The Impact of BRCA1 Expression on Survival Status in Ovarian Serous Carcinoma of Egyptian Patients.

OBJECTIVES: The present study aimed to investigate the impact of BRCA1 protein expression on the patients' outcome of ovarian serous carcinoma, and its correlation with different clinicopathologic features. METHODS: Immunohistochemistry with BRCA1 was done for 80 cases of ovarian serous carcinoma that had a positive family history. Correlation with clinico-pathologic variables and patients' outcomes was investigated. RESULTS: BRCA1 expression was detected in 61.2% of the studied cases. A significant relation with patients' age, tumor grade and tumor stage was found (P<0.05). Also, there was a significant decrease in disease free survival (DFS) & overall survival (OS) in the positive BRCA1 group. Metastasis, recurrence, residual disease, and mortality rate showed significantly higher figures in patient with BRCA1 expression (P<0.05). CONCLUSION: Positive BRCA1 expression had proven to be associated with advanced stage & grade of tumors, as well as worsened prognostic survival parameters (metastasis, recurrence, residual disease, and mortality) in patients with ovarian serous carcinoma.

Expression of PD-L1 in Early-Stage Invasive Breast Carcinoma and Its Relation to Tumor-Infiltrating Lymphocytes.

OBJECTIVES: Immunotherapeutic targets became one of the promising approaches in breast cancer (BC), especially in advanced stage triple-negative subtype (TNBC). However, the role of programmed cell death ligand 1 (PD-L1) targeting in other BC subtypes, especially in early-stage carcinoma is less explored. We aimed in this study to investigate the prevalence of PD-L1 in early-stage invasive BC of different molecular subtypes and to elucidate its relation to tumor-infiltrating lymphocytes (TILS) density (cytotoxic and regulatory T-cells), established clinicopathological factors and patients' outcome. MATERIAL AND METHODS: One hundred and nine cases of early-stage BC were enrolled in our study. Cases were classified into five molecular subtypes according to the Immunohistochemical data. PD-L1, FOXP3 and CD8 immunostaining were analyzed for all studied cases. PD-L1 expression was correlated with CD8+ cytotoxic T-cells, FOXP3+ regulatory T-cells, histopathologic parameters, BC molecular subtypes, 7-years disease-free survival (DFS) and overall survival (OS). RESULTS: PD-L1 was expressed in 11% of the studied early-stage BC cases. It showed a significant correlation with high tumor grade (p= <0.001), development of metastasis (p=0.037), high FOXP3+ T-cell density (p= <0.001) and low CD8+ T-cells density (p= <0.001). PD-L1 expression was higher in TNBC (16.1%), followed by HER2/neu-enriched group (14.3%). All luminal A cases showed negative PD-L1 expression. PD-L1 was found to be an independent prognostic factor for patients' survival (DFS; p=0.031 and OS: p=0.04). CONCLUSION: Although the impact of PD-L1 on early-stage BC outcomes had not been clearly established, our results indicated that PD-L1 is a negative prognostic marker in early settings. PD-L1 can serve as a new therapeutic target for patients with high-grade early-stage breast carcinoma.

Prognostic Value of Tumor Infiltrating Lymphocytes in Locally Advanced HER2 Enriched Breast Cancer.

