Serum ganciclovir drug exposure in children receiving standard ganciclovir dosing.

Intravenous ganciclovir (GCV) is used for the treatment of cytomegalovirus (CMV) infection in immunocompromised children. Although the therapeutic target for treatment is unclear, studies have shown a serum area under the concentration-time curve (AUC24h) ≥40 mg/L·h correlates with effective CMV prevention. This study aimed to externally validate existing GCV population pharmacokinetic (PopPK) models and develop a model if needed and evaluate the serum AUC24h achieved with standard GCV dosing and propose an optimized dosing strategy for immunocompromised children. Ganciclovir drug monitoring data from two pediatric hospitals were retrospectively collected, and published pediatric PopPK models were externally validated. The population AUC24h with standard GCV dosing (5 mg/kg twice daily) was calculated, and an optimized dosing strategy was determined using Monte Carlo simulations to achieve an AUC24h between 40 and 100 mg/L·h. Overall, 161 samples from 23 children with a median (range) age of 9.0 years (0.4-17.0) and weight of 28.2 kg (5.6-73.3) were analyzed. Transferability of published pediatric PopPK models was limited. Thus, a one-compartment model with first-order absorption and elimination with weight and serum creatinine as covariates was developed. The median (5th-95th percentiles) steady state AUC24h with standard dosing was 38.3 mg/L·h (24.8-329.2) with 13 children having an AUC24h <40 mg/L·h, particularly those aged <4 years (8/13). An optimized simulated GCV dosing regimen, ranging from 2 to 13 mg/kg twice daily for children with normal renal function, achieved 61%-78% probability of target attainment. Standard GCV dosing likely results in inadequate drug exposure in more than half of the children, particularly those aged <4 years. An optimized dosing regimen has been proposed for clinical validation.

Oral Valganciclovir Initiated Beyond 1 Month of Age as Treatment of Sensorineural Hearing Loss Caused by Congenital Cytomegalovirus Infection: A Randomized Clinical Trial.

OBJECTIVE: The objective of this study was to determine if valganciclovir initiated after 1 month of age improves congenital cytomegalovirus-associated sensorineural hearing loss. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled phase 2 trial of 6 weeks of oral valganciclovir at US (n = 12) and UK (n = 9) sites. Patients of ages 1 month through 3 years with baseline sensorineural hearing loss were enrolled. The primary outcome was change in total ear hearing between baseline and study month 6. Secondary outcome measures included change in best ear hearing and reduction in cytomegalovirus viral load in blood, saliva, and urine. RESULTS: Of 54 participants enrolled, 35 were documented to have congenital cytomegalovirus infection and were randomized (active group: 17; placebo group: 18). Mean age at enrollment was 17.8 ± 15.8 months (valganciclovir) vs 19.5 ± 13.1 months (placebo). Twenty (76.9%) of the 26 ears from subjects in the active treatment group did not have worsening of hearing, compared with 27 (96.4%) of 28 ears from subjects in the placebo group (P = .09). All other comparisons of total ear or best ear hearing outcomes were also not statistically significant. Saliva and urine viral loads decreased significantly in the valganciclovir group but did not correlate with change in hearing outcome. CONCLUSIONS: In this randomized controlled trial, initiation of antiviral therapy beyond the first month of age did not improve hearing outcomes in children with congenital cytomegalovirus-associated sensorineural hearing loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01649869.

Comparison of prophylaxis and preemptive strategy as cytomegalovirus prevention in liver transplant recipients.

