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Oncology Letters Aug 2023Idiopathic CD4+ lymphocytopenia (ICL) is a rare immunodeficiency disorder characterized by decreased CD4+ T-cell counts in the absence of human immunodeficiency virus...
Idiopathic CD4+ lymphocytopenia (ICL) is a rare immunodeficiency disorder characterized by decreased CD4+ T-cell counts in the absence of human immunodeficiency virus (HIV) infection. Similar to HIV infection, ICL is commonly associated with acquired immunodeficiency syndrome-defining cancers, such as Kaposi sarcoma, non-Hodgkin lymphoma and cervical cancer; however, the presentation of breast cancer in a patient with ICL is rare. The current study presented the clinical course of a patient with early breast cancer and ICL. Following surgery, the patient underwent adjuvant chemotherapy comprising doxorubicin plus cyclophosphamide, followed by paclitaxel. The patient's immunodeficiency status required the prophylactic administration of clarithromycin, trimethoprim-sulfamethoxazole and valganciclovir. Throughout the course of chemotherapy, the patient experienced severe complications of febrile neutropenia, anemia, neutropenia and thrombocytopenia, and was eventually forced to discontinue anticancer chemotherapy, as the relative dose intensity (RDI) could not be maintained. Similar hematological complications and reduced RDI, leading to worse outcomes, are also common in patients with HIV infection receiving chemotherapy, suggesting that CD4+ T cell-deficient patients are prone to developing cytopenia during chemotherapy. The present study demonstrates the importance of further data accumulation in patients with ICL with cancer and the development of a methodology for maintaining the RDI.
PubMed: 37545613
DOI: 10.3892/ol.2023.13943 -
Journal of Ophthalmic Inflammation and... Aug 2023To describe unusual clinical features and therapeutic management of a case of cytomegalovirus (CMV) ocular disease in a patient on immunomodulatory therapy.
PURPOSE
To describe unusual clinical features and therapeutic management of a case of cytomegalovirus (CMV) ocular disease in a patient on immunomodulatory therapy.
SETTING/VENUE
Moorfields Eye Hospital NHS Foundation Trust, London, UK.
METHODS
Medical history, clinical findings, investigation results, and multimodal imaging were retrospectively collected.
RESULTS
A 61-year-old, South-East Asian man, developed CMV-related endotheliitis and occlusive retinal vasculitis, diagnosed by wide-angle fluorescein angiography. No retinitis was present on the fundus examination. Suspicion of CMV etiology was based on anterior segment findings, especially the presence of coin-shaped endothelial lesions. The diagnosis was confirmed by aqueous polymerase chain reaction (PCR) analysis which was positive for CMV DNA. The combined use of topical and systemic valganciclovir resulted in significant improvement of the picture.
CONCLUSIONS
CMV can manifest in the eye as occlusive retinal vasculitis without the presence of typical retinitis.
PubMed: 37540447
DOI: 10.1186/s12348-023-00356-z -
Blood Advances Oct 2023Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a...
Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B-non-Hodgkin lymphoma [B-NHL], [n = 10]; angioimmunoblastic T-cell lymphoma-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For angioimmunoblastic T-cell lymphoma-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706.
Topics: Humans; Adolescent; Adult; Valganciclovir; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Histone Deacetylase Inhibitors; Neoplasm Recurrence, Local; Lymphoma, Non-Hodgkin; Lymphoma; Thrombocytopenia; Lymphoma, T-Cell
PubMed: 37530631
DOI: 10.1182/bloodadvances.2023010330 -
Pharmaceutics Jun 2023Ganciclovir and valganciclovir are used for prophylaxis and treatment of cytomegalovirus infection. However, there is great interindividual variability in ganciclovir's...
