tbuckley/cabot-search huggingface dataset:
Intraoperative electron beam radiation therapy for primary locally advanced rectal and rectosigmoid carcinoma.
Authors: C G Willett, P C Shellito, J E Tepper, R Eliseo, K Convery, W C Wood
Journal: Journal of Clinical Oncology (1991)

To improve local control and survival in patients with primary locally advanced rectal and rectosigmoid carcinoma, intraoperative electron beam radiation therapy (IORT) has been used with a combination of moderate- to high-dose preoperative radiation therapy and surgical resection. Sixty-five patients underwent resection with the intention of using IORT if areas at high risk for local recurrence were apparent at surgery. For 20 patients undergoing complete resection with IORT, the 5-year actuarial local control and disease-free survival (DFS) was 88% and 53%, respectively. The results for 22 patients with pathologically documented residual carcinoma were less satisfactory with a 5-year actuarial local control and DFS of 60% and 32%, respectively. In this latter group, local control and DFS correlated with the extent of residual disease: patients with only microscopic disease had a 5-year actuarial local control and DFS of 69% and 47%, respectively, whereas for patients with macroscopic disease, these figures were 50% and 17%, respectively. For 18 patients undergoing complete resection without IORT or additional postoperative radiation therapy, the 5-year actuarial local control and DFS was 67% and 53%, respectively. Because local failure will occur in at least 30% of patients undergoing partial resection with or without IORT as well as patients undergoing complete resection of advanced tumors without IORT, additional postoperative radiation therapy should be considered.
How effective are platelet rich plasma injections in treating musculoskeletal soft tissue injuries?
Authors: David J Keene, Joseph Alsousou, Keith Willett
Journal: BMJ (2016)

#### What you need to know

Platelet-rich plasma (PRP) has become increasingly popular in sports medicine and orthopaedic practice as treatment for muscle, tendon, and ligament injuries, and has received media attention because of its promise as a regenerative therapy.1 2 PRP is an autologous preparation of a patient’s whole blood, which is centrifuged or filtered, allowing separation of a fraction containing a supraphysiological concentration of platelets (fig 1⇓). PRP can be applied on its own, or as an adjunct to surgery, allowing a high “dose” of growth factors and other bioactive proteins such as cytokines and chemokines to be delivered to the target tissue. This has the potential to improve repair and regeneration, although evidence from in vitro and animal studies has been conflicting.3 4 5



Fig 1  Making autologous platelet-rich plasma (PRP): a whole blood sample is taken (a) then a specialised centrifuge (such as the Magellan Autologous Platelet Separator System from Arteriocyte (b)) or filtration system is used to concentrate the platelets, and the resulting PRP is collected in a syringe for injection into the target tissue (c)



As an autologous preparation, PRP has been introduced into clinical practice without being subject to the stringent development required of new drugs. Many commercially available …
Pharmacologic analysis of drug-receptor interaction (2nd edition): Edited by T Kenakin. (Pp 468; $113.50.) New York: Reven Press, 1993. ISBN 0-7817-0065-5
Authors: M. J Curtis
Journal: Cardiovascular Research (1995)

Pharmacologic analysis of drug-receptor interaction (2nd edition): Edited by T Kenakin. (Pp 468; $113.50.) New York: Reven Press, 1993. ISBN 0-7817-0065-5 Pharmacologic Analysis of Drug Receptor Interaction (2nd edition). Edited by Kenakin T. (Pp 468; $113.50.) New York: Raven Press, 1993. ISBN 0-7817-0065-5. Michael J Curtis Michael J Curtis London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 29, Issue 2, February 1995, Page 294, https://doi.org/10.1016/S0008-6363(95)90021-7 Published: 01 February 1995
Toll-Like Receptor Profiles In Splenic Marginal Zone B-Cell Lymphoma and Splenic Diffuse Red Pulp B-Cell Lymphoma
Authors: Aurélie Verney, Alexandra Traverse-Glehen, Evelyne Callet-Bauchu, Francoise Berger, Laurent Jallades, jean-Pierre Magaud, Pascale Felman, Gilles Andre Salles, Lucile Baseggio
Journal: Blood (2013)
Multi-institutional phase I trials involve more patients and longer accrual time compared to single institution trials
Authors: A. Dowlati, S. Manda, L. Patrick, S. Remick, J. Gibbons, P. Fu
Journal: Journal of Clinical Oncology (2007)