OBJECTIVES: Prophylaxis (P) or pre-emptive strategy (PS) in high-risk liver transplant recipients (LTRs) are either recommended. We compared the results of each strategy. METHODS: Two groups of LTR transplanted during two consecutive periods were compared. Only cytomegalovirus (CMV)-mismatched LTR (Donor +/ Recipient -) were included. The primary endpoints were: the onset of polymerase chain reaction-based DNAemia and the proportion of patients with CMV disease. A number of episodes of CMV infection, antiviral therapy, ganciclovir resistance, infectious or immunological complications, cost of both strategies, and survival (1, 5, and 10 years) were also compared. RESULTS: Forty-eight and 60 patients were respectively included in the P and PS groups. Eighteen (38%) in the P group and 56 (93%) in the PS group had CMV DNAemia (p <.0001) with a similar CMV disease rate (16.7% and 15%). Duration of curative therapy was longer in the PS group: 91 days versus 16 (p <.0001). Acute rejection was less frequent (p = .04) and more patients experienced a ganciclovir-resistant CMV infection in the PS group (10% vs. 0, p = .03). The drug-associated cost of PS was higher (10 004 vs. 4804€) and the median number of rehospitalization days tended to be higher (6 vs. 4, p = .06). Survival at any time was similar. CONCLUSION: We reported more CMV DNAemias and ganciclovir-resistant CMV events with PS. The cost of the PS strategy was higher.

Contribution of Adsorption and Hematocrit Levels to Ganciclovir Clearance in an in Vitro Continuous Hemodiafiltration Model.

Estimation of the continuous hemodiafiltration (CHDF) clearance (CLCHDF) of ganciclovir (GCV) is crucial for achieving efficient treatment outcomes. Here, we aimed to clarify the contribution of diafiltration, adsorption, and hematocrit level to the CLCHDF of GCV in an in vitro CHDF model using three membranes: polyacrylonitrile and sodium methallyl sulfonate copolymer coated with polyethylenimine (AN69ST); polymethylmethacrylate (PMMA); and polysulfone (PS). In vitro CHDF was performed with effluent flow rates (Qe) of 800, 1500, and 3000 mL/h. The initial GCV concentration was 10 µg/mL while that of human serum albumin (HSA) was 0 or 5 g/dL. The CLCHDF, diafiltration rates, and adsorption rates were calculated. The whole blood-to-plasma ratio (R) of GCV for a hematocrit of 0.1 to 0.5 was determined using blood samples with 0.5 to 100 µg/mL of GCV. The in vitro CHDF experiment using AN69ST, PMMA, and PS membranes showed that the total CLCHDF values were almost the same as the Qe and not influenced by the HSA concentration. The diafiltration rate exceeded 88.1 ± 2.8% while the adsorption rate was lower than 9.4 ± 9.4% in all conditions. The R value was 1.89 ± 0.11 and was similar at all hematocrit levels and GCV concentrations. In conclusion, diafiltration mainly contributes to the CLCHDF of GCV, rather than adsorption. Hematocrit levels might not affect the relationship between the plasma and blood CLCHDF of GCV, and the CLCHDF of GCV can be estimated from the Qe and R, at least in vitro.

Assessment of patients' characteristics associated with the efficacy and safety of oral valganciclovir treatment for infants with symptomatic congenital cytomegalovirus disease.

INTRODUCTION: Insurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing. MATERIALS AND METHODS: We performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants' baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count. RESULTS: Of the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019). CONCLUSIONS: Infants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.

Bluetongue Virus Particles as Nanoreactors for Enzyme Delivery and Cancer Therapy.

The side effects of chemotherapy can be reduced by targeting tumor cells with an enzyme (or the corresponding gene) that converts a nontoxic prodrug into a toxic drug inside the tumor cells, also killing the surrounding tumor cells via the bystander effect. Viruses are the most efficient gene delivery vehicles because they have evolved to transfer their own nucleic acids into cells, but their efficiency must be balanced against the risks of infection, the immunogenicity of nucleic acids, and the potential for genomic integration. We therefore tested the effectiveness of genome-free virus-like particles (VLPs) for the delivery of Herpes simplex virus 1 thymidine kinase (HSV1-TK), the most common enzyme used in prodrug conversion therapy. HSV1-TK is typically delivered as a gene, but in the context of VLPs, it must be delivered as a protein. We constructed VLPs and smaller core-like particles (CLPs) based on Bluetongue virus, with HSV1-TK fused to the inner capsid protein VP3. TK-CLPs and TK-VLPs could be produced in large quantities in plants. The TK-VLPs killed human glioblastoma cells efficiently in the presence of ganciclovir, with an IC50 value of 14.8 µM. Conversely, CLPs were ineffective because they remained trapped in the endosomal compartment, in common with many synthetic nanoparticles. VLPs are advantageous because they can escape from endosomes and therefore allow HSV1-TK to access the cytosolic adenosine triphosphate (ATP) required for the phosphorylation of ganciclovir. The VLP delivery strategy of TK protein therefore offers a promising new modality for the treatment of cancer with systemic prodrugs such as ganciclovir.

