scholarly journals An Evaluation of the Diagnostic Accuracy of a Panel of Variants in DPYD and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1497
Author(s):  
Claire Palles ◽  
Susan Fotheringham ◽  
Laura Chegwidden ◽  
Marie Lucas ◽  
Rachel Kerr ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Diagnostic Accuracy ◽  
Dihydropyrimidine Dehydrogenase ◽  
Area Under The Curve ◽  
Toxicity Tests ◽  
Serious Adverse Events ◽  
Significant Toxicity ◽  
Good Diagnostic Accuracy ◽  
High Level

Efficacy of 5-Fluorouracil (5-FU)-based chemotherapy is limited by significant toxicity. Tests based upon variants in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines with high level evidence of a link to dihydropyrimidine dehydrogenase (DPD) phenotype and 5-FU toxicity are available to identify patients at high risk of severe adverse events (AEs). We previously reported associations between rs1213215, rs2612091, and NM_000110.3:c.1906-14763G>A (rs12022243) and capecitabine induced toxicity in clinical trial QUASAR 2. We also identified patients with DPD deficiency alleles NM_000110.3: c.1905+1G>A, NM_000110.3: c.2846C>T, NM_000110.3:c.1679T>G and NM_000110.3:c.1651G>A. We have now assessed the frequency of thirteen additional DPYD deficiency variants in 888 patients from the QUASAR 2 clinical trial. We also compared the area under the curve (AUC)—a measure of diagnostic accuracy—of the high-level evidence variants from the CPIC guidelines plus and minus additional DPYD deficiency variants and or common variants associated with 5-FU toxicity. Including additional DPYD deficiency variants retained good diagnostic accuracy for serious adverse events (AEs) and improved sensitivity for predicting grade 4 haematological toxicities (sensitivity 0.75, specificity 0.94) but the improvement in AUC for this toxicity was not significant. Larger datasets will be required to determine the benefit of including additional DPYD deficiency variants not observed here. Genotyping two common alleles statistically significantly improves AUC for prediction of risk of HFS and may be clinically useful (AUC difference 0.177, sensitivity 0.84, specificity 0.31).

Value of Fibrinogen to Discriminate Appendicitis from Nonspecific Abdominal Pain in Preschool Children

2019 ◽  
Vol 30 (04) ◽  
pp. 357-363
Author(s):  
Javier Gómez-Veiras ◽  
Ángel Salgado-Barreira ◽  
José Luis Vázquez ◽  
Margarita Montero-Sánchez ◽  
José Ramón Fernández-Lorenzo ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Preschool Children ◽  
Diagnostic Accuracy ◽  
Prothrombin Time ◽  
Characteristic Curve ◽  
Area Under The Curve ◽  
Diagnostic Value ◽  
Suspected Appendicitis ◽  
Uncomplicated Appendicitis ◽  
Good Diagnostic Accuracy

Introduction The aim of this study was to assess the diagnostic value of the biomarker fibrinogen (FB), along with the markers white blood cell (WBC) count, absolute neutrophil count (ANC), and C-reactive protein (CRP), to discriminate appendicitis from nonspecific abdominal pain (NSAP) in preschool children. Materials and Methods We prospectively evaluated all children aged <5 years admitted for suspected appendicitis at an academic pediatric emergency department during 5 years. Diagnostic accuracy of FB (prothrombin time–derived method), WBC, ANC, and CRP were assessed by the area under the curve (AUC) of the receiver-operating characteristic curve. Results A total of 82 patients were enrolled in the study (27 NSAP, 17 uncomplicated, and 38 complicated appendicitides). WBC and ANC had moderate diagnostic accuracy for appendicitis versus NSAP (WBC: AUC 0.66, ANC: AUC 0.67). CRP and FB had good diagnostic accuracy for appendicitis versus NSAP (CRP: AUC 0.78, FB: AUC 0.77). WBC and ANC are not useful to discriminate complicated versus uncomplicated appendicitis (WBC: AUC 0.43, ANC: AUC 0.45). CPR and FB had good diagnostic accuracy for complicated versus uncomplicated appendicitis (CRP: AUC 0.80, FB: AUC 0.73). Conclusion CRP and FB are more useful than WBC and ANC to discriminate appendicitis from NSAP in preschool children. CRP and FB are especially useful to discriminate complicated from uncomplicated appendicitis and NSAP. In a child with suspected appendicitis, a plasma FB level (prothrombin time–derived method) >540 mg/dL is associated with an increased likelihood of complicated appendicitis.

