Functional diffusion map of malignant brain tumors: A surrogate imaging biomarker for early prediction of therapeutic response and patient survival

Purpose

To evaluate the ability of functional diffusion mapping “fDM” to predict early treatment response and survival in patients with primary malignant brain tumors.

Patients and methods

Forty-six brain tumor patients were examined by diffusion MRI before and 3 weeks after initiation of chemo- and/or radiotherapy. Images were co-registered to pretherapy scans, and tumor volumes with significant changes in apparent diffusion coefficient values were spatially displayed as functional diffusion maps. The predictive values of percentage of change in whole-tumor volume, mean ADC and fDM parameters for treatment response were evaluated by their correlation with the standard clinico-radiologic response criteria and overall survival of the two response groups was determined.

Results

Of the analyzed 46 brain tumors, 21 tumors were responding and 25 were stable/non-responding. At 3 weeks after initiation of therapy, the percentage of tumor volume with significant increase in diffusion (VR; red voxels) was the strongest predictor of treatment response than the changes in whole-tumor volume and mean ADC values determined at the same time point as compared to their pretherapy values. VR threshold of 14.5% at 3 weeks had sensitivity, specificity, positive and negative predictive values of 100% for all differentiating responding from stable/non-responding tumors. Overall survival in stable/non-responding group was shorter than in the responding group (8.7 versus 35.6 months; ∗∗P < 0.001).

Conclusion

The use of fDM provided an early and direct surrogate marker for predicting treatment response and patient survival in patients with malignant brain tumor.     

Association between low molecular polypeptide 7 single nucleotide polymorphism and response to therapy in hepatitis C virus infection

AIM: To investigate the relationship between low molecular polypeptide-7 (LMP-7) gene polymorphism and response to interferon (IFN) therapy in chronic hepatitis C virus (HCV) patients.METHODS: LMP-7 polymorphism at codon 49 with nucleotide substitution from A to C was amplified in 104 chronic HCV patients of genotype 4. The amplicons were digested with restriction endonuclease BsmI and the produced restriction fragment length polymorphism was analyzed. Patients received IFN + regional blood volume therapy for 48 wk and the frequency of this single nucleotide polymorphism (SNP) was statistically correlated with treatment response. The exclusion criteria for these patients were stated by the national health program for treating viral hepatitis. Main exclusion criteria included co-infection with hepatitis B virus or schistosomiasis, thyroid dysfunction, uncontrolled diabetes mellitus, history of long term drug or alcohol intake and autoimmune hepatitis. Multivariate analyses were done to correlate LMP-7 SNP plus several factors such as age, gender, weight, serum alpha-fetoprotein (AFP) and alanine aminotransferase levels, liver activity, fibrosis score and viral load with response to therapy.RESULTS: The data presented in this study clearly demonstrated statistically significant differences between sustained virological response (SVR) (defined as the absence of HCV RNA levels in the patient’s sera at least 6 mo after discontinuation of treatment) and non-response (NR) (where HCV RNA levels in the patient’s sera never become undetectable for 6 mo during or after treatment). Variables were described as odds ratio with 95%CI. The data were considered significant if P values were ≤ 0.05; highly significant if P < 0.01 and very highly significant if P < 0.001. Current data showed that 91.7% of patients carrying LMP-7 C/C allele were associated with SVR, while the other two genotypes C/A and A/A were associated with NR patients, 83.3% and 64.3% respectively, showing that genotype CC was strongly associated with response to interferon (95%CI: 12.0719-134.6572, P = 0.0001). The majority of parameters recorded in SVR and NR patients included higher values of mean age (P = 0.004), alanine aminotransferase (P = 0.001), AFP (P = 0.001), body weight (P = 0.025), viral load (P = 0.025), higher fibrosis and histological activity index indices among NR vs SVR patients. Also, the multivariate statistical analysis of the different factors of fibrosis score, liver activity grade, genotypes and alleles of LMP-7 gene polymorphism in responders and NRs of HCV patients in this study showed that HCV patients with A allele had a very highly significant association with the NRs, high fibrosis and higher liver activity, while the C allele had a very highly significant association with the responders, low fibrosis and lower liver activity (95%CI: 3.5800-13.2519, P = 0.0001).CONCLUSION: LMP-7 SNP is a candidate gene that should be considered when designing a mathematical model for predicting response to therapy and disease progression in HCV patients.     

