Identification of hub genes involved in cisplatin resistance in head and neck cancer.

BACKGROUND: Cisplatin resistance is one of the major contributors to the poor survival rate among head and neck cancer (HNC) patients. Focusing on the protein-protein interaction rather than a single protein could provide a better understanding of drug resistance. Thus, this study aimed to identify hub genes in a complex network of cisplatin resistance associated genes in HNC chemotherapy via a series of bioinformatic tools. METHODS: The genes involved in cisplatin resistance were retrieved from the NCBI gene database using "head and neck cancer" and "cisplatin resistance" as key words. The human genes retrieved were analyzed for their interactions and enriched using the STRING database. The interaction between KEGG pathways and genes was visualized in Cytoscape 3.7.2. Further, the hub gene was identified using the Cytohubba plugin of Cytoscape and validated using UALCAN and Human Protein Atlas database. Validated genes were investigated for the drug-gene interaction using the DGIbd database. RESULTS: Out of 137 genes obtained using key words, 133 were associated with cisplatin resistance in the human species. A total of 150 KEGG pathways, 82 cellular components, 123 molecular functions, and 1752 biological processes were modulated on enrichment analysis. Out of 37 hub genes, CCND1, AXL, CDKN2A, TERT, and EXH2 genes were found to have significant (p < 0.05) mRNA expression and effect on overall survival whereas protein expression was found to be positive for all the significant genes except TERT. Thus, they can be targeted with palbociclib, methotrexate, bortezomib and fluorouracil, sorafenib, dasatinib, carboplatin, paclitaxel, gemcitabine, imatinib, doxorubicin, and vorinostat. CONCLUSION: As the pathogenesis of head and neck cancer is complex, targeting hub genes and associated pathways involved in cisplatin resistance could bring a milestone change in the drug discovery and management of drug resistance which might uplift overall survival among HNC patients.

Role of Otoacoustic Emission in Early Detection of Cisplatin Induced Ototoxicity.

Cisplatin is a chemotherapeutic agent effective against head and neck carcinoma but unfortunately it is cochleotoxic. This study has been designed to investigate the efficacy of OAE in identifying early effects of cisplatin on the cochlea and the importance of protocol for audiological monitoring of cisplatin induced ototoxicity. This is a prospective observational study conducted from October 2012 to September 2014 on 70 patients, receiving Cisplatin for various malignant conditions. Audiological criteria for ototoxicity was considered as a difference of 10 d B or more in pure tone thresholds of two or more adjacent frequencies in conventional audiometry and in DPOAE-Signal noise ratio less than 6 dB or DPOAE amplitude less than 20 dBSPL (irrespective of SNR > 6 dB). According to PTA, 60.7% patients showed ototoxicity after completion of chemotherapy. In DPOAE, according to SNR and amplitude criteria more than 60% patients showed ototoxicity after first cycle of cisplatin at high frequencies (4-8 kHz). DPOAEs is a sensitive tool for early detection of ototoxicity and protocol is necessary for monitoring ototoxicity in patients receiving cisplatin to improve the quality of life.

Alpha1-antitrypsin combined fatty acids induced angiopoietin-like protein 4, expression in breast cancer: A pilot study.

INTRODUCTION: The effect of nutrition on inflammation and breast cancer (BC) prognosis is still inconclusive. Mechanism of data suggests that different types of fatty acids (FAs) play an essential role in carcinogenesis, and binding of alpha 1 antitrypsin (A1AT) may modulate carcinogenesis. The increased expression in the bound form of A1AT and release of Angiopoietin-like protein 4 (Angptl4) targets the gene of peroxisome proliferator-activated receptor-gamma (PPAR-γ). Our aim of the study was to compare the effect of FA-free (A1AT-0) and FAs bound forms of A1AT on levels of IL-1ß, PPAR-gamma, and Angplt4 in breast cancer and control women. METHODOLOGY: 10 women with breast cancer and ten control women within the age group 25-60 years with normal (Pi) M allele A1AT were recruited. Mononuclear cells were isolated and treated with different A1AT and FAs on the various combinations (linoleic acid, alpha-linolenic acid) for time-dependent study (2,4,18 and 24 h) and analyzed for the interleukin -1 beta(IL-1b), PPAR-gamma, and Angiopoietin-like protein 4 (Angptl4) expression by using ELISA method and gas chromatography for analyzing FAs. One-way ANOVA combined with multiple comparisons is used to compare the means. RESULTS: 100% of the study subjects were homozygous for the normal allele of A1AT. Time-dependent effects of A1AT and A1AT conjugated fatty acids on IL-I b, PPAR-g and Angptl4 showed statistically significant P = 0.07, P = 0.001, and P = 0.02 respectively, compared to those of the former study subjects. But within the groups, PPAR-g levels in case group (F(15,40)1.606, P = 0.003) and Angptl4 in the control group (F(15,32)0.64, P = 0.043) differed significantly. CONCLUSION: To the best of our knowledge, it's the first kind of study, and we speculate that the A1AT complex with different types of FAs results in a new form of A1AT having a solid capability to regulate the inflammation-induced synthesis, processing, and release of an active form of IL-1ß. Our experimental data shows that the anti-inflammatory property of A1AT combined FAs likely to be mediated PPAR γand Angptl4 activation, thereby inhibiting the IL-1b. These findings may be worth assessing BC's biological effects and therapeutic effectiveness.