Phase II Trial of Standard Dose Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) and Rituximab (R-CHOP) Plus Bevacizumab for Advanced Stage Diffuse Large B-Cell (DLBCL) NHL: Southwest Oncology Group Study S0515

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 591-591 ◽  
Author(s):  
Alison T. Stopeck ◽  
Joseph M Unger ◽  
Lisa M. Rimsza ◽  
Brent Farnsworth ◽  
Michael LeBlanc ◽  
...  
Keyword(s):  
Adverse Events ◽  
Standard Dose ◽  
Immunohistochemical Analysis ◽  
Patient Characteristics ◽  
Tissue Microarrays ◽  
Left Ventricular ◽  
Serious Adverse Events ◽  
Significant Toxicity ◽  
Southwest Oncology Group Study ◽  
Grade 3

Abstract Abstract 591 Introduction: VEGF and VEGF receptors (VEGFR) are frequently over-expressed in DLBCL. Elevated levels of circulating VEGF have also been associated with a worse prognosis and resistance to chemotherapy. This trial was initiated to determine if the addition of anti-VEGF targeted therapy to standard R-CHOP would improve PFS without adding significant toxicity in previously untreated patients with stage III, IV or bulky stage II DLBCL. Methods: 64 eligible patients were treated with standard dose R-CHOP plus bevacizumab administered at 15mg/kg on day1. Patients received therapy every 21 days for a maximum of 8 cycles. Both biologics were administered prior to chemotherapy. Pretreatment tumor biopsies from 40 patients were submitted for construction of tissue microarrays for VEGF/VEGFR immunohistochemical analysis. Two 1 mm tissue cores were assessed for each DLBCL specimen and expression of VEGF and VEGFR scored on a scale of 0 (no expression) to +3 (strong expression) by 2 pathologists. Both lymphoma and endothelial cell (blood vessel) staining was assessed with the higher score being recorded. Results: 73 patients were enrolled with 9 patients found ineligible, the majority (n = 7) secondary to incorrect histology. Patient characteristics for the 64 eligible patients included: median age 68 years with 77% of the patients over 60 years (age range: 22–85), 44 males, IPI scores: 3 low, 22 low-intermediate, 29 high-intermediate, and 8 high. Median follow-up is 2.0 years. Based on prior studies, and adjusted for the observed IPI factor frequencies seen in this study, the projected 1 year historical PFS rate in this population would be 71%, while the observed 1 year PFS estimate was 77% (95% CI: 66 – 87%). The PFS estimate at 2-years was 69% (95% CI: 57 – 80%). The 1 and 2 year overall survival estimates were 86% and 79%, respectively. Among all patients (including ineligibles), a total of 30 patients experienced 40 serious adverse events (SAE) while on study. The majority of SAE were hematologic, but also included 2 patients with sudden death, 5 patients with GI perforations (4 occurring after cycle 1), and 5 patients with grade 3 or 4 thrombotic events. Additional adverse events of interest included 7 patients who developed hypertension (4 patients with grade 3), and 13 patients who developed grade 2 or 3 left ventricular dysfunction. VEGF expression was observed in 98% (IHC scoring: +1 in 18%, +2 in 38%, and +3 in 43%) of lymphoma cells and VEGFR was expressed in 95% (IHC scoring:+1 in 28%, +2 in 40%, and +3 in 28%) of blood vessels by immunohistochemistry analysis. Conclusions: Despite high protein expression of VEGF and VEGFR in newly diagnosed DLBCL specimens, the addition of bevacizumab to standard R-CHOP chemotherapy did not significantly improve PFS from expected results with R-CHOP alone. Although the observed 1-year PFS estimate trended higher than the historical estimate, a target PFS of 81% was pre-specified as warranting further investigation. Significant toxicities were associated with the addition of bevacizumab, including an increased incidence of cardiac dysfunction and GI perforation. Our results do not support additional studies of this regimen in this patient population. Disclosures: Stopeck: Genentech: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Bevacizumab therapy in NHL. Fisher:Roche: Consultancy.

