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Annals of Oncology : Official Journal... Aug 2022'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and...
BACKGROUND
'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. Understanding SD would facilitate drug development and improve precision in correlative research.
PATIENTS AND METHODS
A systematic review was carried out to characterize SD in ICI trials. SD and objective response were compared to proliferation index using The Cancer Genome Atlas gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of non-small-cell lung cancer (NSCLC). Serial cutpoints of two variables, % best overall response and progression-free survival (PFS), were tested to define a subgroup of patients with SD with similar survival as responders. Results were then tested in external validation cohorts.
RESULTS
Among trials of ICIs (59 studies, 14 280 patients), SD ranged from 16% to 42% in different tumor types and was associated with disease-specific proliferation index (ρ = -0.75, P = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of NSCLC [1220 patients, 313 (26%) with SD to ICIs], PFS ranged widely in SD (0.2-49 months, median 4.9 months). The subset with PFS >6 months and no tumor growth mirrored partial response (PR) minor (overall survival hazard ratio 1.0) and was proposed as the definition of SD responder. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab and found to apply in tumor types treated with immunotherapy in which depth and duration of benefit were correlated.
CONCLUSIONS
RECIST-defined SD to immunotherapy is common, heterogeneous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS >6 months and no tumor growth may be considered 'SD responders'. This definition may improve the efficiency of and insight derivable from clinical and translational research.
Topics: Antineoplastic Agents, Immunological; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms
PubMed: 35533926
DOI: 10.1016/j.annonc.2022.04.450 -
Kidney International Reports Feb 2023Posttransplant disease recurrence is a feared and severe complication in children with steroid resistant nephrotic syndrome (SRNS), but little is known about its...
INTRODUCTION
Posttransplant disease recurrence is a feared and severe complication in children with steroid resistant nephrotic syndrome (SRNS), but little is known about its incidence. Recent data suggest relapse is exceptional in patients with genetic SRNS, and initial steroid sensitivity may represent a risk factor for recurrence.
METHODS
Systematic review and meta-analysis were performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to describe the post-transplant relapse rate among children with SRNS; as well as the association between recurrence and all potential risk factors, including the presence of causative genetic mutations, initial steroid sensitivity, underlying histology, and gender. The inclusion criteria were as follows: (i) children with SRNS who are undergoing kidney transplant, (ii) available data on post-transplant recurrence, (iii) no patient selection according to the underlying histology, (iv) available data on genetic testing, and (v) prospective or retrospective cohort design.
RESULTS
Of the 5818 records identified, 8 studies including 581 children with SRNS met the inclusion criteria. Overall posttransplant recurrence rate was 39% (95% confidence interval [CI] 34%-44%). No genetic patient relapsed, whereas the recurrence rate in patients with no causative genetic mutation identified was 61% (95% CI 53%-69%). Children with initial steroid sensitivity were at a higher risk for recurrence with a 1.91 relative risk (RR) (95% CI 1.48-2.46) compared with those with primary SRNS (PSRNS). Gender and histology did not significantly affect relapse rate.
CONCLUSION
Post-transplant recurrence is a common event in children with idiopathic non-genetic SRNS, complicating the clinical course in over 60% of patients. The presence of a causative genetic mutation virtually excludes a recurrence. Initial steroid sensitivity is the only other significant risk factor, doubling the risk of relapse.
PubMed: 36815113
DOI: 10.1016/j.ekir.2022.10.030 -
Microbiological Research Jun 2023Innumerable pathogens including RNA viruses have catastrophic pandemic propensity, in turn, SARS-CoV-2 infection is highly contagious. Emergence of SARS-CoV-2 variants... (Review)
Review
Innumerable pathogens including RNA viruses have catastrophic pandemic propensity, in turn, SARS-CoV-2 infection is highly contagious. Emergence of SARS-CoV-2 variants with high mutation rate additionally codifies infectious ability of virus and arisen clinical imputations to human health. Although, our knowledge of mechanism of virus infection and its impact on host system has been substantially demystified, uncertainties about the emergence of virus are still not fully understood. To date, there are no potentially curative drugs are identified against the viral infection. Even though, drugs are repurposed in the initial period of infection, many are significantly negative in clinical trials. Moreover, the infection is dependent on organ status, co-morbid conditions, variant of virus and geographic region. This review article aims to comprehensively describe the SARS-CoV-2 infection and the impacts in the host cellular system. This review also briefly provides an overview of genome, proteome and metabolome associated risk to infection and the advancement of therapeutics in SARS-CoV-2 infection management.
