Behavior Problems and Cognitive Function in Pediatric Liver Transplant Recipients

BackgroundLiver transplant (LT) is a lifesaving treatment providing excellent clinical outcomes. However, data regarding behavioral and cognitive issues after LT are sparse in Asia. This study aimed to investigate behavior and cognitive problems among pediatric LT recipients.MethodsWe used the Child Behavior Checklist (CBCL) to evaluate behavior problems and/or the Wechsler Intelligence Scale for Children, Third Edition (WISC-III) to assess cognitive function. Participants were children aged 2 to 18 years who were treated with LT for at least 2 years.ResultsWe included 77 children with a median age of 7.8 years (interquartile range, 5.0-10.9). All children were evaluated with the CBCL, and 26 children were available for WISC-III assessment. Approximately one-third (34%) of the children had a total CBCL score above a clinical cutoff for significant behavior problems, and 29% of school-aged children had abnormal competence scores in a clinically significant range. Most of the evaluated children (17 of 26; 65%) had a normal full-scale intelligence quotient. Lower cognitive function was associated with having a single parent (P < .01). Higher behavior problems were associated with lower parental education level (P = .01) and correlated with longer post-transplant duration (Spearman’s rho = 0.443; P < .001).ConclusionsSignificant numbers of children have behavior problems after LT. Most children have normal cognitive function, although a larger sample size is required to confirm this result. Long-term support for cognitive and behavior problems after LT should be implemented, particularly in children with single parents and lower parental education level.     

C646, a selective small molecule inhibitor of histone acetyltransferase p300, radiosensitizes lung cancer cells by enhancing mitotic catastrophe

Background and purpose

Chromatin remodeling through histone modifications, including acetylation, plays an important role in the appropriate response to DNA damage induced by ionizing radiation (IR). Here we investigated the radiosensitizing effect of C646, a selective small molecule inhibitor of p300 histone acetyltransferase, and explored the underlying mechanisms.

Materials and methods

A549, H157 and H460 human non-small cell lung carcinoma (NSCLC) cells, and HFL-III human lung fibroblasts were assessed by clonogenic survival assay. Apoptosis and necrosis were assessed by annexin V staining. Senescence was assessed by Senescence-associated β-galactosidase staining. Mitotic catastrophe was assessed by evaluating nuclear morphology with DAPI staining. Cell cycle profiles were analyzed by flow cytometry. Protein expression was analyzed by immunoblotting.

Results

C646 sensitized A549, H460 and H157 cells to IR with a dose enhancement ratio at 10% surviving fraction of 1.4, 1.2 and 1.2, respectively. C646 did not radiosensitize HFL-III cells. In A549 cells, but not in HFL-III cells, C646 (i) enhanced mitotic catastrophe but not apoptosis, necrosis, or senescence after IR; (ii) increased the hyperploid cell population after IR; and (iii) suppressed the phosphorylation of CHK1 after IR.

Conclusions

C646 radiosensitizes NSCLC cells by enhancing mitotic catastrophe through the abrogation of G2 checkpoint maintenance.     

Health-Related Quality of Life in Pediatric Liver Transplant Recipients

BackgroundHealth-related quality of life (HRQoL) of liver transplantation (LT) recipients has been widely studied because of increased patient longevity. However, studies in developing countries are scanty. We aimed to evaluate psychometric properties of the Thai version of the PedsQL Transplant Module and used it to determine the HRQoL in LT children.MethodsWe included children aged 2 to 18 years who underwent LT more than 1 year previously. The phase 1 study included a cognitive interview with 20 LT children and their parents using the Thai version of PedsQL Transplant Module and revised the module accordingly. Then, the finalized version was evaluated for psychometric properties in 50 LT children. In phase 2, HRQoL was evaluated in 52 LT children who did not participate in the phase 1 study.ResultsIn the Thai PedsQL Transplant Module, both parent report and child self-report had good internal consistency (α = 0.94 and 0.93, respectively) and substantial reliability (interclass correlation coefficient = 0.82 and 0.77, respectively). Median HRQoL scores from the parent report and child self-report were 80 (interquartile range [IQR], 70, 88) and 77 (IQR, 71, 88), respectively. From the parent report, lower HRQoL was associated with opportunistic viral infection (P = .004) and correlated with a greater number of immunosuppressive agents (ρ = –0.346, P = .014). However, none of these factors were significant according to the child self-report.ConclusionsThe Thai PedsQL Transplant Module has satisfactory psychometric properties. Post-LT children have good HRQoL. To improve their HRQoL, specific attention should be focused on managing viral infection and optimizing immunosuppressive therapy.     

