scholarly journals Drug Resistance Mutations and Associated Phenotypes Detected in Clinical Trials of Maribavir for Treatment of Cytomegalovirus Infection

2020 ◽  
Author(s):  
Sunwen Chou ◽  
Kening Song ◽  
Jingyang Wu ◽  
Tien Bo ◽  
Clyde Crumpacker
Keyword(s):  
Clinical Trials ◽  
Drug Susceptibility ◽  
Asymptomatic Infection ◽  
Response To Therapy ◽  
Low Grade ◽  
Resistance Mutations ◽  
Cmv Infection ◽  
Days Of Therapy ◽  
Polymerase Inhibitor ◽  
Ganciclovir Resistance

Abstract Background In separate phase 2 trials, 120 patients received maribavir for cytomegalovirus (CMV) infection failing conventional therapy (trial 202) and 119 received maribavir for asymptomatic infection (trial 203). Overall, 172 cleared their CMV infection (CMV DNA <200 copies/mL) within 6 weeks. Methods Baseline and posttreatment plasma samples were tested for mutations in viral genes UL97, UL54, and/or UL27. Selected viral mutants were phenotyped for drug susceptibility. Results Baseline samples revealed UL54 mutations newly phenotyped as conferring resistance to standard DNA polymerase inhibitor(s), including K493N, P497S, K513T, L565V, V823A, A987V, and E989D. Of 29 patients (including 25 from trial 202) who cleared but later experienced recurrent CMV infection while on maribavir, 23 had available UL97 genotyping data; 17 had known resistance mutations (T409M or H411Y) and 5 additional had UL97 C480F alone. The newly phenotyped mutation C480F conferred high-grade maribavir resistance and low-grade ganciclovir resistance. Among 25 who did not respond to >14 days of therapy, 9 showed T409M or H411Y and 4 others showed C480F alone. Conclusions After maribavir therapy (400–1200 mg twice daily), UL97 mutations T409M, H411Y, or C480F emerge to confer maribavir resistance in patients with recurrent CMV infection while on therapy or no response to therapy. Clinical Trials Registration NCT01611974 and EudraCT 2010-024247-32.

scholarly journals Importance of the Genetic Diversity within the Mycobacterium tuberculosis Complex for the Development of Novel Antibiotics and Diagnostic Tests of Drug Resistance

2012 ◽  
Vol 56 (12) ◽  
pp. 6080-6087 ◽  
Author(s):  
Claudio U. Köser ◽  
Silke Feuerriegel ◽  
David K. Summers ◽  
John A. C. Archer ◽  
Stefan Niemann
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Clinical Trials ◽  
Mycobacterium Tuberculosis ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Resistance Mutations ◽  
Content Type ◽  
Phenotypic Methods ◽  
Multiple Antibiotics

ABSTRACTDespite being genetically monomorphic, the limited genetic diversity within theMycobacterium tuberculosiscomplex (MTBC) has practical consequences for molecular methods for drug susceptibility testing and for the use of current antibiotics and those in clinical trials. It renders some representatives of MTBC intrinsically resistant against one or multiple antibiotics and affects the spectrum and consequences of resistance mutations selected for during treatment. Moreover, neutral or silent changes within genes responsible for drug resistance can cause false-positive results with hybridization-based assays, which have been recently introduced to replace slower phenotypic methods. We discuss the consequences of these findings and propose concrete steps to rigorously assess the genetic diversity of MTBC to support ongoing clinical trials.

Effect of coronavirus disease in patients with kidney disease in India

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 1255-1259
Author(s):  
Shashi Prabha Singh ◽  
Preeti Sharma ◽  
Durgesh singh ◽  
Pradeep kumar ◽  
Rakesh Sharma ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Clinical Trials ◽  
Kidney Disease ◽  
Meta Analysis ◽  
Tertiary Care ◽  
Type Ii Diabetes Mellitus ◽  
Asymptomatic Infection ◽  
Type Ii ◽  
Cardiorespiratory Failure ◽  
Inflammatory State

