Journal of Carcinogenesis最新文献

Background: Diffuse gliomas in the adult population are the most common primary central nervous system (CNS) tumors. The World Health Organization incorporated isocitrate dehydrogenase (IDH) mutations and 1p/19q co-deletion with histopathological features into an "integrated diagnosis" in the revised classification of tumors of CNS. These molecular subgroups of diffuse gliomas are found to stratify patients into prognostically distinct groups better than the histological classification. The objectives of the current study were to assess the frequency of IDH mutation, ATRX expression loss, p53 overexpression, and 1p/19q co-deletion detection in adult diffuse gliomas (Grade II, III, and IV) and to correlate them with clinicopathological and histopathological features.

Materials and methods: The current study was a tertiary care hospital-based retrospective case series of 112 cases of adult diffuse gliomas. Immunohistochemistry (IHC)-based molecular detection was performed for IDH-1, ATRX, and p53 and fluorescent in situ hybridization (FISH) was performed for 1p/19q co-deletion detection.

Results: IDH-1 mutation was present in 30.4% (n = 34/112) cases, ATRX expression was lost in 18% (n = 19/104) cases, p53 was mutated in 39.3% (n = 42/107) cases and 1p19q was co-deleted in 25% (n = 4/16) cases. In the IDH1 mutant cases, with retained ATRX, FISH for 1p/19q co-deletion was performed and was co-deleted in four cases.

Conclusion: The results of the present study indicate that IHC including IDH1/2, ATRX, and p53 is useful for the molecular classification of diffuse gliomas, which could be useful for the evaluation of prognosis, especially Grade III and II. Although the immunohistochemical approach does not replace genetic testing completely, it is a practical and powerful means of assessing molecular genetic changes. IDH mutations are the established markers of better prognosis in diffuse gliomas.

Aim: Elevated Src-Family tyrosine kinase (SFK) activity drives carcinogenesis in vivo and elevated SFK activity is found ubiquitously in human cancers. Although human squamous cell carcinomas (SCCs) demonstrate increased SFK activity, in silico analysis of SCCs demonstrates that only 0.4% of lesions contain mutations that could potentially increase SFK activity; similarly, a low frequency of activating SFK mutations is found in other major cancers. These findings indicate that SFK activation in cancers likely is not due to activating mutations but alternative mechanisms. To evaluate potential alternative mechanisms, we evaluated the selectivity of c-Cbl and Srcasm in downregulating native and activated mutant forms of SFKs.

Materials and methods: We co-transfected native and activated forms of Src and Fyn with c-Cbl and Srcasm into HaCaT cells and monitored the ability of Srcasm and c-Cbl to downregulate native and activated forms of SFKs by Western blotting. The mechanism of downregulation was probed using mutant forms of Srcasm and c-Cbl and using proteosomal and lysosomal inhibition.

Results: The data indicate that Srcasm downregulates native Fyn and Src more effectively than c-Cbl, whereas c-Cbl preferentially downregulates activated SFK mutants, including Fyn Y528F, more effectively than Srcasm. Srcasm downregulates SFKs through a lysosomal-dependent mechanism while c-Cbl utilizes a proteosomal-dependent mechanism.

Conclusion: Given the rarity of activating SFK mutations in human cancer, these data indicate that decreasing Srcasm level/function may represent a mechanism for increasing SFK activity in SCC and other human tumors.

Background: Gallstone disease is one of the commonest surgical ailments encountered in our setup. Its prevalence in India varies from 2% to 29%. Although cholelithiasis accounts for more than 95% of gall bladder related disease, routine histopathological examination (HPE) is vital. It reveals a myriad of benign as well as the malignant surgical pathology of the gallbladder (GB). This part of the world is considered as an endemic region for GB carcinoma as well as gallstone disease. This study intends to evaluate the outcome of the routine HPE of laparoscopic cholecystectomy specimens.