Topics: Humans; COVID-19; SARS-CoV-2; Antiviral Agents; Mutation Rate
PubMed: 36989761
DOI: 10.1016/j.micres.2023.127364 -
Cureus Jun 2022Erdheim Chester disease (ECD) is a type of histiocytosis characterized by a variable clinical presentation. The treatment of ECD is complex and mainly unknown. We aim to... (Review)
Review
Erdheim Chester disease (ECD) is a type of histiocytosis characterized by a variable clinical presentation. The treatment of ECD is complex and mainly unknown. We aim to conduct a literature review of the treatment of ECD and consolidate the knowledge about the most recent and updated treatment for ECD. To conduct the systematic review, we used the preferred reporting items for systematic reviews and meta-analysis (PRISMA) protocol. To analyze the bias, we used the Cochrane collaboration risk-of-bias tool to assess the bias. We included observational studies and clinical trials on humans, which were written in English. Papers not fulfilling the objective of our study were excluded. Overall, the drug showed efficacy in the clinical trials, showing prolonged improvement and high rates of response rate. Overall, the drug was not well tolerated, and patients had a long list of side effects. Nevertheless, the drug seems to be a good option for second-line treatment for patients with ECD and BRAFV600 mutation.
PubMed: 35844342
DOI: 10.7759/cureus.25935 -
Annals of Clinical Microbiology and... Aug 2023The emergence of multidrug-resistant (MDR) strains of genital pathogens, notably Mycoplasma genitalium and Ureaplasma spp., constitutes a significant global threat... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The emergence of multidrug-resistant (MDR) strains of genital pathogens, notably Mycoplasma genitalium and Ureaplasma spp., constitutes a significant global threat today. The present study aimed to evaluate the prevalence and trend of changes in MDR mycoplasma and ureaplasma strains.
METHODS
An exhaustive search was performed across the ISI Web of Science, PubMed, Scopus, ScienceDirect, and Google Scholar databases to accumulate relevant studies without restrictions until April 2023. We used event rate and corresponding 95% confidence intervals to determine the frequency of resistance-related mutations and examine the trend of antibiotic resistance changes.
RESULTS
The data from 27 studies, including 24,662 patients across 14 countries, were evaluated. Out of the total studies, 20 focused on M. genitalium infections, and five on Ureaplasma spp. The frequency of resistance-associated mutations to macrolides, tetracyclines, and fluoroquinolones in clinical strains of M. genitalium was 43.5%, 13.1%, and 18.6%, respectively. The prevalence of M. genitalium strains with double resistance and MDR was 11.0% and 17.4%, respectively. The incidence of both double-drug-resistant and MDR strains was higher in the World Health Organization (WHO) Western Pacific Region than in European and American populations. For Ureaplasma strains, resistance-associated mutations to macrolides, tetracyclines, and fluoroquinolones were 40.8%, 25.7%, and 90.3%, respectively. The rate of antibiotic resistance was higher in the African population compared to the European and WHO Western Pacific Regions. The rate of MDR Ureaplasma infections was 13.2%, with a higher incidence in the African population compared to the WHO Western Pacific and European regions.
CONCLUSION
The proliferation and spread of MDR Mycoplasma and Ureaplasma strains present a significant public health challenge. The situation is indeed alarming, and the rising trend of MDR M. genitalium and MDR Ureaplasma infections suggests that therapies involving macrolides and fluoroquinolones may become less effective.
Topics: Humans; Mycoplasma; Mycoplasma Infections; Ureaplasma Infections; Mycoplasma hominis; Anti-Bacterial Agents; Ureaplasma; Fluoroquinolones; Tetracyclines; Macrolides; Mutation; Prevalence
PubMed: 37563660
DOI: 10.1186/s12941-023-00627-6 -
European Journal of Medical Research Feb 2022To determine the effect of polymorphisms and mutations in angiotensin-converting enzyme 2 (ACE2) and Type 2 transmembrane serine proteases (TMPRSS2) genes on...
OBJECTIVE
To determine the effect of polymorphisms and mutations in angiotensin-converting enzyme 2 (ACE2) and Type 2 transmembrane serine proteases (TMPRSS2) genes on susceptibility to corona virus disease 2019 (COVID-19) and patient prognosis.