Coronavirus disease 19 is a global pandemic which infects over millions of people worldwide in a limited time and changes the lifestyle, clinical spectrum lies from asymptomatic infection to pneumonitis with cardiorespiratory failure and finally death. Higher mortality occurs in senior and who are suffering from co-morbidities like chronic kidney disease, (HTN) hypertension, (DM TYPE II) diabetes mellitus or (CVD) cardiovascular diseases. However, rather than normal individuals, patients with chronic kidney disease (CKD) are under higher risk for infections. The chronic systemic inflammatory state is a significant cause for morbidity and mortality in CKD patients. The objective of this review is to discuss the pathogenesis of COVID-19 in CKD, changes observed in the immune system of CKD patients, COVID-19 infections risk in CKD and therapeutic approach of COVID-19 in CKD patients. From the standpoint of frequent renal co-morbidities in covid19 patients, renal complications were explored in covid19 patients received at level 2 tertiary care Santosh Hospital, Ghaziabad, U.P. Delhi-NCR India during March to August 2020 as per the protocol of Nephrology Society of India. Relevant clinical trials were reviewed in support. Meta-analysis and clinical trials are covered in this review study. Duplicate studies are not taken into account. The outcome of the studies shows that CKD patients are more prone to COVID-19. CKD patients are more likely infected with COVID-19 virus. Whereas in intensive care, CKD occurs more frequent than DM type II and CVD. So,COVID-19 pathogenesis in CKD patients, risk of COVID-19, immunologic changes and therapy COVID-19 in CKD can add support in the effective management of COVID-19.

PD-L1 Inhibitors for the Treatment of Prostate Cancer

2020 ◽  
Vol 21 (15) ◽  
pp. 1558-1565
Author(s):  
Matteo Santoni ◽  
Francesco Massari ◽  
Liang Cheng ◽  
Alessia Cimadamore ◽  
Marina Scarpelli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
T Lymphocytes ◽  
Chronic Inflammation ◽  
Immune Cells ◽  
Response To Therapy ◽  
Complex Series

The carcinogenesis of prostate cancer (PCa) results from a complex series of events. Chronic inflammation and infections are crucial in this context. Infiltrating M2 type macrophages, as well as neutrophils and T lymphocytes, contribute to PCa development, progression and response to therapy. The preliminary findings on the efficacy of immunotherapy in patients with PCa were not encouraging. However, a series of studies investigating anti-PD-L1 agents such as Atezolizumab, Avelumab and Durvalumab used alone or in combination with other immunotherapies, chemotherapy or locoregional approaches are in course in this tumor. In this review, we illustrate the role of immune cells and PD-L1 expression during PCa carcinogenesis and progression, with a focus on ongoing clinical trials on anti-PD-L1 agents in this context.

scholarly journals Prevalence of UL97 gene mutations and polymorphisms in cytomegalovirus infection in the colon associated with or without ulcerative colitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Satoshi Tamura ◽  
Satoshi Osawa ◽  
Natsuki Ishida ◽  
Takahiro Miyazu ◽  
Shinya Tani ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Gene Mutations ◽  
Pcr Amplification ◽  
Kinase Domain ◽  
Resistance Mutations ◽  
Cmv Infection ◽  
Nested Polymerase Chain Reaction ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Ul97 Gene

AbstractCytomegalovirus (CMV) reactivation in the colon is common in patients with severe ulcerative colitis (UC). Ganciclovir (GCV) resistance conferring CMV UL97 gene mutations have been reported in recent years. However, the prevalence of UL97 gene mutations in GCV-naive CMV infection in the colon remains unknown. We investigated the prevalence of CMV UL97 gene mutations in patients with colonic CMV infection associated with or without UC. Twenty-two GCV-naive patients with colonic CMV infection, 15 with UC and 7 with other diseases, were enrolled. Frozen biopsy samples or formalin-fixed paraffin-embedded samples were used for nested polymerase chain reaction (PCR) amplification of the UL97 gene. Sanger DNA sequencing was performed. In comparison with AD169 reference strain, natural polymorphisms were frequently detected in codons N68D (100%), I244V (100%), and D605E (86.4%). Seven polymorphisms were detected infrequently (< 10%) outside the kinase domain. However, no known GCV resistance mutations were found. There seemed to be no difference between the ratio of polymorphisms in patients with and without UC. In conclusions, we did not detect UL97 gene mutations associated with GCV resistance in GCV-naive patients with or without UC. Consistent with previous reports, D605E polymorphism may be used as a genetic marker for CMV in East Asian countries.

scholarly journals A 25-year retrospective, single center analysis of 343 WHO grade II/III glioma patients: implications for grading and temozolomide therapy

2021 ◽  
Author(s):  
Eike Steidl ◽  
Katharina Filipski ◽  
Pia S. Zeiner ◽  
Marlies Wagner ◽  
Emmanouil Fokas ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Molecular Markers ◽  
Treatment Time ◽  
Real Life ◽  
Patient Characteristics ◽  
Low Grade ◽  
Who Grade ◽  
Idh1 R132h ◽  
Treatment Data ◽  
Grade Ii