Methods: This retrospective observational study evaluated the results of the routine HPE of elective laparoscopic cholecystectomy specimens of single tertiary care center. Patients suspected or diagnosed with carcinoma gall bladder were excluded. Demographic data such as age, sex, and pathology results were recorded.

Results: From January 2017 to December 2019, HPEs of 921 patients who had undergone laparoscopic cholecystectomy specimens were analyzed. 97.6% specimens had benign lesion of which chronic calculus cholecystitis was predominantly high (95.01%) followed by cholesterosis (9.9%) and xanthogranulomatous cholecystitis (6.51%). Incidental carcinoma gall bladder was observed in 17 specimens accounting for 1.85%. Mean age of patients who underwent cholecystectomy was 43.10 ± 13.90 with female to male ratio of 3.23:1.

Conclusion: Chronic calculus cholecystitis was the most common gall bladder disease with high female preponderance to all GB pathologies. This study affirms the importance of routine HPE after cholecystectomy as early incidental detection of carcinoma gall bladder alters the postoperative management approach and patients are expected to have a better outcome with it.

Background: The TP53 tumor suppressor gene is the most commonly mutated gene in human cancers. Humans who inherit mutant TP53 alleles develop a wide range of early onset cancers, a disorder called Li-Fraumeni Syndrome (LFS). Trp53-deficient mice recapitulate most but not all of the cancer phenotypes observed in TP53-deficient human cancers, indicating that new animal models may complement current mouse models and better inform on human disease development.

Materials and methods: The recent application of CRISPR/Cas9 genetic engineering technology has permitted the emergence of golden Syrian hamsters as genetic models for wide range of diseases, including cancer. Here, the first cancer phenotype of TP53 knockout golden Syrian hamsters is described.

Results: Hamsters that are homozygous for TP53 mutations become moribund on average ~ 139 days of age, while hamsters that are heterozygous become moribund at ~ 286 days. TP53 homozygous knockout hamsters develop a wide range of cancers, often synchronous and metastatic to multiple tissues, including lymphomas, several sarcomas, especially hemangiosarcomas, myeloid leukemias and several carcinomas. TP53 heterozygous mutants develop a more restricted tumor spectrum, primarily lymphomas.

Conclusions: Overall, hamsters may provide insights into how TP53 deficiency leads to cancer in humans and can become a new model to test novel therapies.

Introduction: Focused studies in different geographic regions would delineate the underlying biological differences and molecular alterations in non-small cell lung cancer (NSCLC) worldwide. Previous studies in literature have documented limited characterization by studying a minimal number of biological markers. This study was done to evaluate expression of multiple immunomarkers including diagnostic, prognostic, and predictive markers in NSCLC for its characterization.

Materials and methods: This was an observational study conducted on 60 consecutive cases of NSCLC. Immunomarkers comprising of p63, p40, TTF-1, napsin A, B-Raf, c-Met, phospho-AKT (P-AKT), PTEN, anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR) and K-Ras, synaptophysin, chromogranin and pan-cytokeratin were evaluated on paraffin-embedded tissue sections of NSCLC.

Results: Age of patients with NSCLC in our study ranged from 35 to 90 years, and 93.3% of them were chronic smokers. 93.3% of cases presented in late stages (Stages III and IV) and 78% of cases were squamous cell carcinoma (SCC). EGFR positivity was noted in 83.3% of cases. ALK was positive in one case while C-Met and PTEN immunopositivity was noted in only two cases. Ten cases showed positivity for K-Ras and 90% of these were SCC. Ten cases were positive for B-Raf and 80% of these were SCC. 30% of cases showed immunopositivity for P-AKT. None of the molecular markers was found to have statistically significant correlation with clinicopathological parameters.

Conclusion: SCC is the predominant histological subtype of NSCLC in the region of Uttarakhand, India, with a high proportion of cases harboring EGFR mutation. Variable expression of K-Ras, P-AKT, ALK 1, and PTEN in NSCLC signifies that molecular profile of every case is individualistic and independent. We attribute this to ethnicity, influence of implicated substance or metabolite in tobacco, and variable mutations incurred in tumor cells over a period of time.