Does ganciclovir exert retinal toxicity after multiple continuous intravitreal injections?

BACKGROUND: The objective of this study is to report a case of acute retinal necrosis in which abnormalities in visual function did not correspond to retinal anatomical outcomes. CASE PRESENTATION: A 39-year-old female diagnosed with acute retinal necrosis underwent repeated (nine rounds) intravitreal ganciclovir injection (3 mg/0.1 ml) into the left eye, one injection every 2 weeks. During the therapy, the patient noticed her visual acuity declining gradually. The best corrected visual acuity in the left eye was 20/33. The visual field showed massive visual damage. There was no posterior necrotizing involvement, no macular edema or exudation, and only slight abnormity of the interdigitation zone in the fovea area was visible on OCT. Angio-OCT revealed normal capillary density of three retinal capillary and choriocapillaris layers. The visually evoked potential was normal. The photopic single-flash response showed a declined amplitude of a-wave and b-wave. The amplitudes of photopic 30 Hz flicker were decreased. Multifocal electroretinography revealed macular dysfunction. CONCLUSION: Ganciclovir-associated photoreceptor damage may induce abnormalities in retinal function in response to multiple continuous intravitreal ganciclovir injections at a relatively high dosage (3 mg/0.1 ml).

Novel hepatitis B virus infection mouse model using herpes simplex virus type 1 thymidine kinase transgenic mice.

BACKGROUND AND AIM: The chronicity of hepatitis B virus (HBV) infection is the result of impaired HBV-specific immune responses that cannot eliminate or cure the infected hepatocytes efficiently. Previous studies have used immunodeficient mice such as herpes simplex virus type 1 thymidine kinase NOD/Scid/IL2Rrnull (HSV-TK-NOG) mice. However, it is difficult to analyze the immune response in the previous models. In the present study, we established a novel HBV infection model using herpes simplex virus type 1 thymidine kinase (HSV-TK) mice in which the host immune system was not impaired. METHODS: Herpes simplex virus type 1 thymidine kinase mice were injected intraperitoneally with ganciclovir (GCV). Seven days after GCV injection, GCV-treated mice were transplanted with 1 × 106 hepatocytes from HBV-transgenic (HBV-Tg) mice. RESULTS: Serum alanine aminotransferase levels in HSV-TK mice increased 1 and 2 weeks after GCV injection. The number and viability of hepatocytes from the whole liver of HBV-Tg mice significantly increased using digestion medium containing liberase. Hepatitis B surface antigen (HBsAg)-positive areas in the liver tissue were observed for at least 20 weeks after HBsAg-positive hepatocyte transplantation. In addition, we measured HBsAg in the serum after transplantation. HBsAg levels in HBV-Tg hepatocyte-replaced mice increased 4 weeks after transplantation. Furthermore, we examined the immune response in HSV-TK mice. The increase in hepatitis B surface antibody levels in replaced mice was maintained for 20 weeks. Also, interferon-γ-producing cells were increased in non-replaced mice. CONCLUSIONS: A novel HBV infection mouse model will help to understand the mechanisms of HBV tolerance similar to human chronic HBV-infected patients and can be used to develop a new strategy to treat chronic HBV infection.

Developing Implantable Scaffolds to Enhance Neural Stem Cell Therapy for Post-Operative Glioblastoma.

