Prognostic value of microRNA-125a expression status in molecular groups of pediatric medulloblastoma.

PURPOSE: Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Current treatment allows decent survival rates but often with life-long morbidity. Molecular classification provides a base for novel therapeutic approaches. However, these groups are heterogeneous. MicroRNA-125a has a tumor suppressor function. It is downregulated in several tumors. The expression of microRNA-125a in MB patients remains unclear. Therefore, this study was designed to evaluate the expression of microRNA-125a in molecular groups of pediatric MB patients in Egyptian population and its clinical significance. METHODS: Formalin-fixed, paraffin-embedded tissue blocks from 50 pediatric MB patients were retrospectively collected. Immunohistochemistry for ß-catenin, GAB1, YAP1, and p53 was done for molecular classification. MicroRNA-125a expression analysis was done using qRT-PCR. Follow-up data were obtained from patients' records. RESULTS: MicroRNA-125a expression was significantly lower in MB patients showing large cell/anaplastic (LC/A) histology and in the non-WNT/non-SHH group. Lower levels of microRNA-125a showed a tendency toward poor survival rates; however, difference was not significant. Infants and larger preoperative tumor size were significantly associated with lower survival rates. On a multivariate analysis, preoperative tumor size was an independent prognostic factor. CONCLUSION: MicroRNA-125a expression was significantly lower in categories of pediatric MB patients with worse prognosis namely LC/A histology and the non-WNT/non-SHH group suggesting a pathogenetic role. MicroRNA-125a expression could represent a promising prognostic factor and a potential therapeutic target in the non-WNT/non-SHH group which represents the most common and the most heterogeneous group of pediatric MBs coupled with the highest rates of disseminated disease. Preoperative tumor size represents an independent prognostic factor.

Petrous apex non-secretory plasma cell myeloma with aberrant cytokeratin expression.

Multiple myeloma is a monoclonal proliferation of plasma cells with common involvement of vertebrae, ribs and skull vault. However, involvement of skull base is relatively uncommon and myeloma manifesting initially as a petrous apex mass is distinctly rare. We report a rare case of non-secretory multiple myeloma in a 52-year-old Egyptian male presenting primarily as a right petrous apex mass with abducens nerve palsy. Additionally, neoplastic cells aberrantly expressed cytokeratin. Although rare, plasma cell myeloma should be considered in the differential diagnosis of petrous apex masses.

Reduced expression of GATA3 predicts progression in non-muscle invasive urothelial carcinoma of the urinary bladder.

Urothelial carcinoma (UC) of the urinary bladder is the ninth most common cancer worldwide. The majority of these patients present with non-muscle invasive bladder cancer (NMIBC). GATA3 has recently emerged as one of the diagnostically helpful immunohistochemical markers for UC. The published literature, however, lacks comprehensive studies on the impact of GATA3 expression on the prognosis of UC patients. This study evaluated and statistically analyzed the immunohistochemical expressions of GATA3 and Ki67 in 50 Egyptian patients with NMIBC and correlated the markers' expressions with clinicopathological variables and patients' outcome. Ten control cases were included. The expressions of GATA3 and Ki67 were significantly downregulated and upregulated respectively in UC cases compared to the control group. GATA3 down-expression was significantly associated with high grade tumors and tumor progression with 72% prediction accuracy. Higher proliferative activity was significantly correlated with high grade, non-papillary growth pattern, and lamina propria invasion. The predictive performance of GATA3 and Ki67 in predicting malignancy and tumor grade was good. We concluded that GATA3 downregulation and increased proliferative activity might be implicated in UC tumorigenesis, loss of differentiation, and aggressiveness. Reduced GATA3 expression could predict progression in NMIBC with an accuracy of 72% and thus it constitutes a potentially promising novel prognostic marker in patients with urothelial carcinoma.

Management of Glioblastoma Multiforme in a Patient Treated With Ketogenic Metabolic Therapy and Modified Standard of Care: A 24-Month Follow-Up.