2500 Background: There has been a suggested increase in the number of multi-institutional phase I trials over the past decade. Methods: We reviewed all published phase I studies between 1/98 and 12/05 from the Journal of Clinical Oncology and Clinical Cancer Research. 452 phase I studies were identified. The following data were obtained from each study: sponsor (NIH/foreign equivalent vs. pharma), year published, number of participating institutions, mechanism of drug action (8 categories; most common are cytotoxic and targeted therapies), country, number of patients accrued, accrual time and study endpoint (maximum tolerated dose-MTD vs. optimal biological dose- OBD). Results: 55% of phase I trials were single institutional and 21% accrued patients from = 3 institutions. There was no increase over time in the number of multi-institutional studies and no significant association was seen between sponsor and number of institutions. No association was seen between mechanism of drug action and number of participating institutions. There was a highly significant association between number of institutions and number of patients enrolled with multi-institutional studies having higher number of patients per trial (p=0.0003). Pharmaceutical sponsored studies are associated with a greater number of patients per trial (mean 32.8±0.9) as compared to government sponsored (28.4±1) (p&lt;0.05). Only 34% of trials report accrual time. Accrual time is increased in multi-institutional studies (= 3 centers) as compared to single institutional studies (mean 25 vs 22.5 mos) but does not reach statistical significance (p=0.613). No correlation was seen between endpoint of the phase I trial (MTD vs OBD) and number of institutions. OBD studies were strongly associated with agents defined as “targeted”. Studies of cytotoxic agents defined the MTD in 99% of trials versus only 64% of agents categorized as targeted therapies (p&lt;0.0001). Conclusions: Although there has been no increase in the number of published multi-institutional phase I studies, these multi- institutional trials accrue more patients only to reach the same study endpoint but at a cost of greater accrual time. The clinical value of multi- institutional phase I studies is not apparent. Supported by K23 CA109348–01 No significant financial relationships to disclose.
In vitro sensitivity of myeloblast clonogenic cells to doxorubicin, aclacinomycin A, and 4'-O-tetrapyranyl-doxorubicin: correlations with clinical responses.
Authors: V Georgoulias, Y L Iskandar, F Amesland, P Ribaud, G Mathé, C Jasmin
Journal: Journal of Clinical Oncology (1984)

The in vitro sensitivity of peripheral blood myeloblast clonogenic cells (CFU-MLs) to doxorubicin (DOX), aclacinomycin (ACL), and 4'-O-tetrapyranyl-doxorubicin (THP-DOX) was studied to evaluate the individual chemosensitivity of CFU-MLs. CFU-MLs from untreated patients were sensitive to the three tested anthracyclines (in 60% to 69% of the patients). Conversely, CFU-MLs from relapsed patients previously treated with DOX-containing regimens were sensitive to ACL and THP-DOX (in 71% and 75% of the patients, respectively) but resistant to DOX. Six of ten patients who entered complete remission with a combination of DOX, vincristine, and cytosine arabinoside had CFU-MLs in vitro which were sensitive to DOX. Conversely, none of the 13 patients resistant to this chemotherapy regimen displayed CFU-MLs which were sensitive in vitro to DOX. Nine of ten patients who responded to ACL as well as one of three resistant patients had CFU-MLs sensitive to ACL in vitro. No clinical responses were observed with THP-DOX in five of seven patients with CFU-MLs sensitive to this drug. The results indicate that myeloblast clonogenic assays can be used to predict the in vitro sensitivity of CFU-MLs to compounds with established antileukemic activity (ie, DOX, ACL). However, the discrepancy between in vitro and in vivo sensitivity to THP-DOX underlines the importance of knowledge of drug pharmacokinetics and the difficulty of using the CFU-ML test for screening new drugs.
Abstract 18141: Is There Systolic Myocardial Mechanical Dysfunction in Patients With Different Degrees of Diastolic Dysfunction and Normal Ejection Fraction?
Authors: Sergio Barros-Gomes, Patricia A Pellikka, Angela Dispenzieri, Hector R Villarraga
Journal: Circulation (2014)