PURPOSE: We aim to study the association between stromal tumor infiltrating lymphocytes (TILs) level and disease free survival (DFS) in a group of ER and PR negative, HER2+ locally advanced breast cancer patients who underwent curative intent surgery. METHODS: This is a retrospective cohort study including 66 locally advanced hormone receptor-negative; HER2+ breast cancer patients presented between 2013 and 2015 at NCI-Cairo, Egypt. Enrolled patients had at least clinically T3 and/or node positive disease either clinically or radiologically. Metastatic workup included CT and bone scans or PET-CT. Patients with hormone receptor positive, HER2 negative, inadequate paraffin block and who lost follow up before or immediately after curative surgery were excluded. Patients were followed from breast surgery till relapse date for a minimum of 36 months. TILs and CD8 antigen were assessed on paraffin-embedded blocks using immunohistochemistry. RESULTS: Patients with a median age of 52 years presented with clinical T3 stage (53%) and N1 stage (61%). Modified radical mastectomy was performed in 79%. Only 41% received neoadjuvant chemotherapy and 56% received trastuzumab. TILs were 50, 17 and 33% for absent, intermediate and extensive groups and CD8+ lymphocytes were present in 80% of cases. At the end of follow-up period, 23 patients (35%) were found to have disease recurrence either loco-regional (22%) or distant (78%). TILs were 14, 4 and 5% for absent, intermediate and extensive respectively; while CD8+ lymphocytes were absent in 6% and present (≥1%) in 17%. Higher DFS was recorded for patients with extensive TILs level only who received trastuzumab. CONCLUSION: High TILs is good prognosis in HER2 enriched breast cancer provided that patients received HER2 directed therapy. Moreover, CD8+ lymphocytes are highly representative and maybe used as an alternative for TILs. We recommend considering TILs and specifically CD8+ as one of the risk factors that predict prognosis of HER2+ breast cancer.

Differential expression of p53 family proteins in colorectal adenomas and carcinomas: Prognostic and predictive values.

BACKGROUND: We studied the contribution of p53 family proteins and their isoforms to the development and progression of colorectal carcinoma in relation to VEGF. METHODS: p53, p63, p73 and VEGF proteins were assessed in 45 colorectal adenomas (CRAs), 80 carcinomas (CRCs) and 36 normal colonic tissue samples (NCT) by immunohistochemistry. Different p63 and p73 isoforms were assessed by RT-PCR. Aberrant protein and RNA expressions were correlated to patients' characteristics, disease free and overall survival (DFS and OS). RESULTS: p53, p63, p73 and VEGF proteins were detected in 22.2%, 73.3%, 33.3%, 46.7% CRAs; in 68.8%, 38.8%, 62.5%, 62.5% CRCs and 16.7%, 83.3%; 13.9%, 41.7% NCT (p<0.05 except for VEGF). Commonest isoforms were TAp63α, ΔNp63, TAp73α in CRA and ΔNp63, TAp63α, ΔNp73, TAp73ß in CRC. Significant correlations were found between aggressive tumor phenotypes and aberrations in p73, p53, p63, VEGF. DFS correlated with advanced stage, p73 and VEGF aberrations. While advanced stage, positive lymph nodes, p73 and p53 correlated with OS. Prognosis was worse in patients with aberrant p63 and p73 than in those with normal p63 and p73 expression regardless of p53 gene status (p⟨0.05). CONCLUSIONS: p53 family proteins and VEGF play a pivotal role in colorectal carcinogenesis. p53 prognostic potential is augmented by p73 and p63 aberrations indicating a synergistic effect between the three family members. Nodal status, stage, p73, VEGF and p53 could be used as predictors of DFS and OS.

p16 expression correlates with basal-like triple-negative breast carcinoma.

BACKGROUND: Basal-like breast carcinoma (BLBC) has attracted considerable attention over the past few years. It has been suggested that tumours expressing basal markers have a more aggressive clinical behaviour. However, a molecular basis for this disease remains unclear, and it lacks currently used therapeutic targets. Therefore developing a novel treatment strategy is crucial for improving the prognosis. The aim of this study was to characterise the immunohistochemical (IHC) expression of p16 in patients with BLBC compared with non-BLBC. MATERIALS AND METHODS: Eighty-five cases of grade-3 invasive ductal carcinomas not otherwise specified (IDC-NOS) were analyzed. Immunohistochemical stains for oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor type 2 (HER2), cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and p16 were performed. BLBC was defined as ER-, PR-, Her2- and CK5/6+, and/or EGFR+. RESULTS: Twenty cases were categorised as BLBC versus 65 as non-basal. High mitotic count and presence of necrosis were associated with basal-like phenotype. Distant metastasis developed in 40% of cases of BLBC with frequent spread to brain and lung. p16 had significantly higher expression in the basal subgroup (80% versus 50.8%, P = 0.04). Patients with BLBCs were found to have a lower disease-free survival (DFS) rate (60% versus 70.8%, P = 0.03). CONCLUSION: BLBC typically demonstrates a unique profile. p16 is frequently expressed in breast cancers with basal-like phenotype; this suggests that p16 may play a role in the poor prognosis of this tumour, and it may be used in the development of a targeted therapy that will result in improved patient prognostication and outcome.

