Hematopoietic Stem Cell Transplantation: Current Status of Old Issues

Since 1968 hematopoietic stem cell transplantation (HSCT) has progressed from an experimental to standard therapeutic procedure. There are many obstacles to the successful outcome of HSCT procedures. Some of these obstacles are lack of healthy histocompatible donors, graft versus host disease, graft rejection and infections. Many advances have been made to overcome these obstacles with significant success. However, these issues and associated problems continue to persist at different levels as the field evolves with expanding indications for HSCT, use of alternative sources for hematopoietic stem cells and alternative transplant procedures. Newer interventions have allowed us to overcome some of these obstacles.     

Transabdominal gastroesophageal devascularization without esophageal transection for emergency treatment of variceal hemorrhage.

BACKGROUND: The Suguira procedure is an effective non-shunting operation to treat life-threatening hemorrhage from esophageal or gastric varices. The goal of esophageal transection is interruption of submucosal varices, but this leads to high morbidity and mortality rates from esophageal fistulization. AIM: To evaluate a variant of this procedure in which the esophagus is not transected, but the varices are underrun from outside the lumen. METHODS: During the last four and a half years, we performed this modified gastroesophageal devascularization with or without splenectomy in 18 patients as emergency treatment of bleeding esophageal and gastric varices. The data were analyzed retrospectively. RESULTS: Bleeding was controlled in all patients. Three patients with Child's class C disease undergoing emergency surgery died during the early postoperative period. Rebleeding rate was 17% (3 patients). The overall survival was 72.2% (13 of 18). No patient had encephalopathy over a mean follow up of 30 months. CONCLUSION: Gastroesophageal devascularization with variceal under-running without esophageal transection is an effective and safe alternative to shunt surgery in the emergency situation.     

Optimization of planar high-dose-rate implants

Purpose: Brachytherapy has long been used to deliver localized radiation to the breast and other cancer sites. For interstitial implants, proper source positioning is critical in obtaining satisfactory dose distributions. The present work examines techniques for optimizing source guide placement in high-dose-rate (HDR) biplanar implants, and examines the effects of suboptimal catheter placement.

Methods and Materials: Control of individual dwell times in HDR implants allows a high degree of dose uniformity in planes parallel to the implant planes. Biplanar HDR implants can be considered optimized when the dose at the implant center is equal to the dose at the symmetric target boundaries. It is shown that this optimal dose uniformity is achieved when the interplanar separation is related to the target thickness T through the direct proportionality, s = T/√2. To quantify the significance of source positioning, the average dose and a related quantity, equivalent uniform dose (EUD), were calculated inside the treatment volume for two conditions of suboptimal catheter geometry. In one case, the interplanar spacing was varied from 1 cm up to the target thickness T, while a second study examined the effects of off-center placement of the implant planes.

Results: Both the average dose and EUD were minimized when the interplanar spacing satisfied the relationship s = T/ √2. EUD, however, was significantly smaller than the average dose, indicating a reduced relative cell killing in the high dose regions near the dwell points. It was also noted that in contrast to the average dose, the EUD is a relatively weak function of catheter misplacement, suggesting that the biological consequences of suboptimal implant geometry may be less significant than is indicated by the increase in average dose.

Conclusion: A concise formula can be used to determine the interplanar separation needed for optimal dose uniformity in Manchester-type implants. Deviations from optimal source geometry result in an increase in the average dose inside the treatment volume, but the weaker dependence of the EUD suggests that the surviving fraction of cells may not be not strongly affected by suboptimal source geometry.     