INTRODUCTION
From December 2019 to the current time, an outbreak of epidemic of COVID-19, characterized by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has occurred around the world. It is now clear that SARS-CoV-2 binds to human ACE2 receptors, with expression of these receptors correlated with the rate of SARS-CoV-2 infection and mortality. Polymorphisms in individual patient factors, such as ACE2 and TMPRSS2 genes have been linked with an increase in negative outcomes, although evidence to affirm remains debatable.
METHODS
Here, we performed a systematic review, based on guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, with the aim of assessing whether polymorphisms in ACE2 and TMPRSS2 genes affect the COVID-19 condition. We extensively searched PubMed, MEDLINE, Embase, the Cochrane Library, and Web of Science databases, for relevant articles and reports published in English between December 2019 and December 2021.
RESULTS
A total of 495 full-text articles were downloaded, of which 185 were excluded after preliminary examination as they were duplicates. Finally, 310 articles were evaluated, by reading their titles and abstracts, and 208 of them eliminated based on our selection criteria. Finally, 33 articles met our inclusion criteria and were included in the final assessment. Genetic data from 33,923 patients with COVID-19 drawn from the general population and deriving from over 160 regions and 50 countries, as well as approximately 560,000 samples from global-public genetic databases, were included in our analysis. Ultimately, we identified 10 SNPs and 21 mutations in the ACE2 gene, along with 13 SNPs and 12 variants in the TMPRSS2 gene, which may be associated with COVID-19.
CONCLUSIONS
ACE2 and TMPRSS2 play vital roles in the onset, development, and prognosis of SARS-CoV-2 infection, and have both been strongly associated with vulnerability, intensity, and the clinical result of COVID-19. Overall, these genetic factors may have potential for future development of personalized drugs and vaccines against COVID-19.
TRIAL REGISTRATION
CRD42021239400 in PROSPERO 2021.
Topics: Angiotensin-Converting Enzyme 2; COVID-19; Genetic Predisposition to Disease; Humans; Mutation; Polymorphism, Single Nucleotide; SARS-CoV-2; Serine Endopeptidases
PubMed: 35193695
DOI: 10.1186/s40001-022-00647-6 -
Frontiers in Pharmacology 2023According to the 2023 guidelines for treating non-small-cell lung cancer (NSCLC), first-line treatment and recently developed agents for the treatment of epidermal...
Comparison of the efficacy and safety of first-line treatments for of advanced EGFR mutation-positive non-small-cell lung cancer in Asian populations: a systematic review and network meta-analysis.
According to the 2023 guidelines for treating non-small-cell lung cancer (NSCLC), first-line treatment and recently developed agents for the treatment of epidermal growth factor (EGFR) mutation-positive locally advanced or metastatic NSCLC were compared in this meta-analysis. Treatment regimens involved in the included studies included first, second, and third-generation tyrosine kinase inhibitors (TKIs), TKIs plus chemotherapy, TKIs plus angiogenesis inhibitors, and platinum-containing doublet chemotherapy with or without bevacizumab. Considering the varying efficacy and safety of drugs in people of different ethnic origins, the optimal regimen should be determined, and the safety of first-line treatments should be assessed in the Asian population specifically. PubMed, Embase, the Cochrane Library, Web of Science, and the China National Knowledge Infrastructure (CNKI) were systematically searched to retrieve reports on randomized controlled trials (RCTs) with research data published from inception to 1 February 2023. Adopting Asian patient populations as the target (including studies in which Asian patients accounted for more than 50% of the sample), a network meta-analysis (NMA) was conducted for comparison of treatment regimens and treatments were ranked based on the surface under the cumulative ranking curve (SUCRA). A total of 19 RCTs involving 5,824 patients and covering 14 treatment regimens were included. The primary outcome measure examined in this study was progression-free survival (PFS); other outcome measures examined were overall survival (OS), disease control rate (DCR), objective response rate (ORR), occurrence of any adverse events (AE), occurrence of adverse events of grade 3 or above (≥3AE), and occurrence of serious adverse events (SAE). In terms of PFS, all regimens including TKIs (as a monotherapy or in combination with other therapies), as well as bevacizumab (Bev) plus