Background: Oral submucous fibrosis (OSMF) is a premalignant condition with a greater prevalence in countries such as India. Various classifications have been put forth by multiple authors to determine the clinical, functional, and histopathological grade of the disease. The classification systems have greatly helped to determine the treatment modality for the patients. Understanding the correlation between the various classifications will help us determine the course of the disease, management, and prognosis of OSMF. This study assesses the correlation between clinical, functional, and histopathological grading of OSMF.

Aim: To assess the correlation between clinical staging, functional staging, and histopathological grading of OSMF.

Materials and methods: Thirty patients with clinical and histopathological diagnosis of OSMF were assigned into clinical stage, functional stage, and histopathological grade. The correlation between these three stages assigned was studied.

Statistical analysis: The degree of agreement between the clinical, functional, and histopathological classifications was quantified by the Weighted Kappa statistics. Correlation between the three classifications was done using Kendall's tau and Spearman's correlation coefficient.There was a good agreement and statistically significant correlation between clinical and functional grading. There was a poor agreement and no significant correlation between clinical and histopathological grading. There was a poor agreement and no significant correlation between functional and histopathological grading.

Background and aim: Oxidative stress leads to a compensatory increase in levels of serum ceruloplasmin in patients with such imbalances. Greater than normal serum ceruloplasmin levels are noticed in numerous cancers including the leukemias and Hodgkin's lymphoma. The purpose of the present study was to estimate and evaluate the efficacy of serum ceruloplasmin levels as a potential biomarker in the early detection of oral potentially malignant epithelial lesions (PMELs) including leukoplakia, oral submucous fibrosis (OSMF), and oral squamous cell carcinoma (OSCC) patients.

Materials and methods: The present observational study was conducted over a period of 2 years wherein 100 subjects aged between 18 to 60 years were divided into four groups with Group A consisting of 25 healthy controls, Group B and C with 25 patients each, clinically diagnosed with oral leukoplakia and OSMF and Group D with 25 patients clinically diagnosed and histopathologically proven OSCC. The patients were subjected to incisional biopsy after routine hematological investigation while the same sera samples were used for analysis of serum ceruloplasmin levels.

Statistical analysis used: Comparison of serum ceruloplasmin levels between the groups was performed using one way analysis of variance (one way ANOVA) test while P < 0.05 was considered statistically significant.

Results: The mean serum ceruloplasmin levels were found to be 43.19 ± 1.90mg/dl in subjects of group A, 47.68 ± 1.51mg/dl in group B, 47.74 ± 1.45mg/dl in group C and 47.73 ± 0.74mg/dl in group D. Using one-way ANOVA, statistically significant variations were found in the values of mean serum ceruloplasmin levels in subjects of the four groups (F-value = 59.58, P = 0.0001).

Conclusions: The observations of the present study revealed that serum ceruloplasmin levels were found to be raised in all 3 study groups including oral leukoplakia, OSMF and OSCC as compared to the controls while the results were found to be statistically significant.

Aim: Clinical and dosimetric factors related to toxicity in terms of xerostomia in patients with head and neck squamous cell cancer (HNSCC) treated with intensity-modulated radiotherapy (IMRT).

Materials and methods: Patients older than 18 years, with the WHO Performance Status Score <2 with primary diagnosis of HNSCC Stage II, III, and IV who had undergone primary or postoperative radiotherapy (RT) treated by IMRT at the center, from November 2015 to November 2016 were included in the study. Patients were assessed by physical examination and questioned to score their quality of life for dryness (HNDR) and stickiness (HNSS) by EORTC-HN-35 (Hindi or English version) at baseline (before treatment), at 3, 6, and 12 months following treatment. The validation of EORTC-HN-35 for HNDR and HNSS in patients was handed.

