Background In cervical cancer, presence of lymph-node macrometastases (MAC) is a major prognostic factor and an indication for adjuvant treatment. However, since clinical impact of micrometastases (MIC) and isolated tumor-cells (ITC) remains controversial, we sought to identify a cut-off value for the metastasis size not associated with negative prognosis. Methods We analyzed data from 967 cervical cancer patients (T1a1L1-T2b) registered in the SCCAN (Surveillance in Cervical CANcer) database, who underwent primary surgical treatment, including sentinel lymph-node (SLN) biopsy with pathological ultrastaging. The size of SLN metastasis was considered a continuous variable and multiple testing was performed for cut-off values of 0.01–1.0 mm. Disease-free survival (DFS) was compared between N0 and subgroups of N1 patients defined by cut-off ranges. Results LN metastases were found in 172 (18%) patients, classified as MAC, MIC, and ITC in 79, 54, and 39 patients, respectively. DFS was shorter in patients with MAC (HR 2.20, P = 0.003) and MIC (HR 2.87, P < 0.001), while not differing between MAC/MIC (P = 0.484). DFS in the ITC subgroup was neither different from N0 (P = 0.127) nor from MIC/MAC subgroups (P = 0.449). Cut-off analysis revealed significantly shorter DFS compared to N0 in all subgroups with metastases ≥0.4 mm (HR 2.311, P = 0.04). The significance of metastases <0.4 mm could not be assessed due to limited statistical power (<80%). We did not identify any cut-off for the size of metastasis with significantly better prognosis than the rest of N1 group. Conclusions In cervical cancer patients, the presence of LN metastases ≥0.4 mm was associated with a significant negative impact on DFS and no cut-off value for the size of metastasis with better prognosis than N1 was found. Traditional metastasis stratification based on size has no clinical implication.
Stereotactic body radiotherapy is a recent promising therapeutic alternative in cases of failed catheter ablation for recurrent ventricular tachycardias (VTs) in patients with structural heart disease. Initial clinical experience with a single radiation dose of 25 Gy shows reasonable efficacy in the reduction of VT recurrences with acceptable acute toxicity. Many unanswered questions remain, including unknown mechanism of action, variable time to effect, optimal method of substrate targeting, long-term safety, and definition of an optimal candidate for this treatment."
OTUD1 is a deubiquitinating enzyme involved in many cellular processes including cancer and innate, immune signaling pathways. Here, we perform a proximity labeling-based interactome study that identifies OTUD1 largely present in the translation and RNA metabolism protein complexes. Biochemical analysis validates OTUD1 association with ribosome subunits, elongation factors and the E3 ubiquitin ligase ZNF598 but not with the translation initiation machinery. OTUD1 catalytic activity suppresses polyA triggered ribosome stalling through inhibition of ZNF598-mediated RPS10 ubiquitination and stimulates formation of polysomes. Finally, analysis of gene expression suggests that OTUD1 regulates the stability of rare codon rich mRNAs by antagonizing ZNF598.
Introduction: The aim of this study was to present the indications for a combined endoscopic transnasal and sublabial transantral approach for the surgical treatment of orbital lesions. Material and methods: This case study enrolled 10 patients scheduled for endoscopic transnasal surgery for treating orbital lesions from 2009 to 2020. When the tumour was localised to the medial part of the orbit, patients underwent endoscopy with a transnasal mononostril approach. Alternatively, when the tumour was localised to the mediocaudal part of the orbit, and when instrument manoeuvreability was limited, the transnasal approach was combined with a sublabial transantral approach. Herein, we evaluate the indications, complications, and advantages of monoportal and combined two-portal approaches. Results: 8/10 patients (80%) underwent surgery with the transnasal mononostril approach, and 2/10 (20%) underwent surgery with the combined transnasal mononostril and sublabial transantral approach. In the two latter cases, visualisation of the operation field was excellent, and there was adequate room for manipulating instruments. Conclusions: The combined mononostril-transantral approach provided the space necessary to manoeuvre instruments and to visualise the surgical field in treating mediocaudal orbital lesions. Clinical implications: This two-portal approach enables extensive resections of intraconal lesions. It should be considered to be a suitable and safer alternative to the binostril approach.