Few advances have been made in overall survival for glioblastoma multiforme (GBM) in more than 40 years. Here, we report the case of a 38-year-old man who presented with chronic headache, nausea, and vomiting accompanied by left partial motor seizures and upper left limb weakness. Enhanced brain magnetic resonance imaging revealed a solid cystic lesion in the right partial space suggesting GBM. Serum testing revealed vitamin D deficiency and elevated levels of insulin and triglycerides. Prior to subtotal tumor resection and standard of care (SOC), the patient conducted a 72-h water-only fast. Following the fast, the patient initiated a vitamin/mineral-supplemented ketogenic diet (KD) for 21 days that delivered 900 kcal/day. In addition to radiotherapy, temozolomide chemotherapy, and the KD (increased to 1,500 kcal/day at day 22), the patient received metformin (1,000 mg/day), methylfolate (1,000 mg/day), chloroquine phosphate (150 mg/day), epigallocatechin gallate (400 mg/day), and hyperbaric oxygen therapy (HBOT) (60 min/session, 5 sessions/week at 2.5 ATA). The patient also received levetiracetam (1,500 mg/day). No steroid medication was given at any time. Post-surgical histology confirmed the diagnosis of GBM. Reduced invasion of tumor cells and thick-walled hyalinized blood vessels were also seen suggesting a therapeutic benefit of pre-surgical metabolic therapy. After 9 months treatment with the modified SOC and complimentary ketogenic metabolic therapy (KMT), the patient's body weight was reduced by about 19%. Seizures and left limb weakness resolved. Biomarkers showed reduced blood glucose and elevated levels of urinary ketones with evidence of reduced metabolic activity (choline/N-acetylaspartate ratio) and normalized levels of insulin, triglycerides, and vitamin D. This is the first report of confirmed GBM treated with a modified SOC together with KMT and HBOT, and other targeted metabolic therapies. As rapid regression of GBM is rare following subtotal resection and SOC alone, it is possible that the response observed in this case resulted in part from the modified SOC and other novel treatments. Additional studies are needed to validate the efficacy of KMT administered with alternative approaches that selectively increase oxidative stress in tumor cells while restricting their access to glucose and glutamine. The patient remains in excellent health (Karnofsky Score, 100%) with continued evidence of significant tumor regression.

High Coexpression of Runt-related Transcription Factor 2 (RUNX2) and p53 Independently Predicts Early Tumor Recurrence in Bladder Urothelial Carcinoma Patients.

Conventional prognostic factors for bladder cancer are inadequate to predict tumor recurrence and/or progression successfully; thus, the identification of adjunctive novel prognostic biomarkers is of paramount importance. In this study, the immunohistochemical expression patterns and clinical significance of RUNX2, WWOX, and p53 were investigated in a tissue microarray of 87 primary urothelial carcinomas and 17 control cases. We found that RUNX2, WWOX, and p53 were significantly correlated and overexpressed in urothelial carcinoma cases compared with the control group. RUNX2 and p53 were significantly upregulated in association with high-grade, nonpapillary pattern, and bilharziasis. Muscle-invasive tumors significantly overexpressed RUNX2. WWOX overexpression was significantly associated with high-grade tumors and inversely correlated with age. In a bivariate analysis, the risk of early tumor recurrence and progression was significantly associated with RUNX2 and p53 overexpression and bilharziasis. A multivariate Cox regression analysis proved that RUNX2 and p53 were independent predictors of early tumor recurrence. The ROC curve analysis showed that combined RUNX2 and p53 high expression (scores >3 and >5, respectively) had the highest accuracy (73.6%) for the prediction of early tumor recurrence. We conclude that RUNX2 and p53 might be functionally related and are likely involved in bladder tumor carcinogenesis and aggressiveness, which provides a new perspective for targeted therapy. RUNX2 and p53 independently predict early tumor recurrence in bladder carcinoma patients, with the highest prediction accuracy being achieved on their combined high expression. The role of WWOX in bladder urothelial carcinoma and its relationship with RUNX2 and p53 remains unclear and warrants further investigation.

FGF18 as a potential biomarker in serous and mucinous ovarian tumors.