Introduction: Diastolic dysfunction has been characterized in relation to the relaxation and compliance properties of the left ventricle; limited information exists regarding its relationship to systolic function as assessed by deformation imaging. Objectives: To determine if there is left ventricular systolic dysfunction detected by global longitudinal strain (GLS) measured by two dimensional speckle tracking echocardiography in patients with immunoglobulin light chain (AL) amyloidosis with different degrees of diastolic dysfunction and normal ejection fraction (EF). Methods: Consecutive biopsy-proven AL patients with preserved EF (≥ 55%) who had a comprehensive echocardiogram performed and strain analysis were included. Cohort was divided into 5 groups according to the different grades of diastolic dysfunction: Group 0: normal filling pressures; Group 1: abnormal relaxation; Group 2: pseudo-normal pattern; Group 3: reversible restrictive; Group 4: fixed restrictive. Images were acquired and performed on a Vivid 9 from the 3 apical views, and analyzed on vendor-specific software (Echo-PAC, GE). GLS was averaged from the 16 segments, and their means compared by ANOVA and each pair with Student’s t test. Results: A total of 858 patients were included, mean age was 63.7 years ± 10.1, and 61.5% were male. From those, 205 (24%) were in group 0; 299 (35%) in group 1; 255 (30%) in group 2; 65 (7%) in group 3; and 34 in group 4 (4%). GLS means measurements were -18.95 ± 2.4, -16.86 ± 3.4, -15.60 ± 3.9, -12.31 ± 3.0, and -10.48 ± 3.3, respectively (P&lt;0.0001). All individual GLS values were significantly different statistically when compared between each group (P&lt;0.01 for all pairs; figure). Conclusions: Longitudinal systolic mechanical function is progressively impaired in AL amyloid patients as diastolic dysfunction progresses, despite normal EF. This systolic dysfunction provides insights into the intrinsic relationship between the components of the cardiac cycle.
Abstract 212: Synthesized 18-Lead Electrocardiogram in Patients Treated in the Emergency Department
Authors: Tadashi Ashida, Ken Nagao
Journal: Circulation (2013)

Background: Standard 12-lead electrocardiogram (ECG) speed the diagnosis and shorten the time to reperfusion for acute coronary syndrome (ACS). However, there is insufficient information of posterior (V7-V9) and/or right (V3R-V5R) ventricular area in which data are not routinely recorded. Recently, a non-invasive standard 12-lead ECG system with an additional 6 leads (Synthesized 18-Lead ECG; Nihonkoden Co. Ltd.) has been developed. Methods: We conducted a prospective, blind, observational study of patients who treated in the emergency department (ED) of our hospital. From symptoms and signs on arrival at the ED, physicians judged whether ECG was necessary for diagnosis and primary care. We entrusted the medical examination and primary care to the physicians. When physicians suspected a patient with emergency cardiovascular disease, a synthesized 18-lead ECG was recorded within 10 minutes of ED arrival. The primary endpoint was a diagnosis of acute ST-elevation myocardial infarction (STEMI). Results: Of the 7,638 patients treated in the ED, 6,041 were adults. Of the 6,041 adults, 1,546 (26%) underwent synthesized 18-Lead ECG within 10 minutes of ED arrival. Of the 1,546 patients undergoing synthesized 18-Lead ECG, 407 (26%) were judged as possible cases of emergency cardiovascular disease with chest discomfort in 31%, disturbance of consciousness in 21% and dyspnea in 16% etc. Of these 407 patients with possible emergency cardiovascular disease, 25 (6%) were diagnosed as ACS, including 13 STEMI, 5 Non-STEMI and 7 unstable angina. Of the 13 STEMI patients, 2 (15%) were diagnosed as STEMI complicated by right ventricular infarction, including one moderate right ventricular dysfunction and one syncope. Conclusion: Synthesized 18-Lead ECG with right-sided and posterior precordial leads (V3R-V5R and V7-V9), was useful in the rapid diagnosis of STEMI within 10 minutes of ED arrival, especially in the early detection of right ventricular infarction. 1684
Increased Platelet-Derived CD40L May Modulate Endothelial Cell ICAM-1 Expression and Interact With Leukocytes In Sickle Cell Anemia
Authors: Vanessa Tonin Garrido, Renata Proença-Ferreira, Venina M. Dominical, Marcos André Cavalcanti Bezerra, Aderson S. Araujo, Sara T O. Saad, Fernando Ferreira Costa, Nicola Conran
Journal: Blood (2013)
Abstract 4359: Characterization of GalNAc-conjugated generation 2.5 ASOs in DEN and DEN/CCL4-induced HCC tumors
Authors: Joanna Schmidt, Minji Jo, Tianyuan Zhou, Youngsoo Kim, A. R. MacLeod
Journal: Cancer Research (2015)