Results of the ADRRAD Trial of pelvic IMRT plus radium-223 in men with mHSPC metastatic to bone.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 136-136
Author(s):  
Joe O'Sullivan ◽  
Philip Geoffrey Turner ◽  
Suneil Jain ◽  
Arthur Grey ◽  
Sandra Biggart ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Phase 1 ◽  
Palliative Radiotherapy ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Pelvic Radiotherapy ◽  
Serious Adverse Events ◽  
Radium 223

136 Background: Radiotherapy to the Prostate in mHSPC improves overall survival (OS) and Progression free survival (PFS) for patients with low-volume-disease[1]. Radium-223 in metastatic castration resistant prostate cancer (mCRPC) improves OS [2]. We conducted a prospective phase 1/2 clinical trial in mHSPC, testing the combination of with LHRHa, concurrent pelvic radiotherapy and radium-223. Methods: Thirty patients were recruited with mHSPC; they had a minimum of 3 bone metastases (majority had > 20 bone mets), nil visceral metastases, PS0-1. Patients were encouraged to receive up front docetaxel. They were treated with ongoing LHRHa, pelvic radiotherapy aiming for 74Gy in 37 fractions to prostate PTV with 60Gy concomitantly delivered to pelvic nodal PTV. Concurrently, patients received radium-223, 55kBq/kg for 6 cycles q28 days; fraction 1 radiotherapy was synchronous with cycle 1 day 1 radium-223. Results: Median age was 63 years and 28 (93%) received at least 4 cycles of docetaxel. One patient received prostate only radiotherapy due to bowel constraints. Three patients had cycle 6 radium-223 omitted. At a median follow-up of 28 months, there have been 415 Adverse events, (3% Grade >3), and 6 serious adverse events (SAEs) ( 2 episodes of UTI, 1 each of cystitis non-infective, cardiac chest pain, pyrexia and AKI). Commonest AEs by number were: leucopenia, neutropenia, and diarrhoea. Ten SSE’s have occurred including 8 courses of palliative radiotherapy for bone pain, 1 course of radiotherapy for impending MSCC and 1 pathological fracture. At median follow up 28.0 months, median biochemical PFS is 17.9 months, median OS not yet reached. Conclusions: This trial shows clear tolerability and promising early efficacy data requiring further exploration in a randomised phase 3 trial. Clinical trial information: 2014-000273-39.

scholarly journals Nonrandomized Controlled Trial of Artesunate plus Sulfadoxine-Pyrimethamine with or without Primaquine for Preventing Posttreatment Circulation of Plasmodium falciparum Gametocytes

2013 ◽  
Vol 57 (7) ◽  
pp. 2948-2954 ◽  
Author(s):  
Naman K. Shah ◽  
Allan Schapira ◽  
Jonathan J. Juliano ◽  
Bina Srivastava ◽  
Pia D. M. MacDonald ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Single Dose ◽  
Adverse Events ◽  
Antimalarial Drug ◽  
Controlled Trial ◽  
Artemisinin Combination Therapy ◽  
Area Under The Curve ◽  
Serious Adverse Events ◽  
Gametocyte Density ◽  
Content Type