Pre-clinical and clinical studies have shown that engineered tumoricidal neural stem cells (tNSCs) are a promising treatment strategy for the aggressive brain cancer glioblastoma (GBM). Yet, stabilizing human tNSCs within the surgical cavity following GBM resection is a significant challenge. As a critical step toward advancing engineered human NSC therapy for GBM, we used a preclinical variant of the clinically utilized NSC line HB1.F3.CD and mouse models of human GBM resection/recurrence to identify a polymeric scaffold capable of maximizing the transplant, persistence, and tumor kill of NSC therapy for post-surgical GBM. Using kinetic bioluminescence imaging, we found that tNSCs delivered into the mouse surgical cavity wall by direct injection persisted only 3 days. We found that delivery of tNSCs into the cavity on nanofibrous electrospun poly-l-lactic acid scaffolds extended tNSC persistence to 8 days. Modifications to fiber surface coating, diameter, and morphology of the scaffold failed to significantly extend tNSC persistence in the cavity. In contrast, tNSCs delivered into the post-operative cavity on gelatin matrices (GEMs) persisted 8-fold longer as compared to direct injection. GEMs remained permissive to tumor-tropic homing, as tNSCs migrated off the scaffolds and into invasive tumor foci both in vitro and in vivo. To mirror envisioned human brain tumor trials, we engineered tNSCs to express the prodrug/enzyme thymidine kinase (tNSCstk) and transplanted the therapeutic cells in the post-operative cavity of mice bearing resected orthotopic patient-derived GBM xenografts. Following administration of the prodrug ganciclovir, residual tumor volumes in mice receiving GEM/tNSCs were reduced by 10-fold at day 35, and median survival was extended from 31 to 46 days. Taken together, these data begin to define design parameters for effective scaffold/tNSC composites and suggest a new approach to maximizing the efficacy of tNSC therapy in human patient trials.

Dose banding of intravenous ganciclovir: Banding scheme proposal and audit of toxicity and efficiency.

WHAT IS KNOWN AND OBJECTIVE: Dose banding is a strategy to optimize processing without reducing patient safety. Prescribed doses are rounded up or down to predetermined standard doses. Although it has been mostly used in chemotherapy, other drugs are suitable for this strategy, such as the antiviral ganciclovir. The aim of this work is to assess the safety and efficiency of a dose-rounding system for intravenous ganciclovir. METHODS: Dose bands were established for a maximum of 10% variation from the individualized dose. The number of annual preparations that expired before use and the number of ganciclovir vials saved were documented as indicators of efficiency. Toxicity was assessed comparing haematological parameters before and after ganciclovir treatment in a sample of patients who received doses above the theoretical dose (n = 121) and in the rest of the cohort (n = 129). RESULTS AND DISCUSSION: Five ganciclovir standard doses were established. It was shown that the bulk of the preparations (83.7%) had a maximum variation between the exact dose prescribed and the adjusted dose of ±10%. Three years after its implementation, a mean of 2848 annual preparations were compounded. The average percentage of annual expired preparations was lower than 1% of the total compounded doses, and the dose-rounding system allowed for saving 699 manufactured ganciclovir vials annually. There was no significant difference between haemoglobin and leucocyte levels measured before and after ganciclovir treatment in both groups. WHAT IS NEW AND CONCLUSION: Ganciclovir dose banding allows for efficient management of preparations without an increased risk of acute haematological side effects.

Treating HIV-associated cytomegalovirus retinitis with oral valganciclovir and intra-ocular ganciclovir by primary HIV clinicians in southern Myanmar: a retrospective analysis of routinely collected data.

BACKGROUND: Cytomegalovirus retinitis (CMVR) is an opportunistic infection in HIV-infected people. Intraocular or intravenous ganciclovir was gold standard for treatment; however, oral valganciclovir replaced this in high-income countries. Low- and middle-income countries (LMIC) frequently use intraocular injection of ganciclovir (IOG) alone because of cost. METHODS: Retrospective review of all HIV-positive patients with CMVR from February 2013 to April 2017 at a Médecins Sans Frontièrs HIV clinic in Myanmar. Treatment was classified as local (IOG) or systemic (valganciclovir, or valganciclovir and IOG). The primary outcome was change in visual acuity (VA) post-treatment. Mortality was a secondary outcome. RESULTS: Fifty-three patients were included. Baseline VA was available for 103 (97%) patient eyes. Active CMVR was present in 72 (68%) eyes. Post-treatment, seven (13%) patients had improvement in VA, 30 (57%) had no change, and three (6%) deteriorated. Among patients receiving systemic therapy, four (12.5%) died, compared with five (24%) receiving local therapy (p = 0.19). CONCLUSIONS: Our results from the first introduction of valganciclovir for CMVR in LMIC show encouraging effectiveness and safety in patients with advanced HIV. We urge HIV programmes to include valganciclovir as an essential medicine, and to include CMVR screening and treatment in the package of advanced HIV care.

Systematic review of ganciclovir pharmacodynamics during the prevention of cytomegalovirus infection in adult solid organ transplant recipients.

Human cytomegalovirus (CMV) represents the most common infection among recipients of solid organ transplants (SOTs). Previous meta-analysis showed 0.8% of SOT recipients developed CMV disease whilst receiving valganciclovir (ValGCV) prophylaxis. However, the clinical utility of monitoring ganciclovir (GCV) blood concentrations is unclear. We systematically reviewed the association between GCV concentrations during prophylaxis and the incidence of CMV. MEDLINE and EMBASE databases were searched for studies between 1946 and 2018, where GCV pharmacokinetics and incidence of CMV viraemia or disease in SOT were available. Research designs included randomised trials, comparative, prospective cohort, retrospective, or case report studies. Only human adult studies were included, with English language restriction. The 11 studies that met the eligibility criteria included 610 participants receiving GCV or ValGCV prophylaxis. Quality assessment showed 2/4 randomised trials, 4/6 cohort studies, and 1/1 case report were of high quality. Despite dose adjustments for renal impairment, mean GCV exposures for patients were heterogeneous and ranged between 28 and 53.7 µg·h/mL across three randomised trials. The incidence of CMV infection and disease ranged from 0% to 50% and 0% to 3.1%, respectively, with follow up between 3 to 9 months. One study showed statistical power in determining relationship, where GCV exposure at 40 to 50 µg·h/mL in high-risk SOT recipients was associated with a reduced risk of viraemia. Clinical monitoring for GCV exposure can be applied to high-risk SOT recipients during ValGCV prophylaxis; however, further studies are needed to determine the utility of monitoring in all SOT recipients.

Evaluation of a change in cytomegalovirus prevention strategy following pediatric solid organ transplantation.

BACKGROUND: An optimal cytomegalovirus (CMV) prevention strategy following solid organ transplantation (SOT) remains uncertain. This study reports on the rates of CMV events following a change in a local prevention guideline involving increased surveillance, earlier transition to oral valganciclovir, and decreased CMV-immunoglobulin use. METHODS: A retrospective cohort study utilizing historical controls evaluated the rates of CMV invasive disease pre- and post-intervention among pediatric heart, liver, and kidney recipients. Outcomes were recorded for the 4 years pre- and post-intervention, 9/2009-10/2017. Logistic regression was used to estimate the risk of a CMV event. RESULTS: There was no difference in the rates of CMV invasive disease between the two study groups (P = 1). An increase in the detection of CMV events occurred (P = .04), predominantly asymptomatic CMV infection. This increase was independently associated with increased surveillance testing among high-risk heart and liver recipients, aOR 1.08 (1.06-1.12). Surprisingly, 28.9% of CMV events occurred during antiviral prophylaxis. CONCLUSIONS: Modification of the local CMV prevention guideline did not result in an increase in CMV invasive disease. CMV events occurred while on prophylaxis, highlighting a potential difference from adult solid organ transplant (SOT) and emphasizing the potential need for monitoring on prophylaxis in the pediatric population.

Extending cytomegalovirus prophylaxis in high-risk (D+/R-) lung transplant recipients from 6 to 9 months reduces cytomegalovirus disease: A retrospective study.

RATIONALE: Cytomegalovirus (CMV)-seronegative recipients receiving a seropositive allograft (D+/R-) are at a high risk of developing CMV disease. Our program increased the duration of CMV prophylaxis from 6 to 9 months in May 2013. Here, we present the impact on the incidence of CMV infection, disease, side effects, rejection, and other factors. METHODS: Retrospective cohort of 241 CMV (D+/R-) patients transplanted between January 1, 2008, and December 31, 2017. Blood CMV testing was done according to protocol. All patients received ganciclovir/valganciclovir as prophylaxis. We compared the incidence and timing of CMV infection and disease up to 6 months after cessation of prophylaxis between patients who received 9 months (May 2013 onwards) and a historical control group who received 6 months of prophylaxis (prior to May 2013). CMV infection was defined as detectable CMV viremia in the absence of symptoms. CMV disease was defined as CMV syndrome or tissue-invasive disease. Side effects of prophylaxis and CMV resistance were recorded. RESULTS: A total of 116 patients were included in the 6-month group and 125 in the 9-month group. The extended 9-month CMV prophylaxis delayed the onset of CMV infection (median time to CMV infection after lung transplantation 295 vs 353 days, P < .01) but did not significantly reduce the incidence of CMV infection (65% vs 64%, P = .06, log-rank). The 9-month prophylaxis delayed the onset and decreased the incidence of CMV disease from 50% in the 6-month group to 42% (P = .02 log-rank). There was no difference in the rate of adverse effects (leukopenia in 32% in both groups, P = .53) or development of CMV resistance between the two groups (4 cases in both groups, P = .92). There were no significant differences in overall survival or the rate of chronic lung allograft dysfunction between the groups. CONCLUSIONS: Extending duration of CMV prophylaxis from 6 to 9 months resulted in a delayed and decreased incidence of CMV disease in our lung transplant population. The absolute risk reduction achieved by extended CMV prophylaxis was 8%. The incidence of CMV infection, and ganciclovir resistance and side effects were similar between the two groups. Our results suggest that extending CMV prophylaxis in the highest risk CMV D+/R- group is effective in reducing CMV disease.

Cost analysis of ganciclovir and foscarnet in recipients of allogeneic hematopoietic cell transplant with cytomegalovirus viremia.

BACKGROUND: Ganciclovir (GCV) and foscarnet (FOS) are the most commonly used antivirals for preemptive treatment of cytomegalovirus (CMV) viremia in recipients of allogeneic hematopoietic cell transplantation (alloHCT). The current literature indicates similar efficacy between these agents. Thus, the primary consideration for choice of initial anti-CMV treatment is the safety profile, time period after alloHCT, and concern of myelosuppression or renal dysfunction. METHODS: Herein, we retrospectively reviewed medical records of 124 alloHCT recipients who received GCV or FOS between April 27, 2014, and December 31, 2015, during the first year post-transplant. Healthcare resource use included drug, hospitalization, home health, dialysis, and growth factor costs. RESULTS: Total duration of therapy was longer in the GCV group (37 days vs 28 days, P = .21) but hospitalization days were similar (9 days) in both groups. The total treatment cost was significantly lower in the GCV group ($38 100 vs $59 400, P < .05). CONCLUSION: Preemptive anti-CMV therapy is associated with major healthcare resource costs, which were greater in patients who required FOS than those who were treated with GCV.

Golgi membrane protein GP73 modified-liposome mediates the antitumor effect of survivin promoter-driven HSVtk in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide, and there is currently no effective therapeutic strategy in clinical practice. Gene therapy has great potential for decreasing tumor-induced mortality but has been clinically limited because of the lack of tumor-specific targets and insufficient gene transfer. The study of targeted transport of therapeutic genes in HCC treatment seems to be very important. In this study, we evaluated a gene therapy approach targeting HCC using the herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) suicide gene system in HCC cell lines and in an in vivo human HCC xenograft mouse model. GP73-modified liposomes targeted gene delivery to the tumor tissue, and the survivin promoter drove HSVtk expression in the HCC cells. Our results showed that the survivin promoter was specifically activated in tumor cells and HSVtk was expressed selectively in tumor cells. Combined with GCV treatment, HSVtk expression resulted in suppression of HCC cell proliferation via enhancing apoptosis. Moreover, tail vein injection of GP73-HSVtk significantly suppressed the growth of xenograft tumors through an apoptosis-dependent pathway and extended the survival of tumor-bearing mice without damaging the mice liver functions. Taken together, this study demonstrates an effective cancer-specific gene therapy strategy using the herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) suicide gene system for HCC that can be further developed for future clinical trials.

Paediatric ganciclovir dosing in extracorporeal membrane oxygenation: Is standard dosing good enough?

WHAT IS KNOWN AND OBJECTIVE: Ganciclovir is a first-line antiviral agent to treat cytomegalovirus disease in immunocomprimised patients. Ganciclovir pharmacokinetics in ECMO is unknown. CASE DESCRIPTION: A 6-year-old with a stage IV extra-renal rhabdoid tumor with respiratory failure leading to extracorporeal membrane oxygenation had increasing serum CMV DNAemia while on ganciclovir. WHAT IS NEW AND CONCLUSION: This is the first case report of ganciclovir pharmacokinetics in either paediatric or adult ECMO populations. Recommended dosing provided a low, subtherapeutic AUC24 with an associated increase CMV viral load. Higher doses of ganciclovir may be required in ECMO patients, especially without concurrent CRRT.

Different medications for the treatment of Ménière's disease by intratympanic injection: A systematic review and network meta-analysis.

BACKGROUND: It is generally accepted that intratympanic injection provides an effective approach to manage severe vertigo in Ménière's disease. Although there are several medications available, that which is the most effective is still subject to debate. OBJECTIVE: To assess the effectiveness and safety of the different medications used in the treatment of Ménière's disease by intratympanic injection using a network meta-analysis. METHODS: PubMed, EMBASE, CINAHL and CENTRAL were searched. Only randomised controlled trials that compared the effectiveness of medications used for intratympanic injection to treat Ménière's disease with each other or a placebo were included. The primary outcome assessed was the effectiveness of medication in the management of vertigo symptoms. The effectiveness was expressed in terms of risk ratio (RR) with a 95% credible interval (CrI) for individual studies analysed. Network meta-analyses were performed by Stata version 15.0 using the network package. RESULTS: Nine studies involving 314 patients treated with five different medications were included in the present analysis. A number of injections given varied from 1 to 10 and the follow-up time from 3 to 28 months. When compared to each other or to a placebo, Gentamicin was found to be the most efficacious medication, followed by Methylprednisolone, Latanoprost, Dexamethasone and Ganciclovir in order of effectiveness. However, no significant difference in efficacy was found between Gentamicin and Methylprednisolone when outcomes from studies with a follow-up time equal to or more than 24 months were analysed. It was not possible to conduct subgroup and sensitivity analysis because of the limited number of studies that were included. CONCLUSION: All medications are more effective than a placebo in the treatment of Ménière's disease by intratympanic injection. According to the SUCRA, Gentamicin ranked the most effective, with Gentamicin and Methylprednisolone equally effective in the long-term effect. When the potential risk of hearing loss induced by Gentamicin is taken into consideration, Methylprednisolone may be the best choice for the treatment of Ménière's disease by intratympanic injection.

A Modified Intensive Strategy to Prevent Cytomegalovirus Disease in Seropositive Umbilical Cord Blood Transplantation Recipients.

We previously demonstrated a lower rate of cytomegalovirus (CMV) reactivation and disease among seropositive umbilical cord blood transplantation (CBT) recipients receiving an intensive prophylaxis strategy consisting of ganciclovir on days -8 to -2 pretransplantation, high-dose valacyclovir post-transplantation, and twice-weekly serum CMV polymerase chain reaction testing. We hypothesized that a modified intensive strategy excluding pretransplantation ganciclovir would be similarly effective. We compared the risk of CMV reactivation, occurrence of CMV disease, and duration of anti-CMV therapy by day 100 post-CBT in patients receiving the modified intensive and intensive strategies. Forty patients received the modified intensive strategy, and 43 received the intensive strategy. There was no difference in the hazard for CMV reactivation (hazard ratio, 1.1; P = .77). No patients in the modified intensive cohort, but 2 patients in the intensive cohort, developed CMV disease (P = .53). There was no difference in the hazard for early (≤30 days post-CBT; P = .76) or high-level (>1000 IU/mL; P = .37) CMV reactivation. Patients in the modified intensive cohort had marginally higher CMV viral loads and percentage of days of CMV detection and treatment, although the contribution of pretransplantation ganciclovir to these differences is unclear. The overall percentage of treatment days was 32% in both cohorts after accounting for pretransplantation ganciclovir. In conclusion, exclusion of prophylactic ganciclovir before CBT did not impact the risk of CMV reactivation or disease, although CMV kinetics appeared to differ by prevention strategy. Best practices for CMV prevention will need further study as new prophylactic strategies become available.