Vincamine Ameliorates Epithelial-Mesenchymal Transition in Bleomycin-Induced Pulmonary Fibrosis in Rats; Targeting TGF-ß/MAPK/Snai1 Pathway.

Idiopathic pulmonary fibrosis is a progressive, irreversible lung disease that leads to respiratory failure and death. Vincamine is an indole alkaloid obtained from the leaves of Vinca minor and acts as a vasodilator. The present study aims to investigate the protective activity of vincamine against EMT in bleomycin (BLM)-induced pulmonary fibrosis via assessing the apoptotic and TGF-ß1/p38 MAPK/ERK1/2 signaling pathways. In bronchoalveolar lavage fluid, protein content, total cell count, and LDH activity were evaluated. N-cadherin, fibronectin, collagen, SOD, GPX, and MDA levels were determined in lung tissue using ELISA. Bax, p53, bcl2, TWIST, Snai1, and Slug mRNA levels were examined using qRT-PCR. Western blotting was used to assess the expression of TGF-ß1, p38 MAPK, ERK1/2, and cleaved caspase 3 proteins. H & E and Masson's trichrome staining were used to analyze histopathology. In BLM-induced pulmonary fibrosis, vincamine reduced LDH activity, total protein content, and total and differential cell count. SOD and GPX were also increased following vincamine treatment, while MDA levels were decreased. Additionally, vincamine suppressed the expression of p53, Bax, TWIST, Snail, and Slug genes as well as the expression of factors such as TGF-ß1, p/t p38 MAPK, p/t ERK1/2, and cleaved caspase 3 proteins, and, at the same time, vincamine increased bcl2 gene expression. Moreover, vincamine restored fibronectin, N-Catherine, and collagen protein elevation due to BLM-induced lung fibrosis. In addition, the histopathological examination of lung tissues revealed that vincamine attenuated the fibrotic and inflammatory conditions. In conclusion, vincamine suppressed bleomycin-induced EMT by attenuating TGF-ß1/p38 MAPK/ERK1/2/TWIST/Snai1/Slug/fibronectin/N-cadherin pathway. Moreover, it exerted anti-apoptotic activity in bleomycin-induced pulmonary fibrosis.

High COX-2 immunostaining in papillary thyroid carcinoma is associated with adverse survival outcomes.

BACKGROUND: Thyroid carcinoma is one of the most common malignancies worldwide. More than 70%-80% are papillary thyroid carcinoma (PTC). Many factors influence the PTC pathway of development such as genetic mutations, growth factors, and radiation. More biological understanding of the genetic and molecular pathways is needed in PTC to determine tumor behavior, and initial clinical assessment. OBJECTIVES: Investigate the relation of COX-2 immunostaining in thyroid carcinoma with clinicopathological parameters to assess whether immunostaining results have prognostic significance. DESIGN: Retrospective study SETTING: Pathology department, tertiary care center METHODS: Records of PTC were retrieved and tissue microarrays were constructed. Tissue sections were stained using anti-human COX-2 monoclonal antibody. Immunostaining results were recorded and analysed. MAIN OUTCOME MEASURES: Relationship of COX-2 immunostaining in thyroid carcinoma with clinicopathological parameters. SAMPLE SIZE: 139 tissue samples from 139 patients RESULTS: High versus low COX-2 immunostaining showed no significant differences for most clinicopathological parameters. However, high COX-2 immunostaining showed borderline association with tumor multifocality (P=.05), lower overall (log-rank=8.739 and P=.003), and disease-free survival (log-rank=7.033, P=.008). CONCLUSION: The study showed a positive association of high COX-2 immunostaining with lower survival outcomes in PTC. COX-2 immunostaining could be a potential prognostic factor for survival in PTC. Additional molecular and clinical investigations are needed for further understanding the molecular pathways of COX-2 in PTC and the feasibility of using inhibitors of COX-2 as adjuvant therapy along with current chemotherapy. LIMITATIONS: Relatively low number of PTC variants, and no testing of other thyroid carcinomas. CONFLICT OF INTEREST: None.