ABSTRACTArtemisinin combination therapies eliminate immaturePlasmodium falciparumgametocytes but not mature gametocytes, which may persist for up to 1 month posttreatment. A single dose of primaquine, which is inexpensive and effective against mature gametocytes, could be added to further reduce the potential for posttreatment parasite transmission. Currently, we have few data regarding the effectiveness or safety of doing so. We collected data from 21 therapeutic efficacy trials of the National Antimalarial Drug Resistance Monitoring System of India conducted during 2009 to 2010, wherein 9 sites used single-dose primaquine (0.75 mg/kg of body weight) administered on day 2 along with artesunate plus sulfadoxine-pyrimethamine (AS+SP) while 12 did not. We estimated the effect of primaquine on posttreatment gametocyte clearance and the total number of gametocyte-weeks as determined by microscopy. We compared the median area under the curve for gametocyte density and reported adverse events. One thousand three hundred thirty-five patients completed the antimalarial drug treatment. Adjusting for region, primaquine increased the rate of gametocyte clearance (hazard ratio, 1.9; 95% confidence interval [CI], 1.1 to 3.3), prevented 45% (95% CI, 19 to 62) of posttreatment gametocyte-weeks, and decreased the area under the gametocyte density curve over the 28-day follow-up compared to AS+SP alone (Pvalue = 0.01). The results were robust to other adjustment sets, and the estimated effect of primaquine increased during sensitivity analysis on the measurement of exposure time. No serious adverse events were detected. In conclusion, the addition of primaquine to AS+SP was effective in reducing the posttreatment presence ofP. falciparumgametocytes. Primaquine was well tolerated and could be administered along with an artemisinin combination therapy as the first-line therapy.

Sustained physical activity in peripheral artery disease: Associations with disease severity, functional performance, health-related quality of life, and subsequent serious adverse events in the LITE randomized clinical trial

2021 ◽  
pp. 1358863X2198943
Author(s):  
Joshua T Slysz ◽  
W. Jack Rejeski ◽  
Diane Treat-Jacobson ◽  
Lydia A Bazzano ◽  
Daniel E Forman ◽  
...  
Keyword(s):  
Physical Activity ◽  
Clinical Trial ◽  
Adverse Events ◽  
Peripheral Artery Disease ◽  
Longitudinal Analyses ◽  
Peripheral Artery ◽  
Serious Adverse Events ◽  
Cross Sectional ◽  
Sf 36 ◽  
Artery Disease

This study investigated cross-sectional associations of peripheral artery disease (PAD) severity (defined by the ankle–brachial index (ABI)) and amounts of daily sustained physical activity (PA) (defined as > 100 activity counts per minute lasting 5 consecutive minutes or more). This study also investigated associations of amounts of daily sustained PA with 6-minute walk (6MW) distance and the Short Form-36 physical functioning domain (SF-36 PF) score in cross-sectional analyses and with serious adverse events (SAEs) in longitudinal analyses of people with PAD. PA was measured continuously for 10 days using a tri-axial accelerometer at baseline in 277 participants with PAD randomized to the LITE clinical trial. In regression analyses, each 0.15 lower ABI value was associated with a 5.67% decrease in the number of daily bouts of sustained PA (95% CI: 3.85–6.54; p < 0.001). Every additional bout of sustained PA per day was associated with a 4.56-meter greater 6MW distance (95% CI: 2.67–6.46; p < 0.0001), and a 0.81-point improvement in SF-36 PF score (95% CI: 0.34–1.28; p < 0.001). Participants with values of daily bouts of sustained PA below the median had higher rates of SAEs during follow-up, compared to participants above the median (41% vs 24%; p = 0.002). In conclusion, among participants with PAD, lower ABI values were associated with fewer bouts of daily sustained PA. A greater number of bouts of daily sustained PA were associated with better 6MW performance and SF-36 PF score, and, in longitudinal analyses, lower rates of SAEs. Clinicaltrials.gov ID: NCT02538900.