Plasma fatty acids composition and estimated delta desaturases activity in women with breast cancer.

INTRODUCTION: Fatty acids (FAs) are the vital constituents of membrane structures. De novo synthesis of FAs includes an enzymatic complex of FA synthase and delta desaturases. These enzymes are overexpressed in tumors, and inhibition of these enzymes is gaining interest. Our aim was to determine if delta desaturase activities are altered in breast cancer (BC) cases and if altered whether delta desaturase activities differ among BC genotypes. MATERIALS AND METHODS: In this observational comparative study, 50 women with BC and 30 control women were recruited for the study. Gas chromatography-flame ionization detector was used to measure the plasma FA levels. Desaturase activities were assessed as product-to-precursor FA ratios. The Wilcoxon signed-rank test was used to compare between two groups, and P ≤ 0.05 was considered as statistically significant. RESULTS: The FA analysis revealed higher levels of monounsaturated FAs (MUFAs) and linolenic acid metabolites (C18:3n-6, C20:4n-6) in BC patients, whereas C20:5n-3 was higher in controls. The Delta 9 desaturase (D9D) and D6D were higher in BC cases suggesting greater conversion saturated FA to MUFA and linoleic acid to its metabolites. D9D-16 activity was statistically significant (P = 0.03) in BC women, particularly in estrogen-receptor-positive patients. CONCLUSION: There is limited evidence to substantiate the link between diet and cancer. The current study showed there is an altered lipid desaturase activity. Nutritional intervention and drugs that target the FA pathway may provide a new approach to prevent and treat BC.

Solitary fibrous tumour of cervical spinal cord.

Solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms of fibroblastic origin. They commonly arise from visceral pleura, but also arise from nonserosal sites such as meninges, central nervous system parenchyma, and spinal cord. In the spinal cord, SFTs commonly arise from the thoracic spinal cord, followed by cervical spinal cord, lumbar spinal cord, and sacrum. Histologically, SFTs can be similar to hemangiopericytoma, schwannoma, fibrous meningioma, fibroma, gliofibroma, and ependymoma. Immunohistochemistry (IHC) plays an important role in differentiating SFTs from other identical tumors. Here, we report a rare case of SFT of the cervical spinal cord, which was initially reported as hemangiopericytoma, and the diagnosis of SFT was confirmed by IHC.

Résumé Les tumeurs fibreuses solitaires (SFT) sont des néoplasmes mésenchymateux rares d'origine fibroblastique. Ils proviennent généralement de la plèvre viscérale, mais aussi proviennent de sites non séreux tels que les méninges, le parenchyme du système nerveux central et la moelle épinière. Dans la moelle épinière, les SFT proviennent de la moelle épinière thoracique, suivie de la moelle épinière cervicale, de la moelle épinière lombaire et du sacrum. Histologiquement, les SFT peuvent être similaires à hémangiopéricytome, schwannome, méningiome fibreux, fibrome, gliofibrome et épendymome. L'immunohistochimie (IHC) joue un rôle important dans la différenciation des SFT des autres tumeurs identiques. Ici, nous rapportons un rare cas de SFT de la moelle épinière cervicale, qui a été initialement signalé comme hémangiopéricytome, et le diagnostic de SFT a été confirmé par IHC.

Evaluation of Healthy Tissue Dose at Different Regions between Volumetric-Modulated Arc Therapy and Intensity-Modulated Radiation Therapy Plans in the Treatment of Various Cancers.