Increased Glypican-3 immunostaining is associated with longer survival outcomes in colorectal carcinoma.

Glypicans (GPC) are involved in the developmental morphogenesis and regulatory processes of cell signalling. Abnormal expression has been observed in different cancer types. One hundred and thirty-seven colorectal carcinoma (CRC) and 44 nodal metastases were used to create tissue microarrays. Immunohistochemistry was done to detect and evaluate the impact of immunostaining patterns of GPC-3 protein in CRC. GPC-3 immunostaining is increased in CRC and nodal metastasis (p < 0.001) and was not association with clinicopathological parameters. GPC-3 immunostaining was associated with longer disease-free survival (p = 0.021) and overall survival (p = 0.05). For the first time, we show GPC-3 immunostaining association with survival outcomes in CRC. GPC-3 may be used as an independent prognostic factor for survival in CRC.

Concurrent Urinary Bladder Paraganglioma and Adrenal Phaeochromocytoma With Succinate Dehydrogenase-B Mutation.

Phaeochromocytoma (PHEO) is a neoplasm that arises from chromaffin cells present in the adrenal medulla. The counterpart of the PHEO extra-adrenal is termed paraganglioma (PGL). The urinary bladder PGL is a rare tumour, and it accounts for less than 0.06% of all bladder tumours. In this report, we discuss a case of a young female who presented with symptoms of headache, dizziness, palpitations, and high blood pressure. After workup, she was diagnosed with concurrent urinary bladder PGL and adrenal PHEO, and the genetic study of the whole exon sequence indicated the presence of succinate dehydrogenase-B (SDHB) mutation. Both tumours were treated surgically; however, the patient ultimately developed recurrence, rapid progression, and metastasis. All secondary modalities were unsuccessful, and the patient was referred for palliative treatment and eventually lost to follow-up. PGL should be included in the differential diagnosis of bladder tumours, and testing for SDHB gene mutations should be considered in all urinary PGLs. Therefore, these patients need follow-up and genetic counselling.

The prognostic significance of immunostaining of Wnt signalling pathway molecules, E-cadherin and ß-catenin in colorectal carcinomacolorectal carcinoma.

BACKGROUND AND STUDY AIMS: Colorectal carcinoma (CRC) is associated with high morbidity and mortality. The E-cadherin-catenin complex is crucial in the development and progression of carcinomas. This study was conducted to evaluate the relation between E-cadherin and ß-catenin immunostaining and CRC outcome. PATIENTS AND METHODS: Tissue microarrays were constructed from CRC, nodal metastases, adenomas, and normal mucosa. E-cadherin and ß-catenin immunostaining was performed, and results were analyzed. RESULTS: For E-cadherin, the membranous fraction (MF) was higher in normal mucosa, adenoma, CRC, and nodal metastasis than the cytoplasmic fraction (CF), but no difference in nodal metastasis was observed. A low MF in CRC was associated with disease relapse. For ß-catenin, high MF and CF in normal mucosa, adenoma, CRC, and nodal metastasis were observed, whereas the nuclear fraction (NF) was high only in CRC. In CRC, a high CF was associated with nodal metastasis and the incidence of relapse and predicted nodal metastasis. A high NF could predict distance metastasis. A high CF in CRC was associated with favorable disease-free survival and overall survival. CONCLUSION: Reduced E-cadherin and ß-catenin immunostaining in CRC is related to prognostic factors. The Wnt/ß-catenin pathway may play a crucial role in CRC progression and help identify the high risk of adverse outcomes and indicate close follow-up.

A Case Report of Thyroid Plasmacytoma and Literature Update.

Plasmacytomas of the thyroid gland are rare, whether or not they arise as solitary (primary) lesions or secondary to systemic multiple myeloma. Here, we present the case of a 71-year-old female presenting with goiter and Hashimoto's thyroiditis, in whom the subsequent histopathological diagnosis of plasmacytoma was a surprise. In presenting this case, we summarize the last 25 years of literature on thyroid plasmacytoma and review the salient clinicopathological characteristics, differential diagnoses, management, and outcomes of this rare condition.