chemotherapy (Ch) were found to be significantly superior to basic chemotherapy (HRs: 0.09-0.61, < 0.05 in all cases compared with Ch alone). The highest-ranking therapies were erlotinib (Erl) plus Bev (SUCRA: 0.94) and Erl plus ramucirumab (Ram) (SUCRA: 0.93). Regarding OS, no significant differences was observed between first-line treatment strategies; the top four treatments based on SUCRA, in rank order, were Bev + Ch (0.87), gefitinib (Gef) plus Ch (0.81), dacomitinib (Dac) (0.79), and osimertinib (Osi) (0.69). Additionally, there were no significant differences between first-line treatment strategies in terms of DCR. Regarding ORR, the top three treatments based on SUCRA were Erl + Bev (0.85), Erl + Ram (0.76), and Gef + Ch (0.74). No significant difference between first-line treatment strategies was observed in terms of the risk of AE. However, based on SUCRA, Erl ranked highest on avoidance of ≥ 3AE (0.97), and Osi ranked highest on avoidance of SAE (0.91). Based on these analyses of survival benefits, tumor burden response, and safety, furmonertinib (Fur), Osi, and aumolertinib (Aum) may represent the best treatment regimen options for Asian patients, significantly prolonging survival (as measured by median PFS/OS), eliciting a greater tumor burden response, and exposing patients to a lower risk of adverse events. Although Erl + Bev and Erl + Ram are associated with the best survival benefits in terms of PFS, further clinical studies are still needed to identify ways to reduce the risk of adverse events. https://www.crd.york.ac.uk/prospero/display_record.php? ID=CRD42023407994, identifier CRD42023407994.
PubMed: 37484016
DOI: 10.3389/fphar.2023.1212313 -
RSC Advances Mar 2022The novel human coronavirus pandemic is one of the most significant occurrences in human civilization. The rapid proliferation and mutation of Severe Acute Respiratory... (Review)
Review
The novel human coronavirus pandemic is one of the most significant occurrences in human civilization. The rapid proliferation and mutation of Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) have created an exceedingly challenging situation throughout the world's healthcare systems ranging from underdeveloped countries to super-developed countries. The disease is generally recognized as coronavirus disease 2019 (COVID-19), and it is caused by a new human CoV, which has put mankind in jeopardy. COVID-19 is death-dealing and affects people of all ages, including the elderly and middle-aged people, children, infants, persons with co-morbidities, and immunocompromised patients. Moreover, multiple SARS-CoV-2 variants have evolved as a result of genetic alteration. Some variants cause severe symptoms in patients, while others cause an unusually high infection rate, and yet others cause extremely severe symptoms as well as a high infection rate. Contrasting with a previous epidemic, COVID-19 is more contagious since the spike protein of SARS-CoV-2 demonstrates profuse affection to angiotensin-converting enzyme II (ACE2) that is copiously expressed on the surface of human lung cells. Since the estimation and tracking of viral loads are essential for determining the infection stage and recovery duration, a quick, accurate, easy, cheap, and versatile diagnostic tool is critical for managing COVID-19, as well as for outbreak control. Currently, Reverse Transcription Polymerase Chain Reaction (RT-PCR) testing is the most often utilized approach for COVID-19 diagnosis, while Computed Tomography (CT) scans of the chest are used to assess the disease's stages. However, the RT-PCR method is non-portable, tedious, and laborious, and the latter is not capable of detecting the preliminary stage of infection. In these circumstances, nano-biosensors can play an important role to deliver point-of-care diagnosis for a variety of disorders including a wide variety of viral infections rapidly, economically, precisely, and accurately. New technologies are being developed to overcome the drawbacks of the current methods. Nano-biosensors comprise bioreceptors with electrochemical, optical, or FET-based transduction for the specific detection of biomarkers. Different types of organic-inorganic nanomaterials have been incorporated for designing, fabricating, and improving the performance and analytical ability of sensors by increasing sensitivity, adsorption, and biocompatibility. The particular focus of this review is to carry out a systematic study of the status and perspectives of synthetic routes for nano-biosensors, including their background, composition, fabrication processes, and prospective applications in the diagnosis of COVID-19.