Citation: Dobiáš, R.; Jaworská, P.; Skopelidou, V.; Strakoš, J.; Višňovská, D.; Káňová, M.; Škríba, A.; Lysková, P.; Bartek, T.; Janíčková, I.; et al. Distinguishing Invasive from Chronic Pulmonary Infections: Host Pentraxin 3 and Fungal Siderophores in Bronchoalveolar Lavage Fluids. J. Fungi 2022, 8, 1194. https://doi. Abstract: The multiple forms of pulmonary aspergillosis caused by Aspergillus species are the most common respiratory mycoses. Although invasive, the analysis of diagnostic biomarkers in bron-choalveolar lavage fluid (BALF) is a clinical standard for diagnosing these conditions. The BALF samples from 22 patients with proven or probable aspergillosis were assayed for human pentraxin 3 (Ptx3), fungal ferricrocin (Fc), and triacetylfusarinine C (TafC) in a retrospective study. The infected group included patients with invasive pulmonary aspergillosis (IPA) and chronic aspergillosis (CPA). The BALF data were compared to a control cohort of 67 patients with invasive pulmonary mucormy-cosis (IPM), non-Aspergillus colonization, or bacterial infections. The median Ptx3 concentrations in patients with and without aspergillosis were 4545.5 and 242.0 pg/mL, respectively (95% CI, p < 0.05). The optimum Ptx3 cutoff for IPA was 2545 pg/mL, giving a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 100, 98, 95, and 100%, respectively. The median Ptx3 concentration for IPM was high at 4326 pg/mL. Pentraxin 3 assay alone can distinguish IPA from CPA and invasive fungal disease from colonization. Combining Ptx3 and TafC assays enabled the diagnostic discrimination of IPM and IPA, giving a specificity and PPV of 100%.
Serum monoclonal immunoglobulin (Ig) is the main diagnostic factor for patients with multiple myeloma (MM), however its prognostic potential remains unclear. On a large MM patient cohort (n = 4146), we observe no correlation between serum Ig levels and patient survival, while amount of intracellular Ig has a strong predictive effect. Focused CRISPR screen, transcriptional and proteomic analysis identify deubiquitinase OTUD1 as a critical mediator of Ig synthesis, proteasome inhibitor sensitivity and tumor burden in MM. Mechanistically, OTUD1 deubiquitinates peroxiredoxin 4 (PRDX4), protecting it from endoplasmic reticulum (ER)-associated degradation. In turn, PRDX4 facilitates Ig production which coincides with the accumulation of unfolded proteins and higher ER stress. The elevated load on proteasome ultimately potentiates myeloma response to proteasome inhibitors providing a window for a rational therapy. Collectively, our findings support the significance of the Ig production machinery as a biomarker and target in the combinatory treatment of MM patients.
Background: The outcome of patients with simultaneous diagnosis of haematological malignancies (HM) and COVID-19 is unknown and there are no specific treatment guidelines. Methods: We describe the clinical features and outcome of a cohort of 450 patients with simultaneous diagnosis of HM and COVID-19 registered in the EPICOVIDEHA registry between March 2020 to February 2022. Results: Acute leukaemia and lymphoma were the most frequent HM (35.8% and 35.1%, respectively). Overall, 343 (76.2%) patients received treatment for HM, which was delayed for longer than one month since diagnosis in 57 (16.6%). An overall response rate was observed in 140 (40.8%) patients after the first line of treatment. After a median follow-up of 35 days, overall mortality was 177/450 (39.3%); 30-day mortality was significantly higher in patients not receiving HM treatment (42.1%) than in those receiving treatment (27.4%, p = 0.004), either before and/or after COVID-19, or compared to patients receiving HM treatment at least after COVID-19 (15.2%, p < 0.001). Age, severe/critical COVID-19, ≥2 comorbidities, and lack of HM treatment were independent risk factors for mortality, whereas a lymphocyte count >500/mcl at COVID-19 onset was protective. Conclusions: HM treatment should be delivered as soon as possible for patients with simultaneous diagnosis of COVID-19 and HM requiring immediate therapy.