The role of AKT isoforms in glioblastoma: AKT3 delays tumor progression

The growth factor receptor/PI3K/AKT pathway is an important drug target in many cancers including Glioblastoma. AKT, a key node in the pathway, has 3 isoforms, AKT1, AKT2 and AKT3. Here we investigate their role in GBM. We find each activated, ser473 phosphorylated isoform is present in some GBMs but expression patterns vary. There is a direct relationship between human GBM patient outcome and both AKT1 and AKT2 mRNA levels, but an inverse relationship with AKT3 mRNA. Furthermore, AKT3 mRNA levels were high in a less aggressive GBM subtype. Overexpressing AKT3 improves survival in a rodent model of GBM and decreases colony forming efficiency, but not growth rate, in glioma cells. Silencing AKT3 slows cell cycle progression in one cell line and increases apoptosis in another. Our studies of AKT3 substrates indicate (1) silencing both AKT2 and AKT3 reduces GSK3 phosphorylation (2) only AKT2 silencing reduces S6 phosphorylation. Since S6 phosphorylation is a marker of mTORC1 activity this indicates that AKT2 activates mTORC1, but AKT3 does not. Our results indicate AKT isoforms have different roles and downstream substrates in GBM. Unexpectedly, they indicate AKT3 delays tumor progression. Therefore strategies that inhibit AKT3 may be unhelpful in some GBM patients.     

Management of liver hydatid cysts – Current perspectives

Human hydatid disease or cystic echinococcosis (CE), caused by the larval form of cestode Echinococcus granulosus still continues to a common problem in health care environments as different as Europe/North America and resource poor countries of the South America and the East. The Liver is the most frequently parasatized organ in humans. While ultrasonography remains the main diagnostic tool, computed tomography and serology improve the accuracy of diagnosis in Liver hydatid cysts (LHC). Although surgery is the only modality applicable over the entire spectrum of the disease, systemic chemotherapy and percutaneous drainage have evolved as alternative therapies in the last three decades. Various laparoscopic techniques have also been described for safe and optimal management of this entity. In this paper, we review the current management procedures of LHC with particular emphasis on the evidence base and setting specific problems.     

Impact of Insulin Resistance on Insulin-Like Growth Factor-1/Insulin Like Growth Factor-Binding Protein-3 Axis and on Early Weight Gain in Small for Gestational Age Infants

Objective: To assess insulin-like growth factor-1 (IGF-1)/IGF-binding protein-3 (IGFBP-3) axis and insulin resistance (IR) and the relationship of these parameters with growth in appropriate for gestational age (AGA) and small for gestational age (SGA) infants at birth and in early infancy.Methods: Postnatal blood samples for measurement of glucose, insulin, IGF-1, and IGFBP-3 were taken from 60 infants (30 AGA and 30 SGA) at birth and at one, three, and six months of age. Both SGA and AGA infants were divided into two groups: growing well and not growing well. Blood glucose, insulin, IGF-1, and IGFBP-3 values were assessed in all infants.Results: Homeostasis model assessment-IR (HOMA-IR) values in well-growing SGA infants in the third and sixth months were found to be higher than in not well-growing SGA infants (3.9±0.8 vs. 1.0±0.3 at 3 months and 3.3±0.9 vs. 2.4±0.9 at 6 months, p<0.05). IGF-1 levels in well-growing SGA infants at 3 and 6 months were found to be higher than those in not well-growing SGA infants (83.80±44.50 vs. 73.50±17.60 ng/mL at 3 months and 95.12±50.74 vs. 87.67±22.91 ng/mL at 6 months, p<0.05). The IGF-1 values were significantly lower in well-growing SGA infants than in well-growing AGA infants (83.80±44.50 vs. 103.31±30.81 ng/mL at 3 months and 95.12±50.74 vs. 110.87±26.44 ng/mL at 6 months, p<0.05).Conclusions: This study demonstrates the effects of accelerated early infant growth on IGF-1/IGFBP-3 axis in SGA-born infants.Conflict of interest:None declared.     

Analgesic,Anti-inflammatory and Local Anaesthetic Activity of Moringa pterygosperma in Laboratory Animals

The methanol extract of Moringa pterygosperma (Moringaceae) was used to evaluate its analgesic, anti-inflammatory and local anaesthetic activity in the present study. Analgesic activity was tested in mice using various doses orally. Acetic acid-induced writhing episodes were significantly and dose-dependently reduced. At the same dose, its anti-inflammatory activity was also tested. Carrageenin (a standard inflammatory agent)-induced paw edema in mice was significantly reduced after oral administration. Furthermore, its local anaesthetic activity were tested in frog and guinea pig models, and it was seen that in both animals, the plant (root bark) produces significant local anaesthetic activity.