BACKGROUND: Radiotherapy plays an important role in the management of cancer. Although the improved technologies increase therapeutic index, different delivery techniques deliver different dose pattern to the healthy tissue within and outside treatment volume. OBJECTIVE: The objective of this study was to evaluate the low, intermediate, and high dose to healthy tissue within and outside the treatment volume and to find the relation between tumor volume and various doses received healthy tissue volume. MATERIALS AND METHODS: A total of 150 patients were included. For all patients, planning computed tomography images were acquired. Tumors, critical structures, and healthy tissue volumes at different regions were delineated. Two sets of plans, one with volumetric-modulated arc therapy and another with intensity-modulated radiation therapy (IMRT) were created, optimized for 6 MV photons and dose was calculated. Dosimetry results for tumor, organs at risks (OARs), and healthy tissue from both the techniques were evaluated and compared. RESULTS: Tumor coverage and dose to OARs was significantly better with volumetric-modulated arc therapy (VMAT). Volume of healthy tissue received high-dose within the treatment volume as well as volume of healthy tissue received low and intermediate-dose out of treatment volume were significantly (P < 0.002) lesser with VMAT. Besides, the results showed that as the tumor volume increased, the various dose received healthy tissue volume also increased. CONCLUSIONS: VMAT plan can reduce the risk of secondary malignancy while treating different sites of cancer. VMAT is the most appropriate technique than IMRT, especially in the treatment of large tumor volume. Special attention has to be given, especially while treating women and children.

Evaluation of the Potency of Kinetin on Radiation Induced Behavioural Changes in Swiss Albino Mice.

INTRODUCTION: According to the various independent studies conducted, it is well evident fact that radiation induces oxidative stress in the living system. It is also proved that this oxidative stress will lead to the various behavioural changes such as anxiety and memory impairment. Kinetin is one of the important plant cytokine with anti-aging properties. However, very few studies were conducted to check its potential in ameliorating the behavioural changes induced by the ionizing radiation. AIM: This study was aimed to check the potential of kinetin in ameliorating the radiation induced behavioural changes in albino mice. MATERIALS AND METHODS: In this study, survival analysis was performed using three different dose of kinetin intervention along with, one radiation control group and one normal control group (n=50). Based on the cumulative survival rate, single effective dose of kinetin was selected and used to evaluate the behavioural changes induced by radiation. The open field apparatus was used to evaluate the anxiety level (n=18, six in each group). Eight armed radial maze was used to evaluate the memory and learning ability in mice model. RESULTS: Survival study results suggest 100 mg/kg body weight of kinetin showed highest cumulative survival rate. Therefore, this dose was selected as an effective drug dose for further study. Analysis also showed 6 Gy whole body electron beam radiation had significantly increased anxiety level, increased duration to complete the task as well as mistakes done during the task. Further, kinetin intervention had significantly ameliorated the same. CONCLUSION: A 100 mg/kg body weight of kinetin intervention helps in reducing the anxiety and improves the learning ability in mice exposed to electron beam radiation.

Comparison of Rapid Arc and Intensity-modulated Radiotherapy Plans Using Unified Dosimetry Index and the Impact of Conformity Index on Unified Dosimetry Index Evaluation.

The aim of this study was to evaluate the impact of conformity index in the unified dosimetry index (UDI) score for two different planning techniques namely intensity-modulated radiotherapy (IMRT) and Rapid Arc. Rapid Arc and IMRT plans of 57 patients were evaluated and compared using UDI score which incorporates four indices. To determine the impact of conformity index on the IMRT and Rapid Arc plans, UDI at conformity index one of all plan (UDIunit_CI) score was calculated by assuming conformity index is equal to one. Mean and standard deviations of all indices were calculated. Rapid Arc technique plans of different treatment sites of all patients scored lesser UDI than IMRT plans, and the conformity index of Rapid Arc plan was significantly better than IMRT plan. The average dose gradient, homogeneity, coverage, and conformity index of all sites with Rapid Arc plans were 0.212 ± 0.05, 1.123 ± 0.03, 0.959 ± 0.03, and 1.056 ± 0.09; with IMRT plans were 0.190 ± 0.05, 1.113 ± 0.04, 0.950 ± 0.04, and 1.172 ± 0.16, respectively. UDI score value with actual conformity index of Rapid Arc and IMRT plans differed significantly (P < 0.001). However, UDIunit_CI score values with assumed conformity index equal to one did not differ significantly (P = 0.528). In the comparison of IMRT and Rapid Arc plans using the UDI score, the impact of conformity index was significant.