Background: Serum neurofilaments (sNfs), especially the most investigated serum neurofilament light chain (sNfL), are promising biomarkers in multiple sclerosis (MS). However, their clinical utility is still limited, given the availability and costs of accessible analytical methods. The gold standard for the detection of sNfs is represented by the single molecule arrays (SIMOA). Recently, a high sensitivity enzyme-linked immunosorbent assay (hsELISA) has also been introduced. The objective of the study was to compare both assays for the determination of sNfL and neurofilament heavy chain (sNfH) concentrations in a defined MS cohort. The second objective was to identify contributing factors to sNfs concentrations determined by hsELISA. Methods: Serum samples were collected from MS patients attending the MS Centre, University Hospital Ostrava, Czech Republic. The levels of sNfs were detected using SIMOA and hsELISA assays. Results: The Spearman’s rank correlation coefficient between the sNfL SIMOA and sNfL hsELISA and between the sNfH SIMOA and sNfH hsELISA was moderate rs= 0.543 (p = 0.001) and rs= 0.583 (p = 0.001), respectively. The Passing-Bablok regression analysis demonstrated bias between both methods. Equally significant bias between the methods was confirmed by the Bland-Altman plots. Furthermore, confounding factors affecting the sNfL levels were glomerular filtration rate (eGFR; 95% CI -2.34 to -0.04) and sex (95% CI -2.38 to -0.10). The sNfH levels were affected by age (95% CI 0.01 to 0.07), eGFR (95% CI -2.45 to -0.02), body mass index (BMI; 95% CI -0.31 to -0.05), and blood volume (95% CI 0.69 to 3.35). Conclusion: This analytical study showed significant differences between hsELISA and SIMOA methods, especially for the sNfH concentrations. We identified confounding factors for sNfs levels determined by hsELISA. The sNfs levels were influenced by renal function and sex, whilst sNfH levels were affected by age, BMI, and total blood volume.
Abstract An evidence-based treatment for a Multiple Sclerosis (MS) relapse is an intravenous administration of 3–5 g of Methylprednisolone. In case of insufficient effect or corticosteroids intolerance, the therapeutic plasma exchange (TPE) is indicated. To assess the clinical effect of TPE in treatment of relapse in patients with relapsing-remitting MS (RRMS), we enrolled 155 patients meeting the following criteria (study period: January 2011 to February 2021): (1) age > 18, (2) RRMS according to the McDonald´s 2017 criteria, (3) MS relapse and insufficient effect of corticosteroids/corticosteroids intolerance, (4) baseline EDSS
Teriflunomide belongs to disease-modifying drugs and is used in treatment of multiple sclerosis. According to in vitro studies more than 99.4% of drug is binding to plasma proteins and only less than 1% is free for clinical activity. The rapid and simple ultra-performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS) was developed and validated for determination of total and free teriflunomide (TFM) in serum of patients with multiple sclerosis. To determine the total teriflunomide samples were precipitated with a precipitation reagent consisting of 11% solution of ZnSO4 in acetonitrile/methanol (40:60, v/v). To determine the free fraction of teriflunomide, an ultracentrifugation method was used. The analysis was performed on a UPLC system connected to a XEVO TQ-XS mass spectrometer. Chromatographic separation was carried out on an Acquity UPLC BEH C18 1.7 µm (100 ×2.1 mm) column heated to 30 °C and teriflunomide-D4 was used as an internal standard. Ionization was performed by electrospray in negative ion mode. The developed methods were validated according to the rules of the European Medicines Agency (EMA) for the analytical method validation of bioanalytical methods. The coefficients of variation were in the range of 0.53-14.84% and the recovery 97.92-108.33%, respectively. Share of free teriflunomide was 0.15-0.40% (mean 0.25 ± 0.05%) of total teriflunomide and there was a significant correlation between free and total teriflunomide r²= 0.9083 (p <0.0001). This newly developed method allows the rapid and easy determination of the teriflunomide concentration with high sensitivity and can be applied to clinical samples of patients with multiple sclerosis.