Abstract Purpose Classification and treatment of WHO grade II/III gliomas have dramatically changed. Implementing molecular markers into the WHO classification raised discussions about the significance of grading and clinical trials showed overall survival (OS) benefits for combined radiochemotherapy. As molecularly stratified treatment data outside clinical trials are scarce, we conducted this retrospective study. Methods We identified 343 patients (1995–2015) with newly diagnosed WHO grade II/III gliomas and analyzed molecular markers, patient characteristics, symptoms, histology, treatment, time to treatment failure (TTF) and OS. Results IDH-status was available for all patients (259 mutant, 84 IDH1-R132H-non-mutant). Molecular subclassification was possible in 173 tumors, resulting in diagnosis of 80 astrocytomas and 93 oligodendrogliomas. WHO grading remained significant for OS in astrocytomas/IDH1-R132H-non-mutant gliomas (p < 0.01) but not for oligodendroglioma (p = 0.27). Chemotherapy (and temozolomide in particular) showed inferior OS compared to radiotherapy in astrocytomas (median 6.1/12.1 years; p = 0.03) and oligodendrogliomas (median 13.2/not reached (n.r.) years; p = 0.03). While radiochemotherapy improved TTF in oligodendroglioma (median radiochemotherapy n.r./chemotherapy 3.8/radiotherapy 7.3 years; p < 0.001/ = 0.06; OS data immature) the effect, mainly in combination with temozolomide, was weaker in astrocytomas (median radiochemotherapy 6.7/chemotherapy 2.3/radiotherapy 2.0 years; p < 0.001/ = 0.11) and did not translate to improved OS (median 8.4 years). Conclusion This is one of the largest retrospective, real-life datasets reporting treatment and outcome in low-grade gliomas incorporating molecular markers. Current histologic grading features remain prognostic in astrocytomas while being insignificant in oligodendroglioma with interfering treatment effects. Chemotherapy (temozolomide) was less effective than radiotherapy in both astrocytomas and oligodendrogliomas while radiochemotherapy showed the highest TTF in oligodendrogliomas.

Lessons learned from randomised clinical trials in adult low grade glioma

2005 ◽  
Vol 6 (4) ◽  
pp. 240-244 ◽  
Author(s):  
Michael A Papagikos ◽  
Edward G Shaw ◽  
Volker W Stieber
Keyword(s):  
Clinical Trials ◽  
Lessons Learned ◽  
Low Grade Glioma ◽  
Randomised Clinical Trials ◽  
Low Grade

scholarly journals 18F-FDOPA PET/MRI for monitoring early response to bevacizumab in children with recurrent brain tumors

2017 ◽  
Vol 5 (1) ◽  
pp. 28-36 ◽  
Author(s):  
Karen Gauvain ◽  
Maria Rosana Ponisio ◽  
Amy Barone ◽  
Michael Grimaldi ◽  
Ephraim Parent ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Antiangiogenic Therapy ◽  
Standardized Uptake Value ◽  
Progression Free Survival ◽  
Early Response ◽  
Metabolic Tumor Volume ◽  
Pediatric Brain Tumors ◽  
Initial Study ◽  
Response To Therapy ◽  
Low Grade

Abstract Background Noninvasively predicting early response to therapy in recurrent pediatric brain tumors provides a challenge. 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine (18F-FDOPA) PET/MRI has not been previously studied as a tool to evaluate early response to antiangiogenic therapy in children. The purpose of this study was to evaluate the safety and feasibility of using 18F-FDOPA PET/MRI to assess response to bevacizumab in children with relapsed brain tumors. Materials and Methods Six patients with recurrent gliomas (5 low-grade, 1 high-grade) planned to undergo treatment with bevacizumab were enrolled. 18F-FDOPA PET/MRI scans were obtained prior to and 4 weeks following the start of treatment, and these were compared with the clinical response determined at the 3-month MRI. The primary PET measure was metabolic tumor volume (MTV) at 10 to 15 min after 18F-FDOPA injection. For each tumor, the MTV was determined by manually defining initial tumor volumes of interest (VOI) and then applying a 1.5-fold threshold relative to the mean standardized uptake value (SUV) of a VOI in the frontal lobe contralateral to the tumor. Results 18F-FDOPA PET/MRI was well tolerated by all patients. All tumors were well visualized with 18F-FDOPA on the initial study, with peak tumor uptake occurring approximately 10 min after injection. Maximum and mean SUVs as well as tumor-to-brain ratios were not predictors of response at 3 months. Changes in MTVs after therapy ranged from 23% to 98% (n = 5). There is a trend towards the percent MTV change seen on the 4-week scan correlating with progression-free survival. Conclusion 18F-FDOPA PET/MRI was well tolerated in pediatric patients and merits further investigation as an early predictor of response to therapy.

