Therapeutic drug monitoring of cancer chemotherapy.

Therapeutic drug monitoring is not routinely used for chemotherapy agents. There are Several reasons, but one major drawback is the lack of established therapeutic Concentration ranges. Combination chemotherapy makes the establishment of Therapeutic ranges for individual drugs difficult, the concentration-effect relationship for a single drug may not be the same as when that drug is used in a drug combination. Pharmacokinetic optimization protocols for many classes of cytotoxic compounds exist in specialized centers, and some of these protocols are now part of large multicentre trials. Nonetheless, TDM clearly has the potential to improve the clinical use of chemotherapy gents, most of which have very narrow therapeutic indices and highly variable pharmacokinetics. A substantial body of literature accumulating during the past 15 years demonstrates relationships between systemic exposure to various chemotherapy agents and their toxic or therapeutic effects. This article reviews TDM concepts in addition to tools based on pharmacokinetic modeling of chemotherapy agents. The administered dose of chemotherapy agents is sometimes adjusted individually using either a priori or a posteriori methods. These models can only be applied by using the same dose and schedule as the original study. Bayesian estimation offers more flexibility in blood sampling times and, owing to its precision and to the amount of information provided is the method of choice for ensuring that a given patient benefits from the desired systemic exposure. Moreover, the role and application of Pharmacogenetics as a tool for individualizing chemotherapy is discussed highlighting the agents and mechanisms that have been well studied and defined and their relevance to clinical practice. Finally, this paper address issues critical to the optimal use of TDM in a clinical setting, and the role of clinical pharmacist in this regard. In addition, it discusses future developments in this field that can contribute to improving cancer chemotherapy In terms of patient outcome and survival.     

In Vitro-Induced High Sugar Environments Deteriorate Human Cortical Bone Elastic Modulus and Fracture Toughness

Advanced glycation end-products (AGEs) have been suggested to contribute to bone fragility in type 2 diabetes (T2D). AGEs can be induced through in vitro sugar incubations but there is limited data on the effect of total fluorescent AGEs on mechanical properties of human cortical bone, which may have altered characteristics in T2D. Thus, to examine the effect of AGEs on bone directly in T2D patients with uncontrolled sugar levels, it is essential to first understand the fundamental mechanisms by studying the effects of controlled in vitro-induced AGEs on cortical bone mechanical behavior. Here, human cortical bone specimens from female cadaveric tibias (ages 57–87) were incubated in an in vitro 0.6 M ribose or vehicle solution (n = 20/group) for 10 days at 37°C, their mechanical properties were assessed by microindentation and fracture toughness tests, and induced AGE levels were quantified through a fluorometric assay. Results indicated that ribose-incubated bone had significantly more AGEs (+81%, p ≤ 0.005), lower elastic modulus assessed by traditional microindentation, and lower fracture toughness compared with vehicle controls. Furthermore, based on pooled data, increased AGEs were significantly correlated with deteriorated mechanical properties. The findings presented here show that the accumulation of AGEs allows for lower stiffness and increased ability to initiate a crack in human cortical bone. Statement of clinical significance: High sugar levels as in T2D results in deteriorated bone quality via AGE accumulation with a consequent weakening in bone's mechanical integrity. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:972-983, 2020     

Controlled Epstein–Barr virus reactivation after allogeneic transplantation is associated with improved survival

Epstein–Barr virus reactivation (EBV‐R) frequently occurs in patients having allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the impact of controlled EBV‐R on survival of 190 patients (114M/76F, median age: 51 yr, range 18–69), having HSCT for hematological malignancies (105 acute leukemias and myelodysplasias, 71 lymphoproliferative disorders, 14 others). Overall survival (OS) and progression‐free survival (PFS) were compared between patients with and without EBV‐R. Of 138, patients had reduced‐intensity conditioning regimen. Various stem cell sources (141 PB, 33 umbilical cord blood and 16 bone marrow) were used. Patients with EBV‐R had longer PFS and OS than those without EBV‐R: PFS at 2 yr 69% vs. 51% and at 5 yr 47% vs. 38% (P < 0.04); OS at 2 yr 76% vs. 64% and at 5 yr 63% vs. 47%) (P < 0.001). The use of rituximab had no impact on OS and PFS, but it reduced the intensity of GVHD, despite the fact that TRM was not significantly different between the two groups of patients. So, rituximab may have an additional effect to other factors on PFS and OS. In multivariate analysis, antithymocyte globulin administration was not a significant factor for PFS (P = 0.68) and for OS (P = 0.81). Circulating NK cells were significantly increased by 22% (P = 0.03) in EBV‐R patients with no differences for other parameters. Controlled EBV‐R in the setting of HSCT is associated with better OS and PFS, with a significant increase in circulating NK cells.     