Purpose: Proteasome inhibitors are the backbone of various treatment regimens in Multiple Myeloma. We recently described the first in-patient point mutations affecting the 20S subunit PSMB5 underlying PI resistance. Notably, in vivo, the incidence of mutations in PSMB5 and other proteasome encoding genes is too low to explain the development of resistance in most of the affected patients. Thus, additional genetic and epigenetic alterations need to be explored. Methods: We performed DNA methylation profiling by Deep Bisulfite Sequencing (DBS) in PSMB5, PSMC2, PSMC5, PSMC6, PSMD1, and PSMD5, a subset of proteasome subunit that have hitherto been associated with PI resistance, recruited from our own previous research, the literature, or a meta-analysis on the frequency of somatic mutations. Methylation was followed up on gene expression level and by dual-luciferase reporter assay. The KMS11 cell line served as a model to functionally test the impact of demethylating agents. Results: We identified PSMD5 promoter hypermethylation and subsequent epigenetic gene silencing in 24% of PI refractory patients. Hypermethylation correlated with decreased expression and the regulatory impact of this region was functionally confirmed. In contrast, NDMM patients, along with PBMCs and CD138+ plasma cells from healthy donors, generally show unmethylated profiles. Conclusion: Under the selective pressure of PI treatment, MM cells acquire methylation of the PSMD5 promoter silencing the PSMD5 gene expression. PSMD5 acts as a key orchestrator of proteasome assembly and its downregulation was described to increase the cell's proteolytic capacity. PSMD5 hypermethylation, therefore, represents a novel mechanism of PI tolerance in Multiple Myeloma.
Introduction: Severe COVID-19 is associated with an important increase of von Willebrand factor and mild lowering of ADAMTS13 activity that may, in the presence of a strong inflammatory reaction, increase the risk of acute thrombotic thrombocytopenic purpura (TTP). Although acute episodes of immune-mediated TTP associated with COVID-19 or SARS-CoV-2 vaccination have been reported, data about clinical evolution of hereditary TTP (hTTP) during the pandemic are scarce. Method: We conducted a survey among adult patients of the International Hereditary TTP Registry about SARS-CoV-2 vaccination, COVID-19, and occurrence of acute hTTP episodes. Results: Of 122 adult hTTP patients invited to participate, 86 (70.5%) responded. Sixty-five had been vaccinated (75.6%), of which 14 had received in addition a booster, resulting in 139 individual vaccine shots. Although vaccinations in patients on plasma prophylaxis were done within 1 week of the last plasma infusion, all 23 patients treated with plasma on demand were vaccinated without prior plasma infusions. One patient on uninterrupted weekly plasma infusions presented within 3 days from his second vaccination with neurological symptoms and computed tomography scan 9 days later showed subacute ischemic/hemorrhagic frontal lobe infarction. A second male patient developed acute myocarditis after his second dose of mRNA-1273 vaccine. Twelve (14%) patients had COVID-19, associated with an acute hTTP episode in three of them: one patient had a transient ischemic attack, one a stroke, and a pregnant woman was hospitalized to intensify plasma treatment. Discussion: The risk of an acute episode triggered by COVID-19 seems higher than following vaccination in hTTP patients, who can be safely vaccinated against SARS-CoV-2.