More than skin deep? Potential nicotinamide treatment applications in chronic kidney transplant recipients

Non-melanoma cutaneous carcinomas, or skin cancers, predominantly squamous cell carcinomas (SCCs), are the most common malignancies occurring in kidney transplant recipients (KTRs). Squamous cell carcinoma risk is dramatically elevated in KTRs, occurring at rates of up 45-250 times those reported in general populations. New non-melanoma skin cancers in KTRs with a prior non-melanoma skin cancer also develop at 3-times the rate reported in non-KTRs with the same clinical history. The unique aggressiveness of SCCs in KTRs increases patient morbidity, due to the high rate of new lesions requiring treatment, frequently surgical excision. Oral nicotinamide shows promise in the chemoprevention of the especially aggressive non-melanoma skin cancers which occur in KTRs. This benefit might be conferred via its inhibition of sirtuin enzymatic pathways. Nicotinamide’s concurrent hypophosphatemic effect may also partially ameliorate the disturbed calcium-phosphorus homeostasis in these patients-a putative risk factor for mortality, and graft failure. Conceivably, a phase 3 trial of nicotinamide for the prevention of non-melanoma skin cancers in KTRs, lasting at least 12-mo, could also incorporate imaging and laboratory measures which assess nicotinamide’s impact on subclinical cardiovascular and chronic kidney disease risk, and progression.     

A comparative study of oxidant–antioxidant status in stable and active vitiligo patients

The pathogenetic mechanisms in vitiligo have not been completely clarified. One of the major hypotheses in the pathogenesis of vitiligo is the oxidative stress hypothesis. The active or stable phase of vitiligo is defined on the basis of the progression or appearance of new lesions in the last 3 months and the absence of new lesions or their progression in the last 6 months, respectively. Eighteen patients with active vitiligo, 18 patients with stable vitiligo, and 40 controls were included in this study. We examined serum levels of malondialdehyde, selenium, vitamin E and A, and the erythrocyte activities of glutathione peroxidase, superoxide dismutase, and catalase. Our results revealed a significantly higher level of serum malondialdehyde, selenium in patients with active disease compared with the controls. Significant higher increase in erythrocytes superoxide dismutase activities was observed in active vitiligo group, erythrocyte glutathione peroxidase activity was decreased significantly in active disease, whereas erythrocyte catalase activity and plasma vitamin E and A levels were not different in vitiligo patients as compared with controls. Our study shows that oxidative stress is involved in the pathophysiology of both active and stable vitiligo but increased imbalance of antioxidants was observed in the blood of active vitiligo patients.I dedicate this article to our dear director (Mme Hentati Basma) who dead in 06/06/06. We will never forget you and you are always in our heart.     

Enhanced healing efficacy of an optimized gabapentin-melittin nanoconjugate gel-loaded formulation in excised wounds of diabetic rats