Nimotuzumab provides survival benefit to patients with inoperable advanced squamous cell carcinoma of the head and neck: a randomized, open-label, phase IIb, 5-year study in Indian patients.

OBJECTIVE: Overexpression of epidermal growth factor receptor (EGFR) in many cancers makes it an attractive therapeutic target. This study evaluated the clinical utility of nimotuzumab, a monoclonal anti-EGFR antibody, used concurrently with radiotherapy (RT) and chemoradiotherapy (CRT) in squamous cell carcinoma of the head and neck (SCCHN). METHODS: This open-label study randomized 92 treatment-naïve patients (1:1) with advanced SCCHN into chemoradiation (CRT ± nimotuzumab) or radiation (RT ± nimotuzumab) group by investigator's discretion; these were further randomized into CRT + nimotuzumab or CRT and RT + nimotuzumab or RT groups, respectively. Treatment included 6 cycles each of cisplatin (50 mg/week), nimotuzumab (200 mg/week), and RT (total dose, 60-66 Gy). Response (tumor size reduction) was assessed at Month 6 post-treatment and survival, at Month 60. RESULTS: Forty and 36 patients in the chemoradiation and radiation groups, respectively (intent-to-treat population) were evaluated. Overall response at Month 6 post-treatment was 100% with CRT + nimotuzumab, 70% with CRT, 76% with RT + nimotuzumab, and 37% with RT. At Month 60, overall survival was 57% with CRT + nimotuzumab, 26% with CRT (P = 0.03), 39% with RT + nimotuzumab, and 26% with RT (P > 0.05). Median overall survival was not reached for CRT + nimotuzumab; it was 21.94 months for CRT (P = 0.0078), 14.36 months for RT + nimotuzumab, and 12.78 months for RT (P = 0.45). Risk of death was 64% lower with CRT + nimotuzumab than with CRT (95%CI: 0.37, 1.56), and 24% lower with RT + nimotuzumab than with RT (95%CI: 0.16, 0.79). Thus nimotuzumab was safe and well tolerated with few mild to moderate self-limiting adverse events. CONCLUSION: Concurrent use of nimotuzumab with CRT/RT is safe and provides long-term survival benefit.

Small-intestine pneumocystis jiroveci pseudotumor as an acquired immunodeficiency syndrome-presenting illness: report of a case and review of the literature.

A Pneumocystis jiroveci infection-associated mass clinically mimicking a malignancy (ie, pseudotumor) is rare and usually occurs in the lung in association with Pneumocystis pneumonia. Pneumocystis jiroveci pseudotumors of the small intestine are extremely rare and represent an unusual form of disseminated P jiroveci infection. We present a case of small-intestine P jiroveci pseudotumor as an acquired immunodeficiency syndrome-presenting illness in a patient with coinfection with cytomegalovirus, no pulmonary symptoms, and no known risk factors for human immunodeficiency virus infection. This case reinforces the potential importance of cytomegalovirus coinfection in the disseminated form of Pneumocystis infection and illustrates the importance of an expanded differential diagnosis when confronted with a clinically atypical mass lesion.

Evaluation of high-performance liquid chromatography laser-induced fluorescence for serum protein profiling for early diagnosis of oral cancer.

The present work deals with the evaluation of a high-performance liquid chromatography laser-induced fluorescence (HPLC-LIF) technique developed in our laboratory for early detection of oral cancer from protein profiles of body fluids. The results show that protein profiles of serum samples from a given class of samples, say, normal, premalignant, or malignant, are statistically very close to each other, while profiles of members of any class are significantly different from other classes. The performance of the technique is evaluated by the use of sensitivity and specificity pairs, receiver operating characteristic (ROC) analysis, and Youden's Index. The technique uses protein profile differences in serum samples, registered by the HPLC-LIF technique. The study is carried out using serum samples from volunteers diagnosed as normal or premalignant clinically, and as malignant by histopathology. The specificities and sensitivities of the HPLC-LIF method at an ideal threshold (M-distance = 2) for normal, malignant, and premalignant classes are 100, 69.5, and 61.5%, and 86.5, 87.5, and 87.5% respectively.