Background and objectives: Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CS) and intravenous immunoglobulin (IVIG). This study was conducted to determine if immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent MG patients. Methods: In this randomized, double-blind, placebo-controlled trial, CS-dependent MG patients (MGFA class II-Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/day) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every three weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (QMG score ≥ 4 points from baseline). CS doses were increased (based on current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy endpoint (at week 39) was a ≥ 50% reduction in CS dose. Secondary and safety endpoints were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available at: ://clinicaltrials.gov/ct2/show/NCT02473965. Results: The primary endpoint (≥ 50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary endpoints. Safety data indicated that IGIV-C was well-tolerated. Discussion: In this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that effects of IGIV-C and CS are not synergistic and may be mechanistically different. Trial registration information: The trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) and clinicaltrials.gov (identifier NCT02473965). Classification of evidence: This study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥ 50% reduction in corticosteroid dose compared to placebo.
Background and objectives: Declines in stroke admission, intravenous thrombolysis, and mechanical thrombectomy volumes were reported during the first wave of the COVID-19 pandemic. There is a paucity of data on the longer-term effect of the pandemic on stroke volumes over the course of a year and through the second wave of the pandemic. We sought to measure the impact of the COVID-19 pandemic on the volumes of stroke admissions, intracranial hemorrhage (ICH), intravenous thrombolysis (IVT), and mechanical thrombectomy over a one-year period at the onset of the pandemic (March 1, 2020, to February 28, 2021) compared with the immediately preceding year (March 1, 2019, to February 29, 2020). Methods: We conducted a longitudinal retrospective study across 6 continents, 56 countries, and 275 stroke centers. We collected volume data for COVID-19 admissions and 4 stroke metrics: ischemic stroke admissions, ICH admissions, intravenous thrombolysis treatments, and mechanical thrombectomy procedures. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases. Results: There were 148,895 stroke admissions in the one-year immediately before compared to 138,453 admissions during the one-year pandemic, representing a 7% decline (95% confidence interval [95% CI 7.1, 6.9]; p<0.0001). ICH volumes declined from 29,585 to 28,156 (4.8%, [5.1, 4.6]; p<0.0001) and IVT volume from 24,584 to 23,077 (6.1%, [6.4, 5.8]; p<0.0001). Larger declines were observed at high volume compared to low volume centers (all p<0.0001). There was no significant change in mechanical thrombectomy volumes (0.7%, [0.6,0.9]; p=0.49). Stroke was diagnosed in 1.3% [1.31,1.38] of 406,792 COVID-19 hospitalizations. SARS-CoV-2 infection was present in 2.9% ([2.82,2.97], 5,656/195,539) of all stroke hospitalizations. Discussion: There was a global decline and shift to lower volume centers of stroke admission volumes, ICH volumes, and IVT volumes during the 1st year of the COVID-19 pandemic compared to the prior year. Mechanical thrombectomy volumes were preserved. These results suggest preservation in the stroke care of higher severity of disease through the first pandemic year. Trial registration information: This study is registered under NCT04934020.
Aim: To evaluate the incidence of ocular adverse events after loading phase of the brolucizumab therapy in patients with neovascular age-related macular degeneration (nAMD) in real-life clinical practice - in treatment-naive patients and in patients after switching from another anti-VEGF agent. Another aim was to evaluate treatment outcomes in patients with adverse events. Methods: This is a multicentre, retrospective, observational study from 16 application centres in the Czech Republic. Patients diagnosed with nAMD were treated with brolucizumab in a fixed regimen of loading phase (3 injections administered at one-month intervals) and the mean follow-up period was 120 ± 10 days after the first injection. The incidence of adverse events and the development of best corrected visual acuity (BCVA) and central retinal thickness (CRT) in patients with complications were evaluated. A total of 1,098 eyes were followed up, of which 783 were treatment-naive and 315 eyes were after switching from another anti-VEGF agent. Results: Adverse events were recorded in 42 eyes (3.83%), of which 30 eyes were treatment-naive (2.7%) and 12 eyes were post-switch (1.09%). The mean baseline BCVA ± SD was 56.7 ± 10.7 ETDRS chart letters in the group of patients with adverse events, 58.8 ± 10.1 letters in treatment-naive patients, and 51.4 ± 10.2 letters in patients after switch from another anti-VEGF agent. The mean baseline CRT ± SD was 432.2 ± 154.7 μm, being 435.8 ± 137.3 μm in treatment-naive patients and 424.5 ± 186.6 μm in patients after switch from another anti-VEGF agent. At the end of the follow-up, the mean BCVA ± SD was 53.4 ± 9.5 ETDRS charts letters in patients with adverse events, 55.6 ± 10 letters in treatment-naive patients, and 47.6 ± 10 letters in patients after switching from another anti-VEGF agent. The mean CRT ± SD at the end of the follow-up was 300.7 ± 115.7 μm in the total patient cohort, 285.2 ± 78.8 μm in treatment-naive patients and 334.5 ± 165.4 μm in patients after switching from another anti-VEGF agent. Conclusion: We observed the development of adverse events in the form of intraocular inflammation or vasculitis with subsequent decrease in BCVA in 3.83% of cases after loading phase of the brolucizumab therapy. The decrease in BCVA was reversible in most cases after initiation of anti-inflammatory steroid treatment. From a functional and morphological point of view, we did not demonstrate any statistically significant difference between the groups of treatment-naive patients and patients after switching from another anti-VEGF agent.