The present study aimed to design and optimize, a nanoconjugate of gabapentin (GPN)-melittin (MLT) and to evaluate its healing activity in rat diabetic wounds. To explore the wound healing potency of GPN-MLT nanoconjugate, an in vivo study was carried out. Diabetic rats were subjected to excision wounds and received daily topical treatment with conventional formulations of GPN, MLT, GPN-MLT nanoconjugate and a marketed formula. The outcome of the in vivo study showed an expedited wound contraction in GPN-MLT-treated animals. This was confirmed histologically. The nanoconjugate formula exhibited antioxidant activities as evidenced by preventing malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymatic exhaustion. Further, the nanoconjugate showed superior anti-inflammatory activity as it inhibited the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). This is in addition to enhancement of proliferation as indicated by increased expression of transforming growth factor-β (TGF- β), vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor receptor-β (PDGFRB). Also, nanoconjugate enhanced hydroxyproline concentration and mRNA expression of collagen type 1 alpha 1 (Col 1A1). In conclusion, a GPN-MLT nanoconjugate was optimized with respect to particle size. Analysis of pharmacokinetic attributes showed the mean particle size of optimized nanoconjugate as 156.9 nm. The nanoconjugate exhibited potent wound healing activities in diabetic rats. This, at least partly, involve enhanced antioxidant, anti-inflammatory, proliferative and pro-collagen activities. This may help to develop novel formulae that could accelerate wound healing in diabetes.     

Gene Variants,mRNA and NOD1/2 Protein Levels in Tunisian Childhood Asthma

Introduction

Asthma is a common respiratory childhood disease that results from an interaction between genetic, environmental and immunologic factors. The implication of nucleotide-binding and oligomerization domain 1 and 2 (NOD1/CARD4, NOD2/CARD15) was highlighted in many inflammatory diseases.

Methods

In this case-control study, we analyzed the association of three NOD2 polymorphisms and one NOD1 variant, in 338 Tunisian asthmatic children and 425 healthy Controls, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. We also assessed NOD1 and NOD2 mRNA and protein levels by qRT-PCR and ELISA techniques.

Results

The homozygous AA genotype of rs2075820 was a risk factor for asthma (OR 2.39). The influence of the E266K variant in the presence of the heterozygous AG genotype was higher in male than female groups. The homozygous AA genotype was a risk factor associated with asthma, for patients aged between 6 and 18 years OR 2.39, IC95% (1.04–5.49) p < 0.01. The mRNA expression of NOD1, but not NOD2, was enhanced in asthma patients compared to Controls. We noted a significant difference between asthmatics and healthy controls in NOD1 protein expression (asthma patients : 31.18 ± 10.9 pg/ml, Controls: 20.10 ± 2.58 pg/ml; p < 0.001).

Conclusions

The NOD1 rs2075820 variant was associated with a higher childhood asthma risk and the NOD1 expression at mRNA and protein levels was significantly increased in asthma patients.

     

Role of metformin in oxaliplatin-induced peripheral neuropathy in patients with stage III colorectal cancer: randomized,controlled study

Purpose

Peripheral sensory neuropathy is the most prominently reported adverse effect of oxaliplatin. The purpose of this study was to evaluate metformin role in oxaliplatin-induced neuropathy.

Patients and methods

From November 2014 to May 2016, 40 patients with stage III colorectal cancer completed 12 cycles of FOLFOX-4 regimen. Twenty patients in the control arm received FOLFOX-4 regimen only, and 20 patients in the metformin arm, received the same regimen along with metformin 500 mg three times daily. The metformin efficacy was evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4.0), a12-item neurotoxicity questionnaire (Ntx-12) from the validated Functional Assessment of Cancer Therapy/Gynecologic Oncology Group and, the brief pain inventory short form “worst pain” item. In addition to neurotensin, malondialdehyde and interleukin-6 serum levels assessment.

Results

At the end of the 12th cycle, there were less patients with grade 2 and 3 neuropathy in metformin arm as compared to control arm. (60 versus 95%, P?=?0.009) In addition, metformin arm showed significantly higher total scores of Ntx-12 questionnaire than control arm (24.0 versus 19.2, P?<?0.001). Furthermore, the mean pain score in metformin arm was significantly lower than those of control arm, (6.7 versus 7.3, P?=?0.005). Mean serum levels of malondialdehyde and neurotensin were significantly lower in metformin arm after the 6th and the 12th cycles.

Conclusion

Metformin may be a promising drug in protecting colorectal cancer patients against oxaliplatin-induced chronic peripheral sensory neuropathy.