Ganciclovir and valganciclovir are used for prophylaxis and treatment of cytomegalovirus infection. However, there is great interindividual variability in ganciclovir's pharmacokinetics (PK), highlighting the importance of individualized dosing. To facilitate model-informed precision dosing (MIPD), this study aimed to establish a parametric model repository of ganciclovir and valganciclovir by summarizing existing population pharmacokinetic information and analyzing the sources of variability. (2) Methods: A total of four databases were searched for published population PK models. We replicated these models, evaluated the impact of covariates on clearance, calculated the probability of target attainment for each model based on a predetermined dosing regimen, and developed an area under the concentration-time curve (AUC) calculator using maximum a posteriori Bayesian estimation. (3) Results: A total of 16 models, one- or two-compartment models, were included. The most significant covariates were body size (weight and body surface area) and renal function. The results show that 5 mg/kg/12 h of ganciclovir could make the AUC within 40-80 mg·h/L for 50.03% pediatrics but cause AUC exceeding the exposure thresholds for toxicity (120 mg·h/L) in 51.24% adults. (4) Conclusions: Dosing regimens of ganciclovir and valganciclovir should be adjusted according to body size and renal function. This model repository has a broad range of potential applications in MIPD.
PubMed: 37513988
DOI: 10.3390/pharmaceutics15071801 -
Children (Basel, Switzerland) Jul 2023Cytomegalovirus (CMV) is the most common agent of congenital infection in humans. It is a main cause of neurodevelopmental delay and sensorineural hearing loss in... (Review)
Review
BACKGROUND
Cytomegalovirus (CMV) is the most common agent of congenital infection in humans. It is a main cause of neurodevelopmental delay and sensorineural hearing loss in infancy. Since the 2000s, a number of studies have used Valganciclovir as a therapy for children with congenital CMV infection.
METHODS
In order to evaluate the efficacy of Valganciclovir in preventing clinical sequelae and its possible side effects, we performed a review of the published literature. This search was completed via PubMed for manuscripts published from January 2007 to December 2021, combining the MeSH words "Valganciclovir", "Congenital", and "Cytomegalovirus".
RESULTS
A total of 27 articles were included (12 retrospective studies, 4 prospective studies, 1 randomized controlled trial, and 10 case reports). The clinical features were similar to those already described in the literature. The therapeutic protocols used were very different between the various studies included and neonatal antiviral treatments were only moderately effective. The therapy proved to be well-tolerated.
CONCLUSIONS
The quality of the included studies and the sample size were limited due to the rarity of the disease. The use of different therapeutic protocols in terms of starting dates, doses, and durations made it impossible to compare and correctly evaluate the efficacy of the treatments. Randomized controlled trials are needed to establish the correct effective dose with the fewest side effects and the most efficient duration of therapy.
PubMed: 37508743
DOI: 10.3390/children10071246 -
Transplantation Direct Aug 2023The optimal strategy for cytomegalovirus (CMV) disease prevention in CMV donor/recipient kidney transplant recipients remains uncertain. Conclusions of prior...
A Systematic Review and Meta-analysis of Optimized CMV Preemptive Therapy and Antiviral Prophylaxis for CMV Disease Prevention in CMV High-Risk (D+R-) Kidney Transplant Recipients.
UNLABELLED
The optimal strategy for cytomegalovirus (CMV) disease prevention in CMV donor/recipient kidney transplant recipients remains uncertain. Conclusions of prior meta-analyses that CMV disease rates with preemptive therapy (PET) and universal prophylaxis (UP) were comparable may have been affected by inclusion of studies lacking key determinants of efficacy of the respective strategies.
METHODS
We conducted a systematic review and meta-analysis of PET with weekly CMV polymerase chain reaction monitoring for ≥3 mo and UP with 6 mo of valganciclovir. PubMed and Embase databases were reviewed from January 1, 2010, to April 1, 2022. Risk of bias was assessed with 3 instruments (Cochrane RoB, Cochrane RoBINS-I, and an instrument for assessing risk in observational studies). The primary outcome was CMV disease incidence by 1-y posttransplant. Secondary outcomes by 1-y were graft loss, acute allograft rejection, and mortality. Results were synthesized using generalized linear mixed model meta-analysis. PET studies were stratified into low-threshold (LT) and high-threshold (HT) PET based on the viral load threshold for initiation of antiviral therapy.
RESULTS
Twenty-five studies met inclusion criteria (6 PET, 19 UP). CMV disease incidence was significantly higher in HT (0.30 [95% confidence interval (CI), 0.22-0.39]) versus LT PET (0.06 [95% CI, 0.03-0.12]). LT PET was associated with a significantly lower CMV disease incidence (0.06 [95% CI, 0.03-0.12]) versus UP (0.21 [95% CI, 0.17-0.27]). Incidence of graft loss, acute allograft rejection, or mortality was not significantly different between LT PET and UP ( > 0.05 for all comparisons). Receipt of lymphocyte-depleting antibodies was not associated with a significant difference in CMV disease incidence (odds ratio = 1.34 [95% CI, 0.80-2.25]).