Results: Thirty patients were included in the study. The mean symptom score values for HNSS at baseline, 3, 6, and 12 months' post-RT treatment were 17.8, 62.2, 64.4, and 20.8, respectively. Dryness and stickiness also increased over 3-6 months in follow-up but slightly relieved at 12 months, but it could not reach to baseline. In subgroup analysis, at baseline mean score of dryness of mouth in elderly patients (≥60 years) (P = 0.248), poor performance status (Eastern Cooperative Oncology Group 2) (P = 0.80) and patients with advanced stage (Stage III and IVA) (P = 0.185) was higher. Correlation of normal tissue complication probability for xerostomia with contralateral mean parotid gland showed insignificant linearity with shallow curve.

Conclusion: Patients remained symptomatic for xerostomia chiefly till 6 months' postirradiation, but it was slightly relieved in 12 months but could not reach the baseline. Dosimetric sparing ofcontralateral parotid resulted in decreased probability of developing xerostomia.

Objective: Radiation dose in computed tomography (CT) has been the concern of physicists ever since the introduction of CT scan. The objective of this study was to evaluate the performance of low-dose 128-slice CT scanner with different mAs values.

Materials and methods: Quantitative study was carried out at different values of mAs. Philips brilliance CT phantom with Philips ingenuity 128-slice low-dose CT scanner was chosen for this study. CT number linearity, CT number accuracy, slice thickness accuracy, high-contrast resolution, and low-contrast resolution were calculated and estimated computed tomography dose index volume (CTDI_vol) for all the mAs values were recorded. Noise was calculated for all mAs values for comparison.

Results: Data analysis shows that image quality was acceptable for all protocols. High-contrast resolution for all protocols was 20 line pairs per centimeter. Low-contrast resolution for 50 mAs images was 4 mm and 3 mm for other mAs protocols. Images acquired using 100 mAs revealed ring artifacts. CTDI_vol using 50 mAs was 33% of the CTDI_vol using 150 mAs. The dose-length product at 100 mAs was reduced to 66% of the dose-length product at 150 mAs, and the same at 50 mAs was reduced to 33%.

Conclusion: It is evident here that mAs has direct impact on the radiation dose to patient. With iDose4, mAs can be reduced to 50 mAs in multislice low-dose CT scan to reduce the radiation dose with minimal effect on image quality for slice thickness 4 mm. However, noise would dominate at tube current lower than 50 mAs for 120 kVp.

Targeting cancer stem cell (CSC) subpopulation within the tumor remains an obstacle for specific therapy in head-and-neck squamous cell carcinoma (HNSCC). Few studies in the literature describe a panel of stem cell makers, however a distinct panel has not been put forth. This systematic review aims to enhance the knowledge of additional markers to accurately relate their expression to tumorigenesis, metastasis, and therapy resistance. Databases, including PubMed, Google Scholar, Ebsco, and Science Direct, were searched from 2010 to 2017 using various combinations of the following keywords: "Stem cell markers in HNSCC" and "chemoresistance and radioresistence in HNSCC." Original experimental studies (both in vitro and in vivo) published in English considering stem cell markers in HNSCC, were considered and included. We excluded articles on tumors other than HNSCC, reviews, editorial letters, book chapters, opinions, and abstracts from the analyses. Forty-two articles were included, in which 13 types of stem cell markers were identified. The most commonly expressed CSC markers were CD44, aldehyde dehydrogenase, and CD133, which were responsible for tumorigenesis, self-renewal, and therapy resistance, whereas NANOG, SOX-2, and OCT-4 were involved in metastasis and invasion. Identification of an accurate panel of CSC markers is the need of the hour as nonspecificity of the current markers poses a problem. Further studies with a large sample size would help validate the role of these CSC markers in HNSCC. These CSC proteins can be developed as therapeutic targets for HNSCC therapy, making future treatment modality more specific and effective.