Role of cyclooxygenase-2, ezrin and matrix metalloproteinase-9 as predictive markers for recurrence of basal cell carcinoma.

CONTEXT: Recurrence of basal cell carcinoma (BCC) may form a prognostic problem that couldn't be fully predicted. Although there are different clinical and histologic risk factors for BCC recurrence, few reports are available for the role of biologic markers. AIM: The aim of this study was to assess the value of Cyclooxygenase-2 (COX-2), Ezrin and Matrix metalloproteinase-9 (MMP-9) in recurrence of BCC. SETTINGS AND DESIGN: A retrospective controlled study. MATERIALS AND METHODS: Primary tumors of 22 patients who had recurrent basal cell carcinoma (R-BCC) and 22 matched controls that showed non-recurrent basal cell carcinoma (NR-BCC) were collected. Clinical, histopathological, and immunohistochemical results were recorded and analyzed. STATISTICAL ANALYSIS USED: SPSS software version 13 and Pearson χ2 test. RESULTS: R-BCC showed COX-2 expression in 20 (90.9%) cases compared to 13 (59.1%) in NR-BCC with a significant difference (P = 0.04). Moderate to strong intensity was recorded in 13 recurrent and two non-recurrent tumors. Higher frequency for Ezrin immunopositivity was noted in R-BCC (72.7%) than NR-BCC (40.9%), but the difference did not reach the level of significance (P = 0.07). Twelve R-BCC and three NR-BCC revealed moderate to strong staining. For MMP-9, there was no statistically significant difference (P = 1) between recurrent cases (63.6%) and controls (68.2%). No correlation was found between marker expressions and clinical or histologic features of R-BCC. CONCLUSIONS: Biologic markers may have a promising role in assessment of BCC prognosis and early detection of recurrence. High COX-2 expression could be considered as a risk factor of BCC recurrence that can be added to other clinical and histologic factors.

Aberrant expression of cell cycle regulatory genes predicts overall and disease free survival in malignant pleural mesothelioma patients.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive disease with a generally poor prognosis. Since escape from cell cycle checkpoint control is common in several solid tumors, the present study was performed to evaluate the role of some cell cycle regulatory genes in the development and progression of MPM. PATIENTS AND METHODS: Aberrant expression of p14(ARF), p16(INK4A), p21(waf), p27(KIP), p53, mdm2 and Rb was assessed in 55 MPM cases from Egypt using immunohistochemistry and PCR techniques. Results were correlated with clinico-pathological prognostic factors, overall and disease free survival (OS&DFS). RESULTS: Altered expression of p14(ARF), p16(INK4A), p21(waf), p27(KIP1), Rb, p53 and mdm2 proteins was detected in 50.9%, 54.5%, 53.3%, 61.8%, 53.3%, 58.2%, and 50.8% of cases, respectively. SV40 infection significantly correlated with p14(ARF), 16(INK4A), p27(kip1) and Rb aberrations (p=0.014, p=0.02, p=0.01, p=-0.01). Asbestos exposure significantly correlated with p53, p21(waf) and mdm2 aberrations (p=0.001, p=0.03, p=0.02). On multivariate analysis PS ≥ 2, p27(KIP1) and Rb aberrations were independent prognostic factors for OS (p=0.016, p=0.011, p=0.003) whereas on tumor recurrence, p27(KIP1) and Rb aberrations were independent prognostic factors for DFS (p=0.002, p=0.03, p=0.01). CONCLUSIONS: MPM is a complex disease characterized by multiple genetic aberrations; some of them involve cell cycle regulatory genes. p14(ARF), p16(INK4A), Rb and p27(KIP1) seem to be involved in SV40-associated MPM whereas mdm2, p53 and p21(WAF) are related to asbestos exposure. In addition to recurrence and PS, only p27(KIP1)and Rb could be used as molecular prognostic markers in MPM.

Intradermal injection of PPD as a novel approach of immunotherapy in anogenital warts in pregnant women.

