 and p = 0.010, respectively). These two miRNAs were also significantly downregulated in tumor samples of patients with metastatic disease (p = 0.030 and p = 0.048, respectively), but not in patients with non-metastatic disease (p = 0.249 and p = 0.101, respectively). In patients with non-metastatic disease miR-221and miR-885-5p were slightly, albeit significantly upregulated in tumor compared to normal tissue (p = 0.042 and p = 0.027, respectively). When fold change of miRNA expression in tumor versus normal samples was compared between patients with and without metastatic disease, significant downregulation of miR-183, miR-221 and miR-885-5p was observed in patients with metastatic disease (p = 0.027, p = 0.019 and p = 0.024, respectively). Conclusions: Expression of miRNA (miR-183, miR-221, miR-885-5p) in tumor tissue is associated with occurrence of distant metastases in patients with HCTC.
Anti-PD1 (muDX 400) therapy given after radiation has greatest impact on (CD8+ Tim3- CD73+) stem cell like cells: Implications for improved clinical trial design incorporating radiation and anti-PD1.
Authors: Tahseen Nasti, Sejin Im, Haydn Kissick, Candace Daugherty, David H. Lawson, Rafi Ahmed, Mohammad Khurram Khan
Journal: Journal of Clinical Oncology (2018)

e21525 Background: Radiotherapy sometimes leads to remission at sites outside the field, in a phenomenon termed the “abscopal effect.” T cells, in particular CD8 T cells are believed to mediate this response. Methods: We utilized a human equivalent syngeneic mouse model implanted with B16 melanoma cells on both flanks of a B16F10 GP mouse model; using different doses of radiation. For immunotherapy, anti-PD1 antibody (muDX400) was used. Results: We observed significant delay of the radiated site, as well as the remote non-radiated tumor site depending on the single fraction, radiation dose used. The 10 Gy single dose was much more effective in inducing the abscopal response compared to single doses of 2, 5 or 20 Gy. Analysis of immune cells indicated that CD8+ T cells show increased proliferative capacity with the 10 Gy single dose, when combined with muDX400. The frequency of antigen specific CD8 T cells also increased in both irradiated and non-irradiated tumors with the 10 Gy group, compared with other groups. Combination of anti-PD1 (muDX400) with radiation was more effective with 10 Gy radiation dose than other doses. The sequence of radiation followed with anti-PD1 therapy was more effective than radiation following anti-PD1 therapy. RNA seq data on exhausted (CD8+Tim3+CD73-) and stem cell like (CD8+Tim3-CD73+) cells from untreated, radiation, anti-PD1 alone or combination groups show radiation induces interferon signaling while anti-PD1 therapy affects cell cycle genes. The combo affects both genes subsets, with the best responses noted in the combination setting. Conclusions: Our findings indicate that combining radiation with anti-PD1 antibody therapy will produce a persistent abscopal response, with a greater effect on stem cell like cells that produce more effector cells. This study will provide a platform for improved clinical trial designs, regarding optimal radiation dose and sequencing of radiation and anti-PD1 therapy. Our clinical trials to validate our preclinical findings are ongoing.
Successful treatment of good syndrome and pure red cell aplasia in thymic epithelial tumors.
Authors: Margaret Ottaviano, Vincenzo Damiano, Stefano De Falco, Lucia Nappi, Claudia Von Arx, Carmen Forino, Giovannella Palmieri
Journal: Journal of Clinical Oncology (2016)

e20109 Background: Patients (pts) with thymic epithelial tumour (TET) are more likely to have an autoimmune disease during their lives. The association of Good syndrome and hematological manifestations is not uncommon. Here we describe the clinical features and the treatment outcomes of ten pts affected by TET and Good syndrome complicated by Pure Red Cell Aplasia (PRCA). Methods: We retrospectively analyzed ten pts with TET and Good syndrome diagnosis, admitted to our Institution over a 10-years period, who developed PRCA. This series includes five men and five women (1:1 M: F ratio), with a median age of 47.5 years (41-65 years). Seven pts had an advanced disease at diagnosis according to Masaoka-Koga stage system: 4 pts IVA, 1 pt IVB, 1 pt III stage disease. Three patients had a II stage disease. Six patients underwent a first radical surgery. According to WHO 2004 classification, all the cases were thymoma: eight pts B2, 1 pt AB, 1 pt B3 thymoma. Good syndrome and PRCA were diagnosed in all pts. Immunoglobulin infusions at 500 mg/kg daily for 5 days were administrated for Good Syndrome control. High dose corticosteroids (1 mg/Kg/daily of prednisone) were used as first line treatment. The association with long acting somatostatin analogues in OctreoScan positive cases was started in five pts, among these, four received oral cyclosporine (2mg/Kg). The other five were treated with more aggressive immunosuppressive agents, such as alentuzumab and tacrolimus. Results: The only AB case reached a better outcome obtaining thymoma shrinkage and PRCA control by somatostatin analogues and prednisone association. Four pts had long thymoma and PRCA control by adding cyclosporine to long acting somatostatin analogs. Five pts treated with corticosteroids, alentuzumab ad tacrolimus died very soon due to rare viral infectious diseases. Conclusions: The histotype B2 is more likely associated to PRCA. In OctreoScan positive pts, the association of somatostatin analogues to oral cyclosporine seems to be the best treatment in terms of PRCA control and toxicity. In according to our experience more aggressive immunosuppressive agents such as alentuzumab and tacrolimus could be avoid due to the development of fatal infectious disease.
Concurrent boost technique in prostate IMRT and accuracy of planning target volume (PTV) at the periphery.
Authors: Santhanam Sundar, Ananth Sivanandan, Georgina Walker
Journal: Journal of Clinical Oncology (2016)

