Genetic analysis of CFH and MCP in Egyptian patients with immune-complex proliferative glomerulonephritis.

Glomerulonephritis (GN) is a complex disease with intricate underlying pathogenic mechanisms. The possible role of underlying complement dysregulation is not fully elucidated in some GN subsets, especially in the setting of autoimmunity or infection. In the current study, diagnosed cases of lupus nephritis (LN) and post-infectious GN (PIGN) were recruited for molecular genetic analysis and targeted next-generation DNA sequencing was performed for two main complement regulating genes: in the fluid phase; CFH, and on tissue surfaces; MCP. Three heterozygous pathogenic variants in CFH (Q172*, W701*, and W1096*) and one likely pathogenic heterozygous variant in MCP (C223R) have been identified in four of the studied LN cases. Additionally, among the several detected variants of uncertain significance, one novel variant (CFH:F614S) was identified in 74% of the studied LN cases and in 65% of the studied PIGN cases. This variant was detected for the first time in the Egyptian population. These findings suggest that subtle mutations may be present in complement regulating genes in patients with immune-complex mediated category of GN that may add to the disease pathogenesis. These findings also call for further studies to delineate the impact of these gene variants on the protein function, the disease course, and outcome.

Interleukin-1ß and Interleukin-1 receptor antagonist gene polymorphism in pediatric patients with Helicobacter pylori-associated chronic gastritis.

BACKGROUND: The severity of Helicobacter pylori infection is determined by the interplay between bacterial virulence, host genetic and environmental factors. This study aimed to identify interleukin-1 beta (IL-1ß) and interleukin receptor antagonist (IL-1RN) gene polymorphisms and their associations with H. pylori infection, and severity of chronic gastritis in Egyptian children. METHODS: A case control study was conducted on 100 children (50 H. pylori positive and 50 controls). Genotyping of IL-1ß-31 gene was done by PCR-CTPP (confronting two-pair primers), of IL-1ß-511 was performed using allele specific PCR, and investigation of the variable number tandem repeat polymorphism of the IL-1RN gene was done by PCR. RESULTS: The genotype C/T of IL1ß-511 was the predominant genotype (36/50; 72%) among H. pylori positive cases (p ≤ 0.001). The presence of C/T genotype at position 511 of IL1ß was associated with increased risk of infection with H. pylori (p ≤ 0.001, odds ratio = 6.612) and with more severe disease (p = 0.004, odds ratio = 8.333). No association of IL-1ß-31 or IL-1RN gene polymorphisms with H. pylori infection or with risk of severe gastric diseases was found. Children who carry two polymorphisms are almost four times at risk for development of H. pylori infection (p = 0.026, odds ratio = 3.937). CONCLUSIONS: Polymorphism at position -511 of IL1ß gene is associated with increased risk of H. pylori infection as well as of severe corpus gastric disease in Egyptian children. This population should be considered a high-risk group, which needs regular gastric endoscopic surveillance, and should be target for H. pylori eradication. Lay summaryThe genotype C/T of IL1ß-511 gene was the predominant genotype (36/50; 72%) among H. pylori positive children. Polymorphism at position -511 of IL1ß gene is associated with increased risk of Helicobacter pylori infection as well as of severe corpus gastric disease in Egyptian children. No association of IL-1ß-31 or IL-1RN gene polymorphisms with H. pylori infection or with risk of severe gastric diseases in Egyptian children.

Laparoscopic Versus Open Hepatic Resection for Solitary Hepatocellular Carcinoma Less Than 5 cm in Cirrhotic Patients: A Randomized Controlled Study.

BACKGROUND: Current literature is lacking level 1 evidence for surgical and oncologic outcomes of hepatocellular carcinoma (HCC) undergoing laparoscopic versus open hepatectomy. Aim was to compare feasibility, safety, and surgical and oncologic efficiency of laparoscopic versus open liver resection (OLR) in management of solitary small (<5 cm) peripheral HCC in Child A cirrhotic patients. METHODS: Patients were randomly assigned to either OLR group (25 patients) or laparoscopic liver resection (LRR) group (LRR: 25 patients). All were treated with curative intent aiming at achieving R0 resection using radiofrequency-assisted technique. RESULTS: LLR had significantly less operative time (120.32 ± 21.58 versus 146.80 ± 16.59 minutes, P < .001) and shorter duration of hospital stay (2.40 ± 0.58 versus 4.28 ± 0.79 days, P < .001), with comparable overall complications (25 versus 28%, P = .02). LLR had comparative resection time (66.56 ± 23.80 versus 59.56 ± 14.74 minutes, P = .218), amount of blood loss (250 versus 230 mL, P = .915), transfusion rate (P = 1.00), and R0 resection rate when compared with OLR. After median follow-up of 34.43 (31.67-38.60) months, LLR achieved similar adequate oncological outcome of OLR, no local recurrence, with no significant difference in early recurrence or number of de novo lesions (P = .49). One-year and 3-year disease free survival (DFS) rates, 88% and 59%, in the LLR were comparable to corresponding rates of 84% and 54% in OLR (P = .9). CONCLUSION: LLR is superior to the OLR with significantly shorter duration of hospital stay and does not compromise the oncological outcomes.

Ki-67 and Cell Cycle Regulators p53, p63 and cyclinD1 as Prognostic Markers for Recurrence/ Progression of Bladder Urothelial Carcinoma.

Deregulation of the cell cycle regulating genes is common in urothelial bladder carcinoma (UBC). We aimed to examine the prognostic significance of ki-67, p53, p63 and cyclinD1expression in UBC and to identify optimal cut-off points to help identifying patients at high risk of tumor recurrence. We evaluated the immunohistochemical expression of ki-67, p53, p63 and cyclinD1 in 100 UBCs. The conventional and the classification and regression trees-guided (CART-guided) methods were utilized to determine the independent predictors of tumor recurrence. The p53 and Ki-67 expression didn't associate significantly with tumor recurrence.p63 and cyclinD1 exhibited significant hazard ratios. Using CART, no recurrence was observed when p63 was ≥87.5%. The recurrence incidence increased and the disease free survival (DFS) time shortened as the p63 decreased. CyclinD1 associated significantly with tumor recurrence only if p63 was <35%. Using the CART cut-off values¬, cases were categorized into three groups; (groups I: p63 ≥ 35%, II: p63 < 35% and cyclinD1 < 10% and III: p63 < 35% and cyclinD1 ≥ 10%). Group I patients revealed the least incidence of recurrence at the longest DFS. Group III had the worst prognosis followed by Group II. p63 represents a surrogant biomarker to predict UBC recurrence.CyclinD1 can be used only when p63 is <35%. CART proved helpful with data among which the number of cases with positive outcomes is too small relative to the number of studied predictors. Large cohort studies for ki-67 and p53 are recommended to be performed with standardized criteria as regards patients' characteristics, cut-off values, and follow-up time.

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.

Runx2 Expression as a Potential Prognostic Marker in Invasive Ductal Breast Carcinoma.

The Runx family of transcription factors has been implicated in cancer progression, both positively and negatively. Recent studies assigned a role for Runx2 in promoting breast cancer metastasis. However, the role of Runx2 during the early stage of breast carcinoma and its association with clinical outcomes remain unknown. Assessing the clinicopathological significance of Runx2 expression in a cohort of breast invasive ductal carcinomas (IDC). The correlation of nuclear Runx2 LI with clinicopathological parameters was assessed in 84 IDCs. To study the association of Runx2 with patient outcomes, in addition to treating it as a continuous variable, Runx2 was categorized by its median value (65) and by an additional two cut-off points determined by ROC curve analyses, at 45 for disease free survival (DFS) and 40 for overall survival (OS). Multivariate Cox regression models were also constructed. We used the best subset regression to identify models that predict DFS and OS with as few predictors as possible, and validation was performed. Based on the "Predicted R(2)", the three best models were identified. Using Cox-regression, the interaction between Runx2 and other clinicopathological terms was tested. Runx2 LI was significantly associated only with positive Her-2 status, and did not correlate significantly with other clinicopathological parameters. Although Runx2 LI, in the continuous form and when categorized by the median, did not correlate significantly with DFS and OS; after it was categorized using the optimal cut-off points determined using ROC curve analysis, the patients with Runx2 LI >45 % showed a significantly higher event rate and shorter DFS (P = 0.047), whereas patients with Runx2 LI >40 % showed a significantly shorter OS (P = 0.050). Moreover, Runx2 LI contributed significantly in the models built to predict DFS and OS. For DFS, no interaction terms contributed significantly to the models. However, among stage IV cases, the interaction term between centred Runx2 and ER significantly contributed to the prediction of OS. Runx2 was a significant predictor of OS in this model. Runx2 has a role in biological behaviour and affects the outcome of IDC; therefore, its inhibition may be a new therapeutic strategy. The predictability of Runx2 for OS in stage IV tumours differs with different ER states. The pattern of this difference was not determined because the sample size was not sufficient to allow pattern testing.

Feasibility and oncological outcomes of limited duodenal resection in patients with primary nonmetastatic duodenal GIST.

INTRODUCTION: Duodenal gastrointestinal stromal tumors (GISTs) are rare but still represent approximately 30 % of primary duodenal tumors. This study aimed to audit the feasibility and oncological outcomes of limited duodenal resection in patients with primary nonmetastatic duodenal GIST. METHODS: Twelve patients who underwent surgery at our institution since 2002 were prospectively followed up. The duodenal GISTs were located in the first (n = 3), second (n = 1), third (n = 3), and fourth of duodenum (n = 1). Involving both D1/D2 (n = 2), D2/D3 (n = 1), and D3/D4 (n = 1). The primary endpoint for this analysis was disease-free survival. RESULTS: The commonest presentation was melena and anemia (83 %). All the patients underwent limited resection; six wedge resections with primary closures and six segmental resections with end-to-end anastomosis. The median tumor size was 8 cm (range, 5-16 cm). According to Fletcher scale, two GISTs were low risk, while 10 patients were intermediate and high risk. The latter received adjuvant therapy. All the patients had a complete resection with no postoperative mortality. One patient had three liver metastases 4 months after limited resection and had partial hepatectomy. After median follow-up of 45 (15-78) months, all patients are alive and disease free. CONCLUSION(S): When technically feasible, limited resection should be considered a reliable and curative option for duodenal GIST achieving satisfactory disease-free survival. The technical feasibility is guided by the tumor size, possible adjacent organ involvement, and its exact anatomical location.

Stromal caveolin-1 expression in breast carcinoma. Correlation with early tumor recurrence and clinical outcome.

Caveolin- (cav-1) has been linked to tumor progression and clinical outcome in breast cancer, but its role as a prognostic marker is still unclear. We evaluated stromal and tumor caveolin-1 expression in 91 breast carcinomas, and assessed the association between their expression and clinicopathologic variables as well as patient outcome and early tumor recurrence. Absence of stromal caveolin-1 expression was detected in 18.7% of cases, while 25.3% of cases revealed tumor epithelial caveolin-1 expression. Combined stromal and tumor caveolin-1 immunopositivity was seen in 24.2% of cases. Absence of stromal cav-1 associated with larger tumor size, higher grade, higher nodal stage, higher number of positive nodes, higher TNM stage, positive HER2 status, higher recurrence rate, and shorter mean progression free survival (PFS). Stromal cav-1 status was a significant predictor of PFS in ER+, PR +, and HER2 + tumors. In tamoxifen-treated patients, absence of stromal Cav-1 was a significant predictor of poor clinical outcome, suggestive of tamoxifen resistance. Conversely, tumor epithelial and combined caveolin-1 expression, didnot associate with patient outcome. In multivariate analysis, only TNM stage independently associated with survival. Loss of stromal caveolin-1 is a novel breast cancer biomarker that can predict early tumor recurrence, short PFS, and tamoxifen- resistance. Thus, its use as a predictive biomarker, especially in lower grade, lower stage, ER+, PR+, HER2+, and tamoxifen treated patients may allow for early interventions with more aggressive therapies. Thus, stromal marker expression and epithelial-stromal cross talk may be critical for tumor progression and metastasis.

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.

Lymphatic vessel density as prognostic factor in breast carcinoma: relation to clinicopathologic parameters.

Angiogenesis and lymphangiogenesis are essential for breast cancer growth and progression. This study aimed at investigating lymphatic microvessel density (LVD) and microvessel density (MVD) as prognostic markers in breast carcinoma. Forty breast carcinomas were immunostained for D2-40, CD31 and VEGF. Median lymphatic and blood microvessel densities, as well as VEGF expression, were related to each other and to clinicopathologic parameters including lymph node (LN) status. The efficacy of haematoxylin and eosin (H&E) in detecting lymphatic vessel invasion (LVI) compared to D2-40 immunostaining was also investigated. D2-40 stained normal lymphatic endothelium and myoepithelial cells, but with different staining patterns. D2-40 LVD related significantly to CD31 counts (r=0.470; p=0.002), and LN metastasis (Mann-Whitney U=101.500; p=0.043); however, it did not relate to age, tumor grade, tumor size or LVI. D2-40 identified LVI in 3 more cases (7.5%) than those detected by H&E. VEGF was expressed in 85%of cases, and was significantly related to CD31 and D2-40 counts (p=0.033 and 0.007, respectively). In conclusion, D2-40 LVD showed a significant association with LN metastasis, and can be considered to segregate patients with positive from those with negative LNs. D2-40 enhances the detection of LVI relative to H&E staining reflecting a potential for lymphatic metastatic spread and possible poor prognosis.