Fibroblast growth factor 18 (FGF18) has been suggested to play important roles in promoting progression of ovarian high-grade serous carcinoma. Our aim was to investigate FGF18 expression in the whole spectrum of serous and mucinous ovarian tumors, highlighting differences in expression within the adenoma-carcinoma sequence and differences between type I and type II tumors. We also aimed to test the prognostic significance of this expression and its relation to microvessel density (MVD). We evaluated the immunohistochemical expression of FGF18 and CD31 in 103 ovarian tumors and statistically analyzed their association with clinicopathological variables and patients' outcome. FGF18 score increased significantly within the adenoma-carcinoma sequence for serous and mucinous tumors. MVD increased significantly only among serous tumors. FGF18 and MVD correlated significantly (overall and among serous tumors only) and were significantly higher in type II than type I tumors. Cox regression models were built. Independent predictors could not be determined due to multicollinearity between the predictors. However, the combination of International Federation of Gynecology and Obstetrics (FIGO) stage, ovarian carcinoma type, and/or FGF18 score achieved the highest predictability of poor prognosis. FGF18 could play a role within the adenoma-carcinoma sequence in type I tumors and might modulate angiogenesis among serous tumors. Our findings further augment the differences between type I and type II tumors. The combination of FIGO stage, ovarian carcinoma type, and/or FGF18 score could predict poor prognosis among ovarian carcinoma patients. Our work identifies FGF18 in ovarian neoplasia as a promising field of research, although evaluation of the performance of the developed models is still needed.

Lysophosphatidylcholine acyltransferase 1 (LPCAT1) upregulation in breast carcinoma contributes to tumor progression and predicts early tumor recurrence.

Breast cancer is the most common cancer in women worldwide. Aberrant lipid metabolism is an established hallmark of cancer cells. The recently isolated lysophosphatidylcholine acyltransferase 1 (LPCAT1), the most important enzyme in membrane biogenesis, has been currently implicated in cancer development and progression. The published literature lacks comprehensive reports on LPCAT1 expression in breast cancer and its impact on patients' outcome. We evaluated the immunohistochemical expression of LPCAT1 in 80 primary breast carcinomas, 24 metastatic lymph nodes, and 30 non-neoplastic breast tissue specimens and statistically analyzed the association between LPCAT1 expression and clinicopathological variables and patients' outcome. LPCAT1 protein was significantly upregulated in primary breast carcinoma and showed a significant ascending pattern being the lowest in normal breast tissues, relatively increased in fibrocystic disease, and the highest in primary carcinoma. LPCAT1 expression was significantly higher at tumor's advancing edge and correlated positively with tumor's grade and TNM stage. Compared to primary tumor, LPCAT1 expression was significantly lower in ductal carcinoma in situ and significantly higher in metastatic lymph nodes. LPCAT1 overexpression was significantly associated with increased proliferative activity, negative estrogen receptor (ER) and progesterone receptor (PR) status, positive human epidermal growth factor receptor 2 (HER2) status, as well as triple-negative and HER2 disease molecular subtypes. Multivariate analysis showed that advanced stage, high grade, and LPCAT1 overexpression were independent predictors of early tumor recurrence. We conclude that LPCAT1 is implicated in breast cancer pathogenesis, evolution, and progression and appears to play a potentially crucial role as a determinant of local invasiveness and metastasis. LPCAT1 is an independent predictor of early tumor recurrence of breast carcinoma and represents a novel prognostic biomarker that reflects underlying biological alterations and thus constitutes a potentially promising target for new therapeutic strategies.

Stem cell markers OCT4 and nestin in laryngeal squamous cell carcinoma and their relation to survivin expression.

We explored the expression of the stem cell markers OCT4 and nestin in laryngeal squamous cell carcinoma (LSCC) and investigated their relationship to survivin expression. Eighty-five LSCC, and 62 non-neoplastic laryngeal tissues were analyzed immunohistochemically for the presence of OCT4, nestin and survivin. Marker expression was correlated to clinicopathological parameters. The positive detection rates of OCT4 (42.35%) and nestin (51.76%) in LSCC were higher than those of non-neoplastic mucosa (p<0.05). OCT4 expression was positively associated with nestin expression (p=0.0001). High expression of both OCT4 and nestin was associated with higher tumor grade (p=0.0001). Also, high OCT4 expression was related to higher T stage (p=0.0001). Co-expression of OCT4 and nestin was more significantly associated with glottic location, higher T stage and nodal metastasis than high expression of either marker (p=0.015, 0.006 and 0.008, respectively). Survivin expression was not significantly related to expression of OCT4 or nestin (p=0.094 and 0.266, respectively). OCT4 and nestin are overexpressed in LSCC and may contribute to laryngeal carcinogenesis. Their co-expression may help to predict the lymph node metastatic potential of LSCC. No relationship was detected between expression of survivin and OCT4 or nestin.