CONCLUSIONS
LT PET is associated with a significantly lower incidence of CMV disease compared to UP with similar rates of other clinical outcomes. These findings provide rationale and preliminary data for a randomized superiority trial of optimized LT-PET versus UP in donor seropositive recipient seronegative kidney transplant recipients.
PubMed: 37456587
DOI: 10.1097/TXD.0000000000001514 -
Transplant International : Official... 2023Genotypically resistant cytomegalovirus (CMV) infection is associated with increased morbi-mortality. We herein aimed at understanding the factors that predict CMV...
Genotypically resistant cytomegalovirus (CMV) infection is associated with increased morbi-mortality. We herein aimed at understanding the factors that predict CMV genotypic resistance in refractory infections and disease in the SOTR (Solid Organ Transplant Recipients) population, and the factors associated with outcomes. We included all SOTRs who were tested for CMV genotypic resistance for CMV refractory infection/disease over ten years in two centers. Eighty-one refractory patients were included, 26 with genotypically resistant infections (32%). Twenty-four of these genotypic profiles conferred resistance to ganciclovir (GCV) and 2 to GCV and cidofovir. Twenty-three patients presented a high level of GCV resistance. We found no resistance mutation to letermovir. Age (OR = 0.94 per year, IC95 [0.089-0.99]), a history of valganciclovir (VGCV) underdosing or of low plasma concentration (OR= 5.6, IC95 [1.69-20.7]), being on VGCV at infection onset (OR = 3.11, IC95 [1.18-5.32]) and the recipients' CMV negative serostatus (OR = 3.40, IC95 [0.97-12.8]) were independently associated with CMV genotypic resistance. One year mortality was higher in the resistant CMV group (19.2 % s 3.6 %, = 0.02). Antiviral drugs severe adverse effects were also independently associated with CMV genotypic resistance. CMV genotypic resistance to antivirals was independently associated with a younger age, exposure to low levels of GCV, the recipients' negative serostatus, and presenting the infection on VGCV prophylaxis. This data is of importance, given that we also found a poorer outcome in the patients of the resistant group.
Topics: Humans; Cytomegalovirus Infections; Antiviral Agents; Ganciclovir; Valganciclovir; Cytomegalovirus; Organ Transplantation; Transplant Recipients
PubMed: 37398559
DOI: 10.3389/ti.2023.11295 -
Medicine Jun 2023Acute retinal necrosis (ARN) caused by human herpes virus type 6 (HHV-6) is uncommon. We described a case of consecutive bilateral ARN, which was found to be a...
RATIONALE
Acute retinal necrosis (ARN) caused by human herpes virus type 6 (HHV-6) is uncommon. We described a case of consecutive bilateral ARN, which was found to be a coinfection of varicella zoster virus (VZV) and HHV-6 in a 50-year-old woman, not well responded with systemic acyclovir. We showed the atypical findings with corresponding fundus and optical coherence tomography imaging.
PATIENT CONCERNS
She presented with anterior segment inflammation with peripheral retinitis and vasculitis in the left eye with disease progression despite of initial antiviral treatment, end up with retinal detachment. The right eye, subsequently, developed focal retinitis.
DIAGNOSIS
ARN was diagnosed by clinical fundus picture, confirmed by polymerase chain reaction (PCR).
INTERVENTIONS
Initially, she was treated with intravenous acyclovir and intravitreal ganciclovir for left eye. Retinal necrosis progressed, followed by retinal detachment. Pars plana vitrectomy with silicone oil was performed. The right eye, subsequently, developed focal retinitis. Medication was switched to intravenous ganciclovir and then oral valganciclovir.
OUTCOMES
Retinitis was resolved, generalized hyperpigmentation appeared as a salt-and-pepper appearance in the right eye. The left eye presented preretinal deposits on silicone-retina interphase along retinal vessels. Spectral-domain optical coherence tomography (SD-OCT) showed multiple hyperreflective nodules on retinal surface.