Immunotherapy for treatment of recalcitrant warts was used through different modalities including intralesional injection of purified protein derivative (PPD), which is an extract of Mycobacterium tuberculosis, used for testing exposure to tuberculin protein, either from a previous vaccination or from the environment. This method is used to evaluate the efficacy of a new approach of intradermal injection of PPD in the treatment of anogenital warts in pregnant women. A total of 40 pregnant women, aged 20-35 years, and presented with anogenital warts were enrolled in this study. Human papillomavirus (HPV) typing was done using the GP5+/GP6+ PCR assay. The patients were treated with weekly injections of PPD given intradermally in the forearms, and evaluated for the response regularly. HPV type-6 was the predominant genotype (67.5%). Overall, the improvement in this study was 85% and was related to the extent of tuberculin reactivity. Nineteen (47.5%) patients demonstrated complete clearance, 15 (37.5%) had partial response, and three (7.5%) had minimal response. Three (7.5%) cases did not respond to treatment. Side effects were minimal and insignificant. Treatment of anogenital warts in pregnant women with intradermal injection of PPD was found to be a unique, safe, and effective modality of immunotherapy.

Adenomatous colorectal polyps in patients referred for colonoscopy in a regional hospital in Kuwait.

BACKGROUND/AIM: Adenomatous colorectal polyps (ACPs) are known to be the precursor lesions for colorectal cancer. The aim of the study was to determine the prevalence, endoscopic and pathological features of ACPs in patients referred for colonoscopy. PATIENTS AND METHODS: The endoscopic and histological reports of adult patients who underwent complete colonoscopy in the gastroenterology unit of a regional Kuwaiti hospital between January 2008 and December 2008 were retrospectively studied. The specimens of polyps were reviewed by an experienced pathologist who was blinded to the clinical or endoscopic information. Non-neoplastic polyps were not included in the analysis. RESULTS: Of 530 eligible patients (mean age, 45 years; male-female ratio, 2:1), 54 (10%) had 103 ACPs. Of the patients with ACPs (mean age, 57 years), 43 (80%) were males and 36 (67%) were Kuwaitis. Histopathological examination of the most significant polyp in each patient revealed that 40 (74%) polyps were tubular adenomas (TAs); 11 (20%), tubulovillous (TV) adenomas; and 3 (6%), villous adenomas. High-grade dysplasia was noticed in 4 (10%) adenomas. Fifteen (2.8%) of the 530 patients had advanced ACPs. Logistic regression analysis of some variables and their association with ACPs found that age (P < 0.001; OR, 1.9; CI, 1.5-2.3), history of adenoma (P=0.001; OR, 6.4; CI, .2.1-19.4) and being Kuwaitis (P=0.029; OR, 2.1; CI, 1.1-4.1) to be independently associated with ACPs. CONCLUSION: The most common histological type of ACPs was tubular adenoma. Advancing age, being Kuwaiti nationals and prior removal of ACPs were significantly associated with the occurrence of ACPs.

Effect of methimazole treatment on doxorubicin-induced cardiotoxicity in mice.

The major limiting factor in long-term administration of doxorubicin is the development of cumulative dose-dependent cardiomyopathy and congestive heart failure that limit the use of this drug. The present study was undertaken to find out the chemo protective role of methimazole against doxorubicin-induced cardiotoxicity in experimental animals. In the present study, doxorubicin treatment in a dose of 3mg/kg, i.p., every other day for six doses showed a significant 2.6-, 3- and 10.5-fold increase in the cardiac enzyme activities CK-MB and LDH and troponin-I, respectively, in the serum of the animals. Histopathological investigation of heart tissues showed swollen muscle fibers with interstitial edema and inflammatory exudate. Pretreatment of the animals with methimazole at a dose level of 40 mg/kg, i.p., 30 min before doxorubicin, returned the cardiac enzyme levels to nearly normal value with partial reversal of the inflammatory lesions and the swollen muscle fibers induced by doxorubicin. Moreover, methimazole pretreatment, decreased the doxorubicin level in the heart tissues with a significant increase in plasma level and non significant effect on doxorubicin level in tumor cells. At the same time, methimazole pretreatment did not significantly interfere with the antitumor activity of doxorubicin.