PubMed: 35424900
DOI: 10.1039/d2ra01293f -
Medicina (Kaunas, Lithuania) Apr 2020and are associated with many cancer types in addition to hereditary breast and ovarian cancers. However, their relation to lung cancer remains to be explored.... (Review)
Review
and are associated with many cancer types in addition to hereditary breast and ovarian cancers. However, their relation to lung cancer remains to be explored. Observation studies were systematically reviewed to explore the association of or with lung cancer. PubMed, MEDLINE [EBSCOhost], and relevant articles published up to 7 January 2020 were searched. Odd ratio (OR), standardized morbidity rate (SMR), and cancer-specific standardized incidence ratios (SIRs) were pooled together as relative risk (RR) estimates (95% confidence interval [CI], 0.66-1.40). Thirteen studies were included for analysis. Results showed that the RR of is 0.76 (95% CI, 0.48-1.19), the overall RR is 0.96 (95% CI, 0.66-1.40), and that of is 0.66 (95% CI, 0.41-1.05), indicating that it was not associated with lung cancer. With the limitation of the retrospective study design and severe heterogeneity, these results inform clinicians and relevant families that and mutation carriers have no increased risk of lung cancer.
Topics: Adult; Aged; BRCA1 Protein; BRCA2 Protein; Female; Genetic Predisposition to Disease; Humans; Incidence; Lung Neoplasms; Mass Screening; Middle Aged; Odds Ratio; Retrospective Studies
PubMed: 32349445
DOI: 10.3390/medicina56050212 -
Frontiers in Immunology 2022Duvelisib is the first FDA-approved oral dual inhibitor of phosphatidylinositol-3-kinase PI3K-delta (PI3K-δ) and PI3K-gamma (PI3K-γ). Although many clinical studies... (Meta-Analysis)
Meta-Analysis
Safety and efficacy of dual PI3K-δ, γ inhibitor, duvelisib in patients with relapsed or refractory lymphoid neoplasms: A systematic review and meta-analysis of prospective clinical trials.
BACKGROUND
Duvelisib is the first FDA-approved oral dual inhibitor of phosphatidylinositol-3-kinase PI3K-delta (PI3K-δ) and PI3K-gamma (PI3K-γ). Although many clinical studies support the efficacy of duvelisib, the safety of duvelisib remains with great attention. This systematic review and meta-analysis aimed to evaluate the safety and efficacy of duvelisib in treating different relapsed or refractory (RR) lymphoid neoplasm types.
METHODS
We searched prospective clinical trials from PUBMED, EMBASE, Cochrane Library, and ClinicalTrials.gov. For efficacy analysis, Overall response rate (ORR), complete response rate (CR), partial response rate (PR), rate of stable disease (SDR), rate of progressive disease (PDR), median progression-free survival (mPFS), 12-/24-month PFS, and 12-month overall survival (OS) were assessed. For safety analysis, the incidences of any grade and grade ≥3 adverse events (AEs), serious AEs, and treatment-related discontinuation and death were evaluated. Subgroup analysis based on the disease type was performed.
RESULTS
We included 11 studies and 683 patients, including 305 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 187 B-cell indolent non-Hodgkin lymphoma (iNHL), 39 B-cell aggressive non-Hodgkin lymphoma (aNHL), and 152 T-cell non-Hodgkin lymphoma (T-NHL) patients. The pooled ORR in CLL/SLL, iNHL, aNHL and T-NHL was 70%, 70%, 28% and 47%, respectively. Additionally, the pooled ORR in CLL/SLL patients with or without TP53 mutation/17p-deletion (62% vs. 74%, p=0.45) and in follicular lymphoma (FL) or other iNHL (69% vs. 57%, p=0.38) had no significant differences. Mantle cell lymphoma (MCL) patients had higher pooled ORR than other aNHL (68% vs. 17%, p=0.04). Angioimmunoblastic TCL (AITL) patients had higher pooled ORR than other PTCL patients (67% vs. 42%, p=0.01). The pooled incidence of any grade, grade ≥3, serious AEs, treatment-related discontinuation and death was 99%, 79%, 63%, 33% and 3%, respectively. The most frequent any-grade AEs were diarrhea (47%), ALT/AST increase (39%), and neutropenia (38%). The most frequent grade ≥3 AEs were neutropenia (25%), ALT/AST increased (16%), diarrhea (12%), and anemia (12%).
CONCLUSION
Generally, duvelisib could offer favorable efficacy in patients with RR CLL/SLL, iNHL, MCL, and AITL. Risk and severity in duvelisib treatment may be mitigated through proper identification and management.
Topics: Humans; Adult; Phosphatidylinositol 3-Kinases; Leukemia, Lymphocytic, Chronic, B-Cell; Prospective Studies; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Lymphoma, B-Cell; Neutropenia; Diarrhea
PubMed: 36685572
DOI: 10.3389/fimmu.2022.1070660