e16615 Background: The CHHiP trial, (ISRCTN 97182923), supports the hypothesis that alpha-beta ratio is low for prostate cancer & larger fractions (3Gy/#) of radiation have better cell kill. Paradoxically, the concurrent boost technique IMRT, utilized in CHHiP trial, irradiated part of control arm PTV with fraction sizes < 2Gy. To quantify under-treatment, we analyzed the effect of concurrent boost in real world patients (pts) treated in our institution between Apr 2014 & Feb 2015. Methods: Consecutive pts with baseline characteristics comparable to CHHiP trial pts were selected. Pts with T3b cancer or PSA > 30 or those with risk of SV > 30 % were excluded. IMRT target volumes (PTV1 PTV2 PTV3) were outlined as per CHHiP protocol. Over 37 fractions, PTV1 received 60Gy, PTV2 had 71Gy and PTV3 had 74Gy with PTV1-PTV2 receiving 1.62 Gy/fraction and PTV2-PTV3 receiving 1.92 Gy/fraction due to concurrent boost technique. Results: 74 consecutive cases were eligible for analysis. Median absolute volumes of PTV1, PTV2 and PTV3 were 178cc (range 119 - 259), 126cc (range 68 - 229) and PTV3 76cc (range 36 - 144) respectively. A significant proportion of PTV at periphery received radiation with fraction sizes < 2Gy (p < 0.001). Median percentage volume receiving 1.62Gy/fraction was 32% (5 – 54%) and median percentage volume receiving 1.92Gy/fraction was 39% (33 – 61%). Conclusions: Concurrent boost IMRT technique with conventional fractionation has a radiobiological flaw and results in significant proportion of PTV receiving radiation at < 2 Gy/fraction. This is significantly at odds with the low alpha-beta ratio suggested by radiobiological modeling and CHHiP trial results. Adoption of a constant PTV rather than a shrinking PTV would alleviate the problem of concurrent boost IMRT. Median Age (range) 71 yrs (58 – 78) Median PSA (range) 8.2 ( 2 – 19) Gleeson score 7: 90.5% 8: 9.5% T stage T1c; 13.4% T2 : 68.9% T3a: 17.6% PTV1 Median vol (range) cc 178 cc (119 - 259) PTV2 Median vol (range) cc 126 cc (68 - 229) PTV3 Median vol (range) cc 76 cc (36 - 144) PTV1-PTV2 Median vol (range) cc PTV2-PTV3 Median vol (range) cc 54 cc (9 to 108) 49 cc (31 to 109) PTV1 – PTV2 Median % vol (range) PTV2 – PTV3 Median % vol (range) 32% (5 – 54%) 39% (33 – 61%).
Bis(9)-(−)-Meptazinol, a novel dual-binding AChE inhibitor, rescues cognitive deficits and pathological changes in APP/PS1 transgenic mice
Authors: Yuhuan Shi, Wanying Huang, Yu Wang, Rui Zhang, Lina Hou, Jianrong Xu, Zhuibai Qiu, Qiong Xie, Hongzhuan Chen, Yongfang Zhang, Hao Wang
Journal: Translational Neurodegeneration (2018)

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative brain disorder, which is the most common form of dementia. Intensive efforts have been made to find effective and safe treatment against AD. Acetylcholinesterase inhibitors (AChEIs) have been widely used for the treatment of mild to moderate AD. In this study, we investigated the effect of Bis(9)-(-)-Meptazinol (B9M), a novel potential dual-binding acetylcholinesterase (AChE) inhibitor, on learning and memory abilities, as well as the underlying mechanism in the APP/PS1 mouse model of AD.B9M (0.1 μg/kg, 0.3 μg/kg, and 1 μg/kg) was administered by subcutaneous injection into eight-month-old APP/PS1 transgenic mice for four weeks. Morris water maze, nest-building and novel object recognition were used to examine learning and memory ability. Aβ levels and Aβ plaque were evaluated by ELISA and immunochemistry.Our results showed that chronic treatment with B9M significantly improved the cognitive function of APP/PS1 transgenic mice in the Morris water maze test, nest-building test and novel object recognition test. Moreover, B9M improved cognitive deficits in APP/PS1 mice by a mechanism that may be associated with its inhibition of the AChE activity, Aβ plaque burden, levels of Aβ and the consequent activation of astrocytes and microglia in the brain of APP/PS1 transgenic mice. Most of important, the most effective dose of B9M in the present study is 1 μg/kg, which is one thousand of the dosage of Donepezil acted as the control treatment. Furthermore, B9M reduced Aβ plaque burden better than Donepezil.These results indicate that B9M appears to have potential as an effective AChE inhibitor for the treatment of AD with symptom-relieving and disease-modifying properties.
Clinical and Molecular Factors Associated With Histologic Response to Topical Steroid Treatment in Patients With Eosinophilic Esophagitis
Authors: Swathi Eluri, Sara R. Selitsky, Irina Perjar, Johnathan Hollyfield, Renee Betancourt, Cara Randall, Spencer Rusin, John T. Woosley, Nicholas J. Shaheen, Evan S. Dellon
Journal: Clinical Gastroenterology and Hepatology (2018)
Exome-wide analysis of bi-allelic alterations identifies a Lynch phenotype in The Cancer Genome Atlas
Authors: Alexandra R. Buckley, Trey Ideker, Hannah Carter, Olivier Harismendy, Nicholas J. Schork
Journal: Genome Medicine (2018)