Solubilization of Drugs by Physiological Mixtures of Bile Salts

Purpose. The solubilization of a number of steroids was determined in bile salt simple micelles and a bile salt/phospholipid micellar system to provide a better basis to predict the extent of drug solubilization in vivo. Methods. Excess solid drug was dispersed in taurodeoxycholate or mixed micelle solutions prepared with fixed mole ratios of taurocholate, taurodeoxycholate, taurochenodeoxycholate, glycodeoxycholate, glycocholate, and glycochenodeoxycholate with egg phosphatidylcholine. Drug concentrations were determined from the absorbance following centrifugation. Using NMR spectroscopy, the diffusivities of the simple and mixed micelles were 2 × 10^-6 and 8 × 10^-7 cm²/s, respectively. Results. From the change in the concentration of drug in solution with a change in the lipid concentration, the solubilization ratio (SR) was calculated. The SR and aqueous solubility were used to calculate the micelle/aqueous partition coefficients (K_m/w). K_m/w was correlated with octanol/water partition (P_o/w) for the TDC and mixed micelle data sets with correlation lines of logK_m/w = 0.74logP_o/w + 1.55 (r² = 0.91) and logK_m/w = 0.61 logP_o/w + 2.44 (r² = 0.95), respectively. Conclusions. With such data, a refined, predictive relationship between the in vitro and the in vivo solubilization with additional information concerning the bile salt/lipid concentration in the human intestine appears possible.     

Primitive intracranial adenoid cystic carcinoma. A case report

We report the case of a 50-year-old woman presenting a primitive adenoid cystic carcinoma of the middle part of skull base diagnosed by transphenoidal biopsy. She was treated by exclusive radiation therapy with cobalt 60 1.25 MeV and the dose received was 66 Gy in 33 fractions. Our patient remains alive 50 months after the completion of treatment. Adenoid cystic carcinoma is a slow growing malignant tumor with perineural invasion which arises more frequently from salivary glands. The occurrence of primary intracranial adenoid cystic carcinoma is exceptional. The best treatment is radical surgery followed by radiotherapy. Chemotherapy is rarely used. Prognosis is worse than for salivary glands.     

Guérison complète de l’hépatite virale C: une réalité

Acta Endoscopica - La réponse virologique complète soutenue est actuellement synonyme de guérison de l’infection virale C [1, 2). Néanmoins, nous pensons que le degré...     

Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile batten disease.

Classical late infantile neuronal ceroid lipofuscinosis (cLINCL) is a monogenic disorder caused by the loss of tripeptidyl peptidase 1 (TPP1) activity as a result of mutations in CLN2. Absence of TPP1 results in lysosomal storage with an accompanying axonal degeneration throughout the central nervous system (CNS), which leads to progressive neurodegeneration and early death. In this study, we compared the efficacies of pre- and post-symptomatic injections of recombinant adeno-associated virus (AAV) for treating the cellular and functional abnormalities of CLN2 mutant mice. Intracranial injection of AAV1-hCLN2 resulted in widespread human TPP1 (hTPP1) activity in the brain that was 10-100-fold above wild-type levels. Injections before disease onset prevented storage and spared neurons from axonal degeneration, reflected by the preservation of motor function. Furthermore, the majority of CLN2 mutant mice treated pre-symptomatically lived for at least 330 days, compared with a median survival of 151 days in untreated CLN2 mutant controls. In contrast, although injection after disease onset ameliorated lysosomal storage, there was evidence of axonal degeneration, motor function showed limited recovery, and the animals had a median lifespan of 216 days. These data illustrate the importance of early intervention for enhanced therapeutic benefit, which may provide guidance in designing novel treatment strategies for cLINCL patients.     

AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease.

Niemann-Pick A disease (NPA) is a fatal lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. The lack of functional ASM results in cellular accumulation of sphingomyelin and cholesterol within distended lysosomes throughout the brain. In this study, we investigated the potential of AAV-mediated expression of ASM to correct the brain pathology in an ASM knockout (ASMKO) mouse model of NPA. An AAV serotype 2 vector encoding human ASM (AAV2-hASM) was injected directly into the adult ASMKO hippocampus of one hemisphere. This resulted in expression of human ASM in all major cell layers of the ipsilateral hippocampus for at least 15 weeks postinjection. Transduced cells were also present in the entorhinal cortex, medial septum, and contralateral hippocampus in a pattern consistent with retrograde axonal transport of AAV2. There was a substantial reduction of distended lysosomes and an almost complete reversal of cholesterol accumulation in all areas of the brain that were targeted by AAV2-hASM. These findings show that the ASMKO brain is responsive to ASM replacement and that retrograde transport of AAV2 functions as a platform for widespread gene delivery and reversal of pathology in affected brain.