Expression of mesothelioma-related markers in meningiomas: an immunohistochemical study.

BACKGROUND: Meningiomas are common intracranial tumors. Recently, histogenetic and phenotypic similarities between meningiomas and mesotheliomas have been proposed. We were interested in whether these similarities are reflected on the immunohistochemical level, which would add new potentially diagnostic markers for meningiomas. METHODS: The expression of mesothelioma-related markers (D2-40, Calretinin, Keratin 5/6, WT1, and Methotheioma-Ab1) was investigated in 87 cases of meningiomas and compared to EMA expression. RESULTS: 73.6% of meningioma cases were grade I, 20.7% were grade II, and 5.7% were grade III. 83.9% of meningioma cases were classical and 16.1% had special nonmeningothelial features. D2-40 was expressed in 37.9% of cases and was significantly restricted to classical meningiomas. Calretinin and WT1 were negative while Keratin 5/6 and Mesothelioma-Ab1 were weakly expressed in classical variants (5.7% and 3.4%, resp.). EMA was consistently expressed in all cases. Its expression was significantly higher than that of mesothelioma-related markers; this held true also when D2-40 expression was considered separately. CONCLUSIONS: Mesothelioma-related markers are not extensively expressed in meningiomas, a finding that argues against their proposed histogenetic and phenotypic similarities. Compared to EMA, the significantly lower expression of mesothelioma-related markers and their restricted expression to classical meningioma variants hamper their potential future use as diagnostic markers for meningioma.

Long-term prognostic value of mesorectal grading after neoadjuvant chemoradiotherapy for rectal cancer.

BACKGROUND: Mesorectal grading was reported to be a valuable prognostic factor in rectal cancer surgery. Previous studies were retrospective, and had short follow-up. OBJECTIVE: To assess the long-term influence of total mesorectal excision quality on disease recurrence in mid and low rectal cancer patients who received preoperative neoadjuvant chemoradiotherapy (CRT) and postoperative chemotherapy. METHODS: One hundred twenty-one patients with rectal cancer had either low anterior resection or abdominoperineal resection. All patients received neoadjuvant CRT and postoperative chemotherapy. Main outcome measures included TNM staging, involvement of the circumferential resection margin (ICRM), mesorectal grading, local and systemic recurrences were recorded. RESULTS: Follow-up was done for at least 5 years or up to disease recurrence whatever comes first. Mean follow-up time was 59.4 months. Twenty-nine patients had abdominoperineal resection and 92 had low anterior resection. About 7.5% had positive CRM which was significantly correlated with mesorectal grading. Grade 3 mesorectal specimens were obtained in approximately 60% of patients, 27% had grade 2, and only 13% had grade 1 (poor) mesorectal specimens. Poorer mesorectal grading increased with APR and lower rectal tumors. Recurrences occurred in 20% of patients (40% in the first 2 years, 32% in the 3rd year, and 28% in the 4th and 5th years); factors affecting recurrence included lymphovascular invasion, ICRM, and N stage. Mesorectal grading was not a valuable prognostic factor for recurrence unless it resulted in ICRM. Recurrences occurred earlier with poorer mesorectal grade, yet this was not statistically significant. CONCLUSIONS: Mesorectal grading is a pathologic description that reflects the quality of surgery. However, in patients who received neoadjuvant CRT and postoperative chemotherapy, grading had no long-term prognostic value regarding recurrences unless it resulted in ICRM.

Biological and demographic profile of meningiomas in a cohort of Egyptian patients: impact on tumor recurrence.

OBJECTIVE: This work was designed to study the biological and demographic characteristics of meningiomas and their impact on tumor recurrence in Egyptian patients. MATERIAL AND METHODS: A cohort of 265 Egyptian patients with meningioma was studied. Immunohistochemistry for VEGF, Ki67, PR, CD20, and CD3 was performed. Statistical analysis was used to detect independent predictors of recurrence. RESULTS: Adults represented 98.9% of cases, with female preponderance (M : F ratio = 1 : 2.4). Histologically, 78.10% of cases were grade I, 19.20% were grade II, and 2.60% were grade III. Transitional variant was the most common (43.40%). VEGF expression (38.50% of cases) correlated positively with perifocal edema, tumor size, and proliferative index (PI). PR expression (64.5% of cases) correlated inversely with the PI (mean 3.75). Lymphocytic aggregates were detected in 7.20% of cases, with a mean CD20 : CD3 ratio of 1 : 10.1. In a multivariate analysis, only tumor size, PR expression and necrosis predicted recurrence independently. Using ROC curve, size was the best predictor of tumor recurrence with a cut-off point of >6 cm and an excellent negative predictive value (97.6%). CONCLUSIONS: Meningiomas in our region showed some distinctive clinicopathological and demographic criteria. Tumor size was found to be the best recurrence predictor factor of meningioma.

Recurrence of benign meningiomas: predictive value of proliferative index, BCL2, p53, hormonal receptors and HER2 expression.

INTRODUCTION: The biological behaviour of meningiomas and the risk of recurrence in individual cases cannot be predicted by using conventional histological criteria alone. A number of histologically benign meningiomas may recur, even after gross complete surgical removal. MATERIAL AND METHODS: A retrospective immunohistochemical and statistical analysis of 60 patients with benign intracranial meningiomas (that have been grossly totally resected) was undertaken to determine the correlation of clinicopathological characteristics and expression of biological markers (proliferation index (PI) assessed by Ki67, hormonal receptors, p53, BCL2 and HER2, estrogen receptors, ER and progesterone receptors, PR) with prediction of recurrence. RESULTS: HER2 expression showed a significant inverse correlation with PR and a significant direct correlation with PI. PR-negative and HER2-positive cases showed a statistically significant higher mean PI than PR positive and HER2-negative cases. Univariate analysis showed that recurrence was significantly associated with male gender, cranial base location, the presence of bone and soft tissue invasion, some atypical histological features, higher PI, negative PR expression, and positive p53, BCL2 and HER2 expression. Multivariate analysis showed that the presence of bone and soft tissue invasion and/or the expression of p53 proved to be independent predictors of tumour recurrence. The presence of some atypical histological features and high PI were significant predictors of tumor recurrence, however, they were statistically excluded to avoid multicolinearity. CONCLUSIONS: Risk stratification based on histomorphology alone remains problematic. We conclude that soft tissue and bone invasion, some atypical histological features, p53 expression and high PI identify meningiomas with benign histological features but unfavourable clinical outcome. We suggest that those patients should be followed more closely for evidence of recurrent tumour or may be treated more aggressively at the time of diagnosis.

Predictive value of immunohistochemical expression of claudin-1 in colonic carcinoma.

OBJECTIVE: Colonic carcinoma is one of the most common cancers worldwide. Recently, the possible involvement of claudin-1, one of the major tight junction proteins, in the process of tumorigenesis has been suggested. Also, claudin-1 has emerged as a potential prognostic factor in different types of tumors. The aim of this study was to detect caludin-1 expression in colonic carcinoma and to correlate its expression with clinicopathological variables in an attempt to delineate its role as a potential new prognostic marker. MATERIAL AND METHODS: Immunohistochemical expression of claudin-1 was assessed in 50 Egyptian patients with colonic adenocarcinoma. The predictive performance of claudin-1 expression was statistically evaluated. RESULTS: Decreased claudin-1 expression was found in 62% of colonic adenocarcinoma cases while similar expression was found in 38% of the cases. Statistical analysis showed a statistically significant inverse correlation between claudin-1 expression and tumor grade, depth of invasion, lymph node involvement, and tumor stage. Regression analysis showed that claudin-1 decreased expression significantly predicts that the tumor is of a high grade, high stage, and is associated with lymph node involvement. ROC curve analysis showed that claudin-1 had a sensitivity of 88.24% and a specificity of 81.25% for the prediction of tumor stage and a sensitivity of 73.33% and a specificity of 82.86% for the prediction of lymph node involvement. CONCLUSIONS: Claudin-1 decreased expression in colonic carcinoma contributes to tumor dedifferentiation, invasion and metastasis. Claudin-1 expression could be used as a predictor of colonic carcinoma stage and lymph node status with a high sensitivity and specificity.