LESSONS
ARN from coinfection of VZV and HHV-6 is rare. Preretinal granulomas and generalized hyperpigmentation could be one of the HHV-6 features. HHV-6 should be in the differential diagnosis for ARN. It responds well to systemic ganciclovir.
Topics: Female; Humans; Middle Aged; Retinal Necrosis Syndrome, Acute; Herpesvirus 3, Human; Retinal Detachment; Coinfection; Herpesvirus 6, Human; Retinitis Pigmentosa; Retina; Retinitis; Acyclovir; Ganciclovir
PubMed: 37390266
DOI: 10.1097/MD.0000000000033958 -
Translational Lung Cancer Research May 2023Lung cancer is one of the most common human malignant tumors and the leading cause of cancer death worldwide. Biphenyl hydrolase-like () is a gene encoding the human...
BACKGROUND
Lung cancer is one of the most common human malignant tumors and the leading cause of cancer death worldwide. Biphenyl hydrolase-like () is a gene encoding the human enzyme, a serine hydrolase that catalyzes the hydrolytic activation of amino acid ester prodrugs of nucleoside analogs such as valacyclovir and valganciclovir. However, the role of in lung cancer is still unknown.
METHODS
In this study, we assessed the effect knockdown on the proliferation, apoptosis, colony formation, metastasis, and cell cycle of cancer cells. knockdown NCI-H1299 and A549 cells demonstrated decreased proliferation, as measured by Celigo cell counting. The MTT assay results were consistent with Celigo cell counting. Caspase 3/7 activity increased significantly in the NCI-H1299 and A549 cells after shBPHL knockdown. Decreased colony formation in the NCI-H1299 and A54 cells after shBPHL knockdown, as measured by crystal violet staining. Transmigration assay using a Transwell demonstrated that there were significantly fewer migrating cells in the lower chamber in the knockdown NCI-H1299 and A549 cells. Cell cycle analysis by Propidium Iodide (PI) staining and fluorescence activated cell sorter (FACS). We also explored the effect of knockdown on tumor growth in a mouse model of tumor implantation in nude mice.
RESULTS
We found that the knockdown of gene expression by short hairpin RNA (shRNA) leads to a decrease in proliferation, colony formation, and metastasis and an increase in apoptosis in two lung adenocarcinoma (LUAD) cell lines . knockdown induces decreased tumor growth, colony formation, and metastasis; increased apoptosis; and altered cell cycle destruction. knockdown results in decreased tumor growth . Moreover, knockdown A549 cells demonstrated slower growth compared to control cells upon implantation in nude mice, confirming the findings.
CONCLUSIONS
In this study, the data indicate that potentially promotes proliferation, inhibits apoptosis, and increases colony formation and metastasis in lung cancer. Overall, our study suggests that may be a gene that promotes tumor growth in lung cancer.
PubMed: 37323178
DOI: 10.21037/tlcr-23-225 -
Cureus May 2023Although cytomegalovirus (CMV) usually colonizes the human body without causing symptoms, CMV infections often develop in immunocompromised hosts. Immunosuppression can...
Although cytomegalovirus (CMV) usually colonizes the human body without causing symptoms, CMV infections often develop in immunocompromised hosts. Immunosuppression can trigger CMV infection, and its prediction is essential; however, this is challenging without specific criteria. We present the case of an 87-year-old male patient who visited a rural community hospital with the chief complaint of persistent cough, productive of bloody sputum. Initially, the patient developed thrombocytopenia without any abnormalities of liver function; however, a positive myeloperoxidase antineutrophil cytoplasmic antibody (ANCA) test and the presence of alveolar hemorrhage and glomerulonephritis confirmed ANCA-associated vasculitis. The patient's symptoms and thrombocytopenia resolved transiently after treatment with prednisolone and rituximab. However, the recurrence of thrombocytopenia and the appearance of urinary intracytoplasmic inclusion bodies during the treatment course were investigated using an antigenemia test, which ultimately confirmed CMV viremia. Valganciclovir treatment resolved all the symptoms. This case report showed that thrombocytopenia might indicate the presence of CMV infection in ANCA-associated vasculitis and that intracytoplasmic inclusion bodies in immunosuppressed patients require investigation of CMV infection for effective treatment.
PubMed: 37303320
DOI: 10.7759/cureus.38850