Introduction: In this study, we measured the volume of customized tumor models in the periocular area using three-dimensional (3D) stereophotogrammetry and evaluated the reproducibility of these measurements. Methods: Five tumor models of different colors and sizes were placed in different periocular positions, and 3D facial images were obtained from 68 healthy adult volunteers. Subsequently, the volumes of the tumor models were measured, and the intra- and interrater reproducibility was assessed. Results: The gray 6 mm model revealed the highest reliable measurements in both Caucasians (intra- and interrater intraclass correlation coefficients of 0.981 and 0.899, mean absolute difference of 1.446 and 3.327 mm3, relative error measurement of 3.497% and 8.120%, technical error of measurement of 1.450 and 3.105 mm3, and relative technical error of measurement of 3.506% and 7.580%) and Asians (0.968 and 0.844, 1.974 and 4.067 mm3, 4.772% and 9.526%, 2.100 and 4.302 mm3, and 5.076% and 10.076%, respectively). The highest reliability of measurements in the lateral upper eyelid (0.88 and 0.95, 4.042 and 3.626 mm3, 9.730% and 9.020%, 5.714 and 3.358 mm3, and 9.730% and 8.350%, respectively) and medial upper eyelid (0.81 and 0.89, 4.313 and 4.226 mm3, 9.730% and 9.020%, 6.098 and 4.069 mm3, and 9.730% and 8.350%, respectively) with eyes closed was evident in Caucasians, while the same trend (0.841 and 0.815, 2.828 and 3.757 mm3, 9.860% and 9.840%, 4.052 and 4.308 mm3, and 9.860% and 9.740%, respectively) was observed in Asians in the medial canthus with eyes closed. Conclusions: This study confirms, for the first time, the high reliability of periocular tumor volume measurements using 3D stereophotogrammetry, suggesting its feasibility for eyelid tumor measurement. Further trials are required to investigate its clinical use for documentation and follow-up of different eyelid tumors.
Introduction: Equinus contracture is a serious disability and attention should be paid to proper and effective treatment. Most attention is given to neurologically impaired patients, but the incidence of equinus contracture is much higher, for example, in post-traumatic patients. In addition to conventional physical therapy, robotic rehabilitation treatment is one of the promising procedures to precede severe contraction cases and the need for surgery. Areas covered: This study aims to cover the description of different types of stationary and wearable ankle rehabilitation devices suitable for the treatment of equinus contracture and point to deficiency in research, clinical trials, and launch of the market. Expert opinion: This review provides insight into ankle rehabilitation devices with a focus on equinus contracture. Due to the fact that robotic devices successfully restore the condition of patients, attention should not be paid only to those with neurological impairments. This paper points that future research should be effectively linked to clinical practice with the aim of covering a wider range of disabilities and make an effort to successfully introduce devices from development into the practice.