Lower urinary tract dysfunction and quality of life in cervical cancer survivors after concurrent chemoradiation versus radical hysterectomy

Introduction and hypothesis

Lower urinary tract dysfunction (LUTD) is a common morbidity. Due to the different pathophysiology of LUT injury, we compared LUTD between patients who received concurrent chemoradiation (CCRT) and radical hysterectomy (RH).

Methods

Seventy cervical cancer survivors were evaluated with multichannel urodynamic studies. The CCRT group received a total dose of 54 Gy pelvic radiation with 2–3 high-dose-rate brachytherapy, concurrent with platinum-based chemotherapy. The RH group underwent type III RH without pre- or postoperative radiation.

Results

Overall, LUTD was insignificantly different between CCRT and RH (60 % and 68.6 %). Voiding dysfunction was significantly higher in RH, particularly high postvoid residual urine and void with abdominal straining. However, storage dysfunction, particularly low bladder compliance and increased bladder sensation, were significantly more prevalent in CCRT; urinary incontinence was not significantly different between groups.

Conclusion

LUTD was prevalent in cervical cancer survivors. Different profiles of dysfunction were demonstrated. Voiding dysfunction was higher followng RH, but storage dysfunction was higher following CCRT.     

Chromatin-regulating proteins as targets for cancer therapy

Chromatin-regulating proteins represent a large class of novel targets for cancer therapy. In the context of radiotherapy, acetylation and deacetylation of histones by histone acetyltransferases (HATs) and histone deacetylases (HDACs) play important roles in the repair of DNA double-strand breaks generated by ionizing irradiation, and are therefore attractive targets for radiosensitization. Small-molecule inhibitors of HATs (garcinol, anacardic acid and curcumin) and HDACs (vorinostat, sodium butyrate and valproic acid) have been shown to sensitize cancer cells to ionizing irradiation in preclinical models, and some of these molecules are being tested in clinical trials, either alone or in combination with radiotherapy. Meanwhile, recent large-scale genome analyses have identified frequent mutations in genes encoding chromatin-regulating proteins, especially in those encoding subunits of the SWI/SNF chromatin-remodeling complex, in various human cancers. These observations have driven researchers toward development of targeted therapies against cancers carrying these mutations. DOT1L inhibition in MLL-rearranged leukemia, EZH2 inhibition in EZH2-mutant or MLL-rearranged hematologic malignancies and SNF5-deficient tumors, BRD4 inhibition in various hematologic malignancies, and BRM inhibition in BRG1-deficient tumors have demonstrated promising anti-tumor effects in preclinical models, and these strategies are currently awaiting clinical application. Overall, the data collected so far suggest that targeting chromatin-regulating proteins is a promising strategy for tomorrow''s cancer therapy, including radiotherapy and molecularly targeted chemotherapy.     

Assessment of the confidence interval in the multivariable normal tissue complication probability model for predicting radiation-induced liver disease in primary liver cancer

We developed a confidence interval-(CI) assessing model in multivariable normal tissue complication probability (NTCP) modeling for predicting radiation-induced liver disease (RILD) in primary liver cancer patients using clinical and dosimetric data. Both the mean NTCP and difference in the mean NTCP (ΔNTCP) between two treatment plans of different radiotherapy modalities were further evaluated and their CIs were assessed. Clinical data were retrospectively reviewed in 322 patients with hepatocellular carcinoma (n = 215) and intrahepatic cholangiocarcinoma (n = 107) treated with photon therapy. Dose–volume histograms of normal liver were reduced to mean liver dose (MLD) based on the fraction size-adjusted equivalent uniform dose. The most predictive variables were used to build the model based on multivariable logistic regression analysis with bootstrapping. Internal validation was performed using the cross-validation leave-one-out method. Both the mean NTCP and the mean ΔNTCP with 95% CIs were calculated from computationally generated multivariate random sets of NTCP model parameters using variance–covariance matrix information. RILD occurred in 108/322 patients (33.5%). The NTCP model with three clinical and one dosimetric parameter (tumor type, Child–Pugh class, hepatitis infection status and MLD) was most predictive, with an area under the receiver operative characteristics curve (AUC) of 0.79 (95% CI 0.74–0.84). In eight clinical subgroups based on the three clinical parameters, both the mean NTCP and the mean ΔNTCP with 95% CIs were able to be estimated computationally. The multivariable NTCP model with the assessment of 95% CIs has potential to improve the reliability of the NTCP model-based approach to select the appropriate radiotherapy modality for each patient.     

Rectal irrigation as rescue therapy for refractory and severe hemorrhagic radiation proctitis: A case report

Rectal irrigation may be considered in refractory and severe hematochezia from chronic radiation proctitis before performing other invasive treatments. It prevents superimposed infection and effectively reduces bleeding.