scholarly journals Increase in post-therapy tumor calcification on CT scan is not an indicator of response to therapy in low-grade serous ovarian cancer

2016 ◽  
Vol 41 (8) ◽  
pp. 1589-1595 ◽  
Author(s):  
Dhakshinamoorthy Ganeshan ◽  
Priya Bhosale ◽  
Wei Wei ◽  
Preetha Ramalingam ◽  
Eniola Mudasiru-Dawodu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ct Scan ◽  
Response To Therapy ◽  
Low Grade ◽  
Serous Ovarian Cancer ◽  
Post Therapy

scholarly journals Low-grade Serous Ovarian Carcinoma

2018 ◽  
Vol 78 (10) ◽  
pp. 972-976 ◽  
Author(s):  
Enzo Ricciardi ◽  
Thaïs Baert ◽  
Beyhan Ataseven ◽  
Florian Heitz ◽  
Sonia Prader ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Ovarian Carcinoma ◽  
Systemic Treatment ◽  
Hormonal Treatment ◽  
Current Treatment ◽  
Low Grade ◽  
Separate Entity ◽  
Serous Ovarian Carcinoma ◽  
Number Of Patients

AbstractIn the early 2000s a two-tier grading system was introduced for serous ovarian cancer. Since then, we have increasingly come to accept that low-grade serous ovarian carcinoma (LGSOC) is a separate entity with a unique mutational landscape and clinical behaviour. As less than 10% of serous carcinomas of the ovary are low-grade, they are present in only a small number of patients in clinical trials for ovarian cancer. Therefore the current treatment of LGSOC is based on smaller trials, retrospective series, and subgroup analysis of large clinical trials on ovarian cancer. Surgery plays a major role in the treatment of patients with LGSOC. In the systemic treatment of LGSOC, hormonal treatment and targeted therapies seem to play an important role.

scholarly journals Biomarkers in Bladder Cancer Surveillance

2021 ◽  
Vol 8 ◽  
Author(s):  
Sukumar S. Sugeeta ◽  
Anand Sharma ◽  
Kenrick Ng ◽  
Arvind Nayak ◽  
Nikhil Vasdev
Keyword(s):  
Bladder Cancer ◽  
Clinical Trials ◽  
Prospective Studies ◽  
Urine Cytology ◽  
Cancer Surveillance ◽  
Invasive Bladder Cancer ◽  
Low Grade ◽  
Protein Biomarkers ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

Aim: This is a narrative review with an aim to summarise and describe urinary biomarkers in the surveillance of non-muscle-invasive bladder cancer (NMIBC). It provides a summary of FDA-approved protein biomarkers along with emerging ones which utilise genetic, epigenetic and exosomal markers. We discuss the current limitations of the available assays.Background: Current guidelines advice a combination of cystoscopy, imaging,and urine cytology in diagnosis and surveillance. Although cytology has a high specificity, it is limited by low sensitivity particularly in low grade tumours. There are six FDA-approved urinary assays for diagnosis and surveillance of bladder cancer. They have shown to improve sensitivity and specificity to be used alongside cytology and cystoscopy but have a lower specificity in comparison to cytology and false positives often occur in benign conditions. Recent developments in laboratory techniques has allowed for use of markers which are RNA-, DNA-based as well as extracellular vesicles in the past decade.Methods: Using the PubMed/Medline search engines as well as Google Scholar, we performed an online search using the terms “bladder cancer,” “non-muscle invasive bladder cancer,” and “urine biomarkers” with filter for articles in English published up to May 2021. Systematic reviews and original data of clinical trials or observational studies which contributed to the development of the biomarkers were collated.Results: Biomarkers identified were divided into FDA-approved molecular biomarkers, protein biomarkers and gene-related biomarker with a table summarising the findings of each marker with the most relevant studies. The studies conducted were mainly retrospective. Due to the early stages of development, only a few prospective studies have been done for more recently developed biomarkers and limited meta-analyses are available.Therefore a detailed evaluation of these markers are still required to decide on their clinical use.Conclusion: Advancements of analytical methods in BC has driven the research towards non-invasive liquid-based biomarkers in adjunct to urine cytology. Further large prospective studies are required to determine its feasibility in a clinical setting as they are not effective when used in isolation as they have their limitation. With the ongoing pandemic, other than reduction in costs and increased accuracy, the need for biomarkers to cope with delay in cystoscopies in diagnosis and surveillance is crucial. Thus clinical trials with direct comparison is required to improve patient care.

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