Abstract The worldwide rate of hepatocellular carcinoma (HCC) occurrence is rising rapidly; however, outside of transplantation, few effective treatment options are available. Hepatocellular carcinogenesis is a complex, multistep process involving many genetic alterations, often occurring in targets that are considered “undruggable” by conventional therapeutic modalities. Antisense oligonucleotide (ASO) technology offers the potential to target these undruggable pathways in HCC tumors in vivo and to determine the sensitivity of HCC to the ablation of these pathways. Using either the diethylnitrosamine (DEN) induced mouse HCC model or DEN in combination with the profibrotic agent carbon tetrachloride (CCl4), we first examined gene expression changes in induced HCC tumors. DEN-induced HCC has a very long latency period (∼8 months). We demonstrate that mice injected with DEN and CCl4 developed HCC with a shorter latency and a higher tumor incidence. We also identified several genes of interest that could potentially be HCC drivers and targets for ASO therapy. Conjugation of ASOs with N-acetyl D-galactosamine (GalNAc) has been shown to increase ASO activity &amp;gt;10x in normal liver. Here we demonstrate that GalNAc conjugated ASOs show similar increased potency in HCC tumors and the complete depletion of Myd88 protein levels. Importantly, in addition to the ability to potently inhibit Myd88 levels in tumors, GalNAc-conjugated Myd88 ASOs also resulted in significantly reduced tumor burden. These data demonstrate that GalNAc-conjugated Gen 2.5 ASOs have potent activity in HCC tumors and that Myd88 maybe be an attractive therapeutic target in this disease. Citation Format: Joanna Schmidt, Minji Jo, Tianyuan Zhou, Youngsoo Kim, A. R. MacLeod. Characterization of GalNAc-conjugated generation 2.5 ASOs in DEN and DEN/CCL4-induced HCC tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4359. doi:10.1158/1538-7445.AM2015-4359
Acral melanocytic lesions in the United States: Prevalence, awareness, and dermoscopic patterns in skin-of-color and non-Hispanic white patients
Authors: Reshmi Madankumar, Priyanka V. Gumaste, Kathryn Martires, Panta R. Schaffer, Sonal Choudhary, Leyre Falto-Aizpurua, Harleen Arora, Penelope J. Kallis, Shailee Patel, Shadi Damanpour, Margaret I. Sanchez, Natalie Yin, Aegean Chan, Miguel Sanchez, David Polsky, Holly Kanavy, James M. Grichnik, Jennifer A. Stein
Journal: Journal of the American Academy of Dermatology (2016)
Clinical application of three-dimensional conformal partial breast external-beam irradiation after breast-conserving surgery in China
Authors: J. B. Li, T. Fan, J. Lu, Z. Ma
Journal: Journal of Clinical Oncology (2008)

11591 Background: At present, partial breast irradiation has been applied for the patients treated by breast-conserving treatment; this study is designed to explore the methods, dosimetric features and short effects of partial breast irradiation carried out by three-dimensional external-beam irradiation assisted by active breathing control (ABC). Methods: Computerized tomography (CT) simulation assisted by active breathing control (ABC) was finished for each patient enrolled to get CT images in condition of 75% deepest inspiration named moderate deep inspiration breath hold (mDIBH). The extent labeled by the silver slips located in the cavity was delineated as gross target volume (GTV), GTV plus the margin of 15mm was defined planning target volume (PTV). Noncoplanar radiation with four three-dimensional conformal fields was employed, the described dose was 34Gy/10f/5d. The percentage of PTV accounted for the affected whole breast, the percentages of PTV included by 100%, 95% and 90% isodose curve, the percentage of volume of the affected breast irradiated by 34Gy, 27.2Gy, 20.4Gy, 13.6Gy and 6.8Gy, and Dmean, D20, D10, D5, V20, V10, V5 of the lungs and heart were calculated respectively. The cosmetic effect of the breast after radiotherapy were appraised. Local tumor control and 1, 2, 3 year survival rate were followed. Results: The mean of the volume covered by 90% isodose curve accounted for 92.54% of the PTV; the volume irradiated by 34Gy (100% of described dose) accounted for 17.23% (mean) of the whole breast and 6.8Gy (20% of described dose) for 46.11%, in other words, the volume covered by 20% of described dose was less than 50% of the whole breast. The Dmean, D5, V20 for affected lateral lung were 1.97Gy, 9.25Gy and 1.58%, it was 0.20Gy, 0.87Gy, and 0% for unaffected lateral lung. The Dmean, D5, V20 for the heart were 0.65Gy, 2.82Gy, and 0.85%. Cosmetic effect was appraised and satisfaction defined as excellent or good appearance of the irradiated breasts for all of the patients. No recurrence of local tumor for all of the patients followed for one year, 1, 2 and 3 year tumor-free survival rates were all 100%. Conclusions: For selected patients with early breast cancer after breast-conserving surgery, 3DCPBI assisted by ABC is feasible in China. No significant financial relationships to disclose.
Targeting the epigenome: A phase I/II study of vorinostat (SAHA), cladribine (2-CdA), and rituximab in relapsed B-cell malignancies.
Authors: S. E. Spurgeon, C. Y. Okada, J. Huang, J. Phillips, E. E. Epner
Journal: Journal of Clinical Oncology (2010)