Cancer susceptibility germline variants generally require somatic alteration of the remaining allele to drive oncogenesis and, in some cases, tumor mutational profiles. Whether combined germline and somatic bi-allelic alterations are universally required for germline variation to influence tumor mutational profile is unclear. Here, we performed an exome-wide analysis of the frequency and functional effect of bi-allelic alterations in The Cancer Genome Atlas (TCGA). We integrated germline variant, somatic mutation, somatic methylation, and somatic copy number loss data from 7790 individuals from TCGA to identify germline and somatic bi-allelic alterations in all coding genes. We used linear models to test for association between mono- and bi-allelic alterations and somatic microsatellite instability (MSI) and somatic mutational signatures. We discovered significant enrichment of bi-allelic alterations in mismatch repair (MMR) genes and identified six bi-allelic carriers with elevated MSI, consistent with Lynch syndrome. In contrast, we find little evidence of an effect of mono-allelic germline variation on MSI. Using MSI burden and bi-allelic alteration status, we reclassify two variants of unknown significance in MSH6 as potentially pathogenic for Lynch syndrome. Extending our analysis of MSI to a set of 127 DNA damage repair (DDR) genes, we identified a novel association between methylation of SHPRH and MSI burden. We find that bi-allelic alterations are infrequent in TCGA but most frequently occur in BRCA1/2 and MMR genes. Our results support the idea that bi-allelic alteration is required for germline variation to influence tumor mutational profile. Overall, we demonstrate that integrating germline, somatic, and epigenetic alterations provides new understanding of somatic mutational profiles.
Readability and compliance of NCI's informed consent documents (ICDs) with its revised ICD template.
Authors: Holly A. Massett, Grace Miskin, Rocio Paul, Lynn Cave, Martha Kruhm, Andrea Denicoff, Margaret M. Mooney, Michael Montello, Jeffrey S. Abrams
Journal: Journal of Clinical Oncology (2016)

e18162 Background: Since 1997, NCI has used a standardized template to develop ICDs for its clinical trials. In 2013 NCI launched a revised template seeking to reduce the length and complexity of its ICDs. We report findings from a comparison of NCI ICDs using the initial vs. the revised template, and an analysis of compliance with the revised template. Methods: 1) Identified baseline sample of ICDs (B-ICD) from adult treatment protocols from 1/1/11 to 1/1/13; 2) Identified sample of ICDs using the revised template (R-ICD) from 7/1/13 to 2/24/15; 3) Compared readability statistics of B-ICDs and R-ICDs; 4) Analyzed R-ICD compliance with template requirements (intercoder reliability 96%); 5) Created correctness score for R-ICDs to assess compliance with template’s recommended text and length (range: 16 = both content/length correct, 48 = both incorrect) and correlated with readability statistics; 6) Identified sections of R-ICDs with poor compliance. Results: Identified 81 B-ICDs and 41 R-ICDs. R-ICDs had fewer pages (p < .001) and better ease of readability scores (p = .01) than B-ICDs, but the same 9thgrade reading level (p = .59). R-ICDs had a mean correctness score of 22.8 with 61% scoring in the top quartile (scores of 16-24). Better scores correlated with fewer pages (p = .01), lower grade levels (p < .05), and better ease of readability (p < .01). For 7 of the 16 main sections, > 80% of R-ICDs had perfect correctness scores. For 6 sections, < 50% had perfect scores. Least compliant sections were: extra tests (34% fully compliant), study groups (29%), length of time in study (27%), and my rights (20%). 62% included an Optional Study section with most using the correct text (86%) but half (50%) over the 3-page limit. Conclusions: The average number of pages decreased from 15 to 12 pages using the revised template but the reading level stayed above the 8th grade. Greater compliance with the new template is associated with shorter ICDs and better readability, suggesting the revisions were beneficial. Some main sections had low compliance and the Optional study section often exceeded the page limit, leading NCI to undertake efforts to further revise and clarify its ICD template to assist PIs in writing ICDs that increase patient understanding.