Objective: To obtain information on the serum concentrations of acyclovir and its metabolite in routine health care with respect to the renal function. Methods: This prospective study analyzed data from 27 patients receiving acyclovir intravenously between June 2019 and October 2021. Patients were divided into two subgroups according to the estimated glomerular filtration rate. Serum concentrations of acyclovir and its metabolite 9-(carboxymethoxymethyl) guanine were mainly analyzed on day 5 after the initiation of treatment before the morning dose (trough concentration) and 30 min after the end of the infusion (peak concentration). Results: Trough acyclovir concentrations ranged from 0.8 to 7.6 mg/L and peak concentrations from 6.3 to 25.7 mg/L, and trough metabolite concentrations ranged from 0.12 to 2.30 mg/L and peak concentrations from 0.47 to 2.70 mg/L, respectively. The ratio of trough metabolite and acyclovir concentrations ranged from 0.07 to 0.63 and the ratio of peak concentrations from 0.03 to 0.24. Patients in the subgroup with reduced renal function were significantly older, smaller, and of lower body weight and received significantly lower doses of acyclovir. Conclusions: A 10-fold difference in the weight-adjusted apparent clearance of acyclovir was observed between patients. This wide interindividual variability in acyclovir pharmacokinetics can lead not only to toxicity but also to suboptimal acyclovir concentrations in severe infections. Therefore, therapeutic monitoring of serum concentrations of acyclovir and its metabolite may be important for optimizing pharmacotherapy, especially in patients with severe clinical conditions.
Purpose Narrow-band imaging is the state of the art in the diagnosis of mucosal lesions of the vocal cords. It is also used in the follow-up of patients after surgical therapy. Unfortunately, if a patient has received radiotherapy the follow-up is much more difficult. Radiation induces inflammatory changes in the mucosa, which lead to changes in the vascular architecture and thus affect the results of the examination. The dynamics and time dependence of vascular changes after radiotherapy have not yet been described. The purpose of this study is to describe the evolution of the vascular pattern in vocal cords after primary radiotherapy for glottic cancer. Methods This was a retrospective cohort study. Each patient underwent NBI videolaryngoscopy and was followed every 3 months. Results The tumor-related mucosal changes diminished at 3 months after radiotherapy. Afterward, growth of new longitudinal vasculature was observed and significantly slowed after 9 months. No perpendicular vasculature or tumor recurrence was observed during the course of the study. Conclusions According to our data, we can conclude that post-radiation mucosal vasculature changes are only longitudinal.
Patients with lymphoproliferative diseases (LPD) are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we describe and analyze the outcome of 366 adult patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin Lymphoma (NHL) treated with targeted drugs and laboratory-confirmed COVID-19 diagnosed between February 2020 and January 2022. Median follow-up was 70.5 days (IQR 0-609). Most used targeted drugs were Bruton-kinase inhibitors (BKIs) (N= 201, 55%), anti-CD20 other than rituximab (N=61, 16%), BCL2 inhibitors (N=33, 9%) and lenalidomide (N=28, 8%).Only 16.2% of the patients were vaccinated with 2 or more doses of vaccine at the onset of COVID-19. Mortality was 24% (89/366) on day 30 and 36%(134/366) on the last day of follow-up. Age >75 years (p<0.001, HR 1.036), active malignancy (p<0.001, HR 2.215), severe COVID-19 (p=0.017, HR 2.270) and admission to ICU (p<0.001, HR 5.751) were risk factors for mortality at last day of follow up. There was no difference in OS rates in NHL vs CLL patients (p=0.306), nor in patients treated with or without BKIs (p=0.151). Mortality in ICU was 66% (CLL 61%, NHL 76%). Overall mortality rate decreased according to vaccination status, being 39% in unvaccinated patients, 32% and 26% in those having received one or two doses, respectively, and 20% in patients with a booster dose (p=0.245). Overall mortality rate dropped from 41% during the first semester of 2020 to 25% at the last semester of 2021. These results show increased severity and mortality from COVID-19 in LPDs patients treated with targeted drugs.
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