TPS301 Background: Epigenetic modifications are important to cancer pathogenesis. Thus, better defining the role of epigenetic therapeutic approaches in B-cell malignancies is paramount. Cladribine combined with rituximab is an effective treatment for many B-cell malignancies. In addition to its cytotoxic effects, recent evidence suggests that cladribine has DNA hypomethylating activity. Vorinostat is a histone deacetylase inhibitor and has clinical activity in some lymphomas and is FDA approved for use in cutaneous T cell lymphoma. To explore epigenetic modifications as a means for improving therapeutic efficacy, while defining potential epigenetic targets, we have initiated a phase I/II trial combining vorinostat, cladribine, and rituximab for the treatment of relapsed B-cell malignancies. Methods: A standard 3x3 dose escalation phase I trial is used to determine the vorinostat MTD. Vorinostat is administered orally on days 1-14 (200 mg, 300 mg, or 400 mg) in combination with 2-CdA 5 mg/m2 IV on days 1-5, and rituximab 375 mg/m2 IV on days 3, 10, 17, and 24 with cycle 1 and then on Day 3 with subsequent cycles. Cycles are repeated every 28 days for up to 6 cycles. Patients with relapsed/refractory B-cell malignancies including non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL) are eligible for phase I. After vorinostat MTD determination, phase II will enroll an additional 40 patients including patients with 1) newly diagnosed mantle cell lymphoma or 2) newly diagnosed CLL. Primary outcome is response rate. Secondary outcomes include overall survival (OS) and progression-free survival (PFS). Currently, 8 patients have been enrolled on study. Blood and/or tumor samples are collected prior to, during, and after therapy for correlative studies and include: global DNA methylation, quantitative analysis of CD20 expression, histone acetylation, total gene microarray analysis, and Q- PCR of potential target genes. Chi-square testing will be used to compare objective response and DNA methylation and/or histone deacetylation status and the log-rank test will be used to compare PFS and OS and DNA methylation and/or histone deacetylation. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck
Tolerability results from the first study of the novel oral prenyl transferase inhibitor AZD3409 in human volunteers
Authors: D. Smethurst, A. Holt, T. Parry, A. Lindsay, D. Wilson, A. Hughes
Journal: Journal of Clinical Oncology (2004)

3177 Background: AZD3409 is a novel, oral prenyl transferase inhibitor that has potential broad antitumor activity both as monotherapy and in combination with other anticancer treatments. It is a double pro-drug that is metabolized to a thiol-ester intermediate and then, intracellularly, to a thiol-acid active species. In preclinical studies, AZD3409 achieves up to 90% inhibition of FTase in tumors at well tolerated doses. In enzyme studies AZD3409 is also known to inhibit GGTase-1. Here we report preliminary results of the tolerability assessments conducted during a single ascending dose study of AZD3409 in healthy human volunteers. Methods: Cohorts of a maximum of 8 healthy male volunteers, with replacements allowed, were dosed at each dose level (6 active, 2 placebo) in a randomized, double-blind, alternating panel design. Single oral doses of 20 to 2500 mg were administered through 9 dose modifications over three months. Once MTD was defined an additional 3 lower doses were investigated. Each volunteer received a maximum of 3 active doses with a 3-week washout between doses. Volunteers were monitored for vital signs, ECGs, clinical chemistry, haematology and urinalysis and adverse events for 21 days after each dose. Data are still blinded and analysis is ongoing. Results: Three cohorts of volunteers aged 20 to 58 years were recruited. The maximum tolerated single dose of AZD3409 was 1750 mg. There were no clinically significant changes in laboratory parameters, heart rate, blood pressure or ECG recordings. Adverse events considered possibly related to AZD3409 were orthostatic hypotension and paraesthesia (both at 500 mg), diarrhea (1750 mg), and nausea, diarrhea, abdominal pain and dizziness (all at 2500 mg). Diarrhea was established as the dose-limiting toxicity, and was associated with nausea, vomiting, abdominal pain and dizziness at the highest dose level (2500 mg); however, it was of short duration and resolved spontaneously. Conclusions: Based on these results, single doses of AZD3409 up to 1750 mg are considered well tolerated in a healthy volunteer setting and the tolerability data are not preclusive to further work. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca