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Clinical, Journal: BK virus encephalitis in children with hematopoietic stem cell transplantation (Pubmed Central) - Nov 22, 2021
Therefore, when there are neurological symptoms and hemorrhagic cystitis in patients with allo-HSCT, it is necessary to be highly vigilant against BKV central nervous system infection. This helps to make clear diagnosis and treatment quickly; thus, improving the survival rate and quality of life of patients with HSCT.
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Journal: ERK-dependent suicide gene therapy for selective targeting of RTK/RAS-driven cancers. (Pubmed Central) - Nov 21, 2021
In contrast to transcriptional strategies for selectivity, regulation of protein stability by ERK allows for high copy expression via constitutive viral promoters, while maintaining tumor selectivity in contexts of elevated ERK activity. Thus, our approach turns a signaling pathway often coopted by cancer cells for survival into a lethal disadvantage in the presence of a chimeric protein and prodrug, as highlighted by a series of in vitro and in vivo examples explored here.
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Preclinical, Journal: Sexual Dimorphism in Hepatocyte Xenograft Models. (Pubmed Central) - Nov 21, 2021
The sexual imbalance for xenograft success was related to higher baseline ALT levels and lower thresholds for ganciclovir induced liver morbidity and mortality in males. These data call for sexual standardization of human hepatocyte xenograft models, but also provide a platform for further studies on mechanisms behind sexual dimorphism in liver diseases.
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Comparing tumor cell invasion and myeloid cell composition in genetically identical primary and relapsing glioblastoma (Exhibit Hall D) - Nov 16, 2021 - Abstract #SNO2021SNO_943;
Strong reduction of the GBM volume is achieved after pharmacologically inducing a tumor-specific cell death mechanism by the prodrug ganciclovir...We interpret that factors released from viable primary GBM cells preferentially attract microglia whereas relapsing tumors preponderantly release chemoattractants for MDMs. All in all, this relapse model has the capacity to provide novel insights into clinically highly relevant aspects of GBM treatment.
- |||||||||| vocimagene amiretrorepvec (Toca 511) / Forte Biosci, Cytovene (ganciclovir) / Roche
Retroviral replicating vectors pseudotyped with Gibbon ape leukemia virus envelope for prodrug activator gene therapy in preclinical glioma models (Exhibit Hall D) - Nov 16, 2021 - Abstract #SNO2021SNO_501;
Amphotropic retroviral replicating vector (RRV) Toca 511, expressing the yeast cytosine deaminase (CD) prodrug activator gene, showed promising evidence of therapeutic benefit and increased survival in early-phase trials for recurrent high-grade glioma...Established and primary human glioblastoma cells infected with RRV(GALV)-TK vector showed ≥ 50%-90% reduction in cell viability after exposure to Ganciclovir prodrug in the range of 1µM-100µM for 5 days, as compared to uninfected control cells or cells infected with RRV(GALV)-GFP control vector...Further data will be presented from on-going studies evaluating these vectors in intracerebral glioblastoma models. These results indicate that GALV envelope-pseudotyped RRV can efficiently deliver prodrug activator gene therapy in experimental glioma models, and open the door to combinatorial gene therapy regimens with this vector platform.
- |||||||||| Cytovene (ganciclovir) / Roche, ceralasertib (AZD6738) / AstraZeneca
Disruption of DNA damage response modulates the efficacy of local immunotherapies in experimental glioma (Exhibit Hall D) - Nov 16, 2021 - Abstract #SNO2021SNO_309;
Here we investigated the effects of HSV-TK gene delivery with a non-replicating serotype 5 adenovirus (AdTK) in murine glioblastoma models in combination with the ATR-inhibitor AZD6738 to disrupt the DNA damage response (DDR)...CONCLUSION DDR signaling is crucial in the therapeutic efficacy of AdTK/GCV. It significantly enhances cytotoxicity in vitro and in vivo while having complex ramifications at the immunological level, requiring further studies to determine ideal conditions for a maximized therapeutic benefit.
- |||||||||| ceftriaxone / Generic mfg., clarithromycin / Generic mfg.
PK/PD data, Journal: Pharmacokinetics of anti-infective agents during CytoSorb hemoadsorption. (Pubmed Central) - Nov 10, 2021
Hemoadsorption with CytoSorb appears to increase to a clinically significant extent the clearance of five among 17 tested anti-infectives. Studies in human patients are required to confirm the need for dosage adjustment of these agents.
- |||||||||| Zirgan (ganciclovir ophthalmic gel) / Bausch Health, Thea Laboratories, Cytovene (ganciclovir) / Roche
Pancytopenia with multiple opportunistic infections in a lupus patient () - Nov 7, 2021 - Abstract #APLAR2021APLAR_766;
She received pulse intravenous (IV) methylprednisolone for presumed haematological flare followed by prednisolone 40 mg daily...She was treated with multiple antibiotics (Levofloxacin, Azithromycin, IV Imipenem and Amikacin for atypical Mycobacterium), anti-tuberculous medications (ethambutol, isoniazid, rifampicin and pyrazinamide), antifungal (amphotericin B, followed by itraconazole and later fluconazole) and anti-viral (ganciclovir) agents...Her prednisolone dose was tapered to 5 mg daily and subsequently converted to replacement hydrocortisone. Opportunistic infections should be considered as a potential cause of pancytopenia especially in lupus patients.
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Horizontal Gene Transfer in Multiple Myeloma and Development of a Non-Viral Gene Delivery System (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_5686;
However, MMZC-HSV-Tk-GFP reduce MM cell viability when ganciclovir was added to the cell culture...Furthermore, tumor tissue expressed GFP. To our knowledge this is the first description of the use of humanized non-viral synthetic technology capable of delivering therapeutic cargo material into MM cell.
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Mutational Consequences of Chemotherapy in Hematopoietic Stem and Progenitor Cells of Pediatric Cancer Patients (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_3766;
Conclusions Enhanced mutation accumulation after pediatric cancer treatment is caused by both direct and indirect mechanisms. The variance in mutagenic effects of (chemo)therapies on healthy HSPCs may influence the risk an individual patient has to develop t-AML and could, in future, play a role in t-AML risk assessment of pediatric cancer survivors and the development of new treatment regimens.
- |||||||||| Darzalex IV (daratumumab) / J&J, Avastin (bevacizumab) / Roche
Treatment Outcomes and Prognostic Factors in 40 Patients with Primary Effusion Lymphoma (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_3008;
Of the 39 patients who received front-line treatment, 38 received combination chemotherapy (EPOCH [36], CHOP [1], ICE [1]) with rituximab added in 34 patients to treat concurrent MCD or deplete the KSHV-infected B cell reservoir...Eleven patients with relapsed/refractory disease received second-line therapy, including combination chemotherapy (3); brentuximab (3); pembrolizumab (1); pembrolizumab and pomalidomide (1); interferon-alpha, ganciclovir, and bevacizumab (1); bortezomib, ganciclovir, and zidovudine (1); and radiation to pelvic lymph nodes (1)...Patients with extracavitary PEL appear to have improved OS, and we confirmed our prior study noting EBER-positive PEL is a positive prognostic marker. Promising chemotherapy-sparing treatment regimens in relapsed/refractory PEL, include pembrolizumab, pomalidomide, and daratumumab.
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Journal: Bluetongue Virus Particles as Nanoreactors for Enzyme Delivery and Cancer Therapy. (Pubmed Central) - Nov 4, 2021
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.
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Clinical, Journal: Cytomegalovirus hepatitis in a 2-month-old infant: a case report (Pubmed Central) - Nov 4, 2021
Cytomegalovirus hepatitis is a complication that may be associated with the involvement of other organs. Antiviral treatment for liver involvement is still controversial; however, it is recommended in children under one month of age if it is associated with neurological damage.
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Clinical, Journal: Ganciclovir therapeutic drug monitoring in transplant recipients. (Pubmed Central) - Oct 30, 2021
This study revealed that a standard weight and kidney function-based dosing regimen resulted in highly variable ganciclovir Cmin and under- and over-exposure were observed in patients on dialysis and in patients with increased renal function. Clearly there is a need to explore the impact of concentration-guided dose adjustments in a prospective study.
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[VIRTUAL] CYTOMEGALOVIRUS REACTIVATION IN PATIENTS WITH DIAGNOSIS OF MULTIPLE MYELOMA OR AMYLOIDOSIS UNDER TREATMENT WITH BORTEZOMIB IN THE HEMATOLOGY AND HEMOTHERAPY SERVICE OF USP RIBEIRÃO PRETO/SP HOSPITAL IN 2020: A SERIES OF CASES () - Oct 27, 2021 - Abstract #HEMO2021HEMO_1417;
In 2020, 5 cases of cytomegalovirus infection were identified in patients being treated for Multiple Myeloma and Amyloidosis using chemotherapy regimens containing Bortezomib in the Hematology and Hemotherapy Service of the Hospital das Clínicas in Ribeirão Preto/SP. Three cases were identified in the etiological investigation of subacute diarrhea, one was identified in the stratification of neutropenic colitis with enteroinvasive characteristics, and the last in the investigation of acute pneumonitis with signs of viral infection on chest tomography (in this case, infection by Covid-19 was excluded after two negative PCR-RT tests). In all cases, after identification of CMV infection (by serology - Elisa and confirmation of viral load by PCR-RT), specific antiviral therapy was instituted, both intravenous Ganciclovir and oral Valganciclovir. Despite the high morbidity and mortality associated with this infection in immunosuppressed patients, only one of the five patients died from associated complications. Discussion The high seroprevalence of cytomegalovirus infection in Brazil is related to socioeconomic factors and poor conditions of basic sanitation and increases morbidity and mortality in immunosuppressed patients . The more frequent use of Bortezomib as a first line in patients with Multiple Myeloma and Amyloidosis in our service and in Brazil brings this agent to light as a differential diagnosis in clinical suspicions of infectious diseases of different organs and systems.
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[VIRTUAL] PRIMARY CEREBELLUM LYMPHOMA POST LIVER TRANSPLANTATION IN POSITIVE EPSTEIN BARR PATIENT: CASE REPORT () - Oct 27, 2021 - Abstract #HEMO2021HEMO_1353;
EBV positive liver transplantation.Materials and Methods After signing the Informed Consent Term, a medical record was analyzed, a literature review was carried out for a case report and a clinical case Discussion .Case report A 63-year-old male, with a history of liver transplantation in 2017 due to alcoholic liver disease and hepatitis C, in the presence of mycophenolate 360 mg twice a day and sirolimus 5 mg once a day, evolved with headache in the occipital region, associated with ataxia and mild aphasia for approximately 02 months, which led to request for cerebral scintigraphy with SESTAMIBI-TC, which showed expansive lesions in the left parietal lobe and right cerebellar hemisphere, with significant perilesional edema. Biopsy of the lesion was performed, with histopathological report compatible with B-cell lymphoma, and immunophenotyping showing a positive CD20 marker. Staging serologies showed the presence of EBV viral DNA in the order of 366,793 log, which motivated the initiation of treatment with intravenous Ganciclovir at a dose of 300 mg/day. Discussion O (LPSNC) is a neoplasm with high association with EBV and immunosuppression, common in solid organ transplant recipients. The most effective therapy in the management of this lymphoma subtype is the suspension or reduction of the current immunosuppression, and regimens with high doses of MTX or local radiotherapy can be used. In the patient in question, it was decided to suspend the two immunosuppressants, in addition to starting radiotherapy, since the liver function requires treatment with adequate doses of MTX. Other therapeutic options would be Interferon and monoclonal antibodies against B cell markers, such as rituximab. The patient is under outpatient follow-up, scheduled to start radiotherapy treatment.
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[VIRTUAL] ALLOGEN TRANSPLANTATION OF HEMATOPOIETIC STEM CELLS (HSCT) FOR THE TREATMENT OF SICKLE ILLNESS (DF): DIFFERENT STRATEGIES AND COMPLICATIONS, BUT SIMILAR RESULTS WITH HAPLOIDENTIC (HAPLO) AND HLA-IDENTIC BROTHER HCT () - Oct 27, 2021 - Abstract #HEMO2021HEMO_70;
Introduction Despite neonatal diagnosis, supportive treatment and early onset of hydroxyurea (HU), morbidity and mortality from sickle cell disease (FD) is still high in Brazil. The only curative treatment available is HSCT, indicated for patients with severe complications of FD. As there is a greater risk of graft rejection in FD and most children do not have an HLA-compatible healthy donor, several groups have been developing strategies to improve the Results obtained with HSCT Haplo.Objective To present experience with HSCT for FD with HLA-identical and Haplo donors with strategies developed by the group from USP-Ribeirão Preto and by the multi-institutional learning collaborative, led by the HSCT team from Vanderbilt. Method For HLA-identical donor related transplants, conditioning was ATG, Busulfan and Fludarabine (Flu) and prophylaxis of DECH with CsA-Mtx. For Haplo transplants, Flu, Cyclophosphamide (Cy), ATG, Thiotepa and TBI 200 cGy were used. Only one patient in this group did not receive Thiotepa, and the TBI dose was increased to 400 cGy, a conditioning option developed by the international consortium based on the experience of the Johns Hopkins Oncology Center. GVHD prophylaxis for Haplo was Cy post-HSCT, Sirolimus-MMF. The only source of cells was bone marrow. Before Haplo, patients must remain on a hypertransfusion regimen for at least 2 months pre-BMT, maintain reticulocytes <10%, HbS <20% and HU at a minimum dose of 20 mg/kg/day. They received ganciclovir up to D-1 and prophylactic acyclovir in a dose of zoster during hospitalization. During HSCT, they maintain platelets >50000/mm3, Hb 9–10 g/dL, strict control of blood pressure and anticonvulsant during the period of use of sirolimus or CsA.Result From 2016–2021, 6 HSCT for FD were performed in girls with aged between 3 and 18 years. Two had HLA-identical related donors, for 4, the donor was father Haplo. The total number of CD34 cells in the bone marrow ranged from 4 to 10×10(6)/kg. The neutrophilic graft on Haplo was on average on D+22, versus D+18. Two of the 4 patients who underwent Haplo had mild acute GVHD and moderate chronic GVHD, all of which responded well to corticosteroids. After HLA-identical HSCT, 1 child had dry eye and another had moderate chronic GVHD in skin and GIT and still receives immunosuppression 5 years after HSCT. One patient in each group had mixed chimerism, stable after compatible HLA HSCT and decreasing in Haplo without Thiotepa, coinciding with poor adherence to sirolimus and reverted with medication adjustment and DLI. With a median follow-up of 563 days, all are healthy.Conclusion In this small cohort, we saw good Results in HSCT for the treatment of FD and similar outcomes in Haplo and HLA-identical donor transplants. Children face numerous complications and need teams with experience in haploidentical transplants, infrastructure to treat their complications and thiotepa in conditioning to ensure adequate grafting.
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Journal, Tumor Mutational Burden: Antiviral treatment causes a unique mutational signature in cancers of transplantation recipients. (Pubmed Central) - Oct 27, 2021
Using a machine learning approach, we detected this signature in cancer genomes of individuals who received HSCT or solid organ transplantation earlier in life. Antiviral treatment with nucleoside analogs can cause enhanced mutagenicity in transplant recipients, which may ultimately contribute to therapy-related carcinogenesis.
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Clinical, Journal: Caught in the antiviral crossfire: Ganciclovir-associated mutagenesis in HSC transplant recipients. (Pubmed Central) - Oct 27, 2021
(2021) show that most allogeneic hematopoietic stem cells do not acquire additional somatic mutations following transplantation. However, they observe somatic mutagenesis associated with the antiviral drug ganciclovir and find plausible evidence that it may contribute to some post-transplant malignancies.
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Clinical, Journal: Discordance Between Using Estimated and Measured Glomerular Filtration Rate for Drug Dosing in Kidney Transplant Recipients. (Pubmed Central) - Oct 22, 2021
Large prospective studies on UL97-GCV-R are warranted. Until developing more accurate methods for estimating kidney function during first 1 to 2 weeks after kidney transplantation, CGTBW method is suggested for drug dose adjustment and MDRD or CKD-EPI equation for the staging of kidney function in these patients, keeping in mind that these formulas underestimate the level of kidney function in new transplant recipients.
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Journal: Screening and application of a broad-spectrum aptamer for acyclic guanosine analogues. (Pubmed Central) - Oct 22, 2021
Finally, the aptamer CIV6 was used to construct GO fluorescence assay to detect five acyclic guanosine analogues. The limits of detection (LOD) of acyclovir, famciclovir, ganciclovir, penciclovir, and valaciclovir were 0.48 ng·mL, 0.53 ng·mL, 0.50 ng·mL, 0.56 ng·mL, and 0.38 ng·mL, respectively.
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[VIRTUAL] HEPATIC REGENERATION REQUIRES HEPATIC STELLATE CELLS (HSCs) – EVIDENCE FROM HSC DEPLETION MODELS () - Oct 21, 2021 - Abstract #AASLD2021AASLD_1600;
Mice were pretreated with low doses of CCl4 and allyl alcohol to induce proliferation, rendering Tk+ HSCs susceptible to Ganciclovir (GCV) induced depletion... Depletion of HSCs leads to impaired hepatocyte proliferative activity and decreased survival after partial hepatectomy which is not simply through secretion of hepatocyte mitogens .
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