119 A Descriptive Epidemiological Study of Clinical Trials, Comparing Trials Targeted At Older People to Adults of All Ages

2021 ◽  
Vol 50 (Supplement_1) ◽  
pp. i12-i42
Author(s):  
J P Renton ◽  
D McAllister
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Adverse Events ◽  
Older People ◽  
Exclusion Criterion ◽  
Trial Participation ◽  
Exclusion Criteria ◽  
Eligibility Criteria ◽  
Serious Adverse Events ◽  
Icd 10

Abstract Introduction Fewer clinical trials are carried out in older people. It is unclear how representative and applicable clinical trials carried out exclusively in older people are. We compared clinical trials recruiting older people exclusively “older trials” to those recruiting adults of all ages “all age trials”, using anti-hypertensives acting on the renin-angiotensin aldosterone system (RAAS drugs) as an exemplar. Method We searched the US clinical trials register 1, to identify all trials carried out exclusively in those aged over 60. From these we selected trials of RAAS drugs. These were matched in a 2:1 ratio to trials carried out in adults of all ages. Data regarding baseline characteristics, adverse events and eligibility criteria were collected from clinical trial reports and clinicaltrials.gov. Estimated associations were calculated for age, sex and adverse events. Eligibility criteria were described and ICD- 10 coded, as appropriate. Results 71 clinical trials were carried out exclusively in older people.13 related to RAAS drugs. Participants in “Older trials” had higher mean age (73.1 and 55.9 respectively), mean difference 16.17 (CI 15.31–17.02). Older trials had fewer male participants. Participants in older trials had lower mean body mass index (BMI). A higher rate of participants in older trials experienced serious adverse events. (2.07, CI 1.55–2.75.) Few older trials had upper age limits (23.1% V 27% all age trials). All trials had exclusion criteria in multiple ICD blocks. Concurrent medications were a more common exclusion criterion in older trials (61.5% v 40.9%). Conclusions Clinical trials carried out exclusively in older people are representative in terms of age, serious adverse events and eligibility. Although there are multiple exclusion criteria for clinical trial participation in both groups, this is not prohibitive. This supports carrying out more trials exclusively in older people. References 1. NIH, US national library of medicine.ClinicalTrials.gov Available at https://clinicaltrials.gov/

scholarly journals Dynamic Ultrasonographic Measurement of Inferior Joint Cap-Sule Thickness in Patients with Unilateral Frozen Shoulder

Diagnostics ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 898
Author(s):  
Jun-Gyu Lee ◽  
Hyung-Sun Peo ◽  
Jang-Hyuk Cho ◽  
Chul-Hyun Cho ◽  
Don-Kyu Kim ◽  
...  
Keyword(s):  
Diagnostic Accuracy ◽  
Glenohumeral Joint ◽  
Frozen Shoulder ◽  
Area Under The Curve ◽  
Diagnostic Value ◽  
Neutral Position ◽  
Anterior Axillary Line ◽  
Linear Transducer ◽  
The Us ◽  
Good Diagnostic Accuracy

The diagnostic value of ultrasonography (US) for frozen shoulder (FS) is not well established. This study aimed to assess the diagnostic value of US measurement of inferior joint capsule (IJC) thickness and evaluate changes in the thickness of the IJC by US depending on arm position. A total of 71 patients with clinically diagnosed unilateral FS who underwent bilateral US measurement of the IJC were enrolled in this study. The US measurement of the IJC was performed with a linear transducer positioned around the anterior axillary line with the shoulder 40° abducted and with neutral rotation of the glenohumeral joint (neutral position). We also measured the IJC thickness in the externally rotated and internally rotated positions with the shoulder 40° abducted. In the neutral position, as well as in the internally rotated and externally rotated positions, the thickness of the IJC on US was significantly higher in the affected shoulder than that in the unaffected shoulder (all p < 0.001). On both the affected and unaffected sides, the US thickness of the IJC in the neutral position was significantly higher than that in the externally rotated position (p < 0.001), but lower than that in the internally rotated position (p < 0.001). Regarding IJC thickness in the neutral position, a 3.2-mm cutoff value yielded the highest diagnostic accuracy for FS, with a sensitivity and specificity of 73.2% and 77.5%, respectively. The area under the curve for IJC thickness was 0.824 (95% confidence interval, 0.76–0.89). US measurement of the IJC in the neutral position yielded good diagnostic accuracy for FS. Because IJC thickness is affected by arm rotation, it is important to measure the IJC thickness in a standardized posture to ensure diagnostic value.

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