Increased osteopontin expression in endometrial carcinoma is associated with better survival outcome.

OBJECTIVES: Osteopontin (OPN) is a key extracellular matrix protein that is involved in cancer progression. The aim of the current study is to investigate the relation of OPN immunostaining in endometrial carcinoma with clinicopathological parameters. MATERIAL AND METHODS: Archival 71 endometrial carcinomas and 30 non-neoplastic endometrial tissues were obtained from the Department of Pathology at King Abdulaziz University Jeddah, Saudi Arabia. Tissue microarrays were constructed. Tissue sections were stained using anti-human OPN monoclonal antibody. Immunostaining results were recorded and analysed. RESULTS: In non-neoplastic endometrial tissues, high (increased) OPN immunostaining was observed in 100%. In endometrial carcinoma, high (increased) OPN immunostaining was seen in 64.8% of cases. High (increased) OPN immunostaining was more frequent in non-neoplastic tissues than in endometrial carcinoma (p < 0.001). OPN immunostaining showed no association with histological type, FIGO tumour grade, tumour size, myometrial invasion, lymphovascular invasion, surgical resection margin or lymph node metastasis. On the other hand, high (increased) OPN immunostaining was associated with better overall survival [Log Rank (Mantel-Cox) = 4.385, p = 0.003]. CONCLUSIONS: In endometrial carcinoma, immunohistochemical staining of OPN could be a helpful tool in the prediction survival pattern. OPN immunostaining showed no association with most clinicopathological features. Further investigations both clinical and molecular are needed to explore the downstream of OPN in endometrial carcinoma.

SOX2 Is a Potential Novel Marker of Undifferentiated Thyroid Carcinomas.

Background Thyroid cancer is a very common endocrine malignancy. Cancer stem cells are attributable to initiation, progression, and treatment failure in thyroid carcinoma. In the current study, immunostaining of SRY-box 2 (SOX2) in thyroid carcinoma is investigated. Material and methods Tissue microarrays were generated from 219 thyroid carcinomas distributed as follows: papillary thyroid carcinoma (175), follicular thyroid carcinoma (11), medullary thyroid carcinoma (11), Hurthle cell carcinoma (three), poorly differentiated thyroid carcinoma (PTDC; nine), and anaplastic thyroid carcinoma (ATC; 10). Immunohistochemistry for SOX2 was done and examined for nuclear staining. The results were analysed.  Results SOX2 immunostaining was positive in one PDTC (out of nine; 11.1%) and in three ATC (out of 10; 30%). The rest of the thyroid cancers showed no immunostaining for SOX2. Conclusion The study represents for the first time SOX2 immunostaining on a large number of thyroid carcinomas. We discovered that SOX2 immunostaining is found in PDTC and ATC while SOX2 immunostaining is lacking in other thyroid cancer. SOX2 may be a marker of loss of differentiation in thyroid carcinoma. In vitro as well as in vivo molecular studies are required to explore the possible role of SOX2 in thyroid carcinoma.

A Rare Concomitant Oncocytic Adrenocortical Neoplasm and Hepatocellular Carcinoma over a Four-year Duration: A Case Report and Review of Literature.

Oncocytic adrenocortical neoplasms (OANs) are very rare. Although most cases have benign behavior, the risk of recurrence/metastasis is variable. Based on Lin-Weiss-Bisceglia (LWB) system criteria, OANs can be classified as benign, borderline, or malignant. A concomitant development of OANs with second primary neoplasm is extremely uncommon, and is limited to very few case reports. None of these reported cases was found to be associated with hepatocellular carcinoma (HCC). In this case report, we present a 64-year-old female patient who had a progressively increasing left supra-renal mass over a three-year interval. During her regular imaging-based follow up after successful left adrenalectomy, a new suspicious solitary, hypodense liver mass was detected and removed. All necessary work-up was done and strongly support the diagnosis of two distinct primary tumors including borderline malignant potential OAN and subsequent HCC. A significant clinical and morphological characteristic of OANs make its identification valuable.

Prognostic value of Osteopontin (SPP1) in colorectal carcinoma requires a personalized molecular approach.

Stratification of colorectal cancer for better management and tangible clinical outcomes is lacking in clinical practice. To reach this goal, the identification of reliable biomarker(s) is a prerequisite to deliver personalized colorectal cancer theranostics. Osteopontin (SPP1) is a key extracellular matrix protein involved in several pathophysiological processes including cancer progression and metastasis. However, the exact molecular mechanisms regulating its expression, localization, and molecular functions in cancer are still poorly understood. This study was designed to investigate the SPP1 expression profiles in Saudi colorectal cancer patients, and to assess its prognostic value. Hundred thirty-four (134) archival paraffin blocks of colorectal cancer were collected from King Abdulaziz University Hospital, Saudi Arabia. Tissue microarrays were constructed, and automated immunohistochemistry was performed to evaluate SPP1 protein expression patterns in colorectal cancer. About 20% and 23% of our colorectal cancer samples showed high SPP1 cytoplasmic and nuclear expression patterns, respectively. Cytoplasmic SPP1 did not correlate with age, gender, tumor size, and location. However, significant correlations were observed with tumor grade (p = 0.008), tumor invasion (p = 0.01), and distant metastasis (p = 0.04). Kaplan-Meier survival analysis showed a significantly lower recurrence rate in patients with higher SPP1 cytoplasmic expression (p = 0.05). At multivariate analysis, high SPP1 cytoplasmic expression was an independent favorable prognostic marker (p = 0.02). However, nuclear SPP1 expression did not show any prognostic value (p = 0.712). Our results showed a particular SPP1 prognostic relevance that is not in line with most colorectal cancer previous studies that may be attributed to the molecular pathophysiology of our colorectal cancer cohort. Saudi Arabia has both specific genomic makeup and particular environment that could lead to distinctive molecular roots of cancer. SPP1 has several isoforms, tissue localizations and molecular functions, signaling pathways, and downstream molecular functions. Therefore, a more individualized approach for CRC studies and particularly SPP1 prognosis outcomes' assessment is highly recommended toward precision oncology.

Analytical study of clinicopathological data of Saudi patients with osteoarthritis subjected to total knee arthroplasty / Estudio analítico de datos clínico-patológicos de pacientes sauditas con osteoartritis sometidos a artroplastia total de rodilla

Knee osteoarthritis (OA) is a common disabling disease. Epidemiological studies have revealed various risk factors for OA, including sex, aging, obesity, occupational illnesses, and chronic diseases. Here we evaluate the clinical, pathological, and radiological findings of knee OA in a subset of Saudi patients who were subjected to total knee replacement (TKA). The study population included 30 Saudi patients with knee OA who were operated by TKA (from June 2014 to December 2015) in the Department of Orthopedics, Faculty of Medicine, King Abdulaziz University, Saudi Arabia. Patient's clinical and radiological data were collected from the hospital files. Pathological examination of the excised superior articular surface of tibia and femoral condyles were done. Pearson Chi-squared analysis was used to test for differences between the variables in associated risk factors. There were more women than men. Sixty per cent of patients were older than 60 years [mean age, 59.2 (females) and 61.7 (men) years-old]. All patients exceeded obesity class 1, with females being more obese than males. Pathological examination of the superior articular surface of tibia and femoral condyles showed high score lesions, which was more apparent in females than in males. Radiological findings showed that most lesions were high grade. The findings of this study will help to understand the pathogenesis of OA and improve treatment decision making relevant to TKA in knee OA in Saudi Arabia and elsewhere.

La artrosis de rodilla (OA, por sus siglas en inglés) es una enfermedad invalidante común. Los estudios epidemiológicos han revelado diversos factores de riesgo para la OA, que incluyen el sexo, el envejecimiento, la obesidad, las enfermedades profesionales y las enfermedades crónicas. Aquí evaluamos los hallazgos clínicos, patológicos y radiológicos de la OA de rodilla en un subconjunto de pacientes sauditas que fueron sometidos a reemplazo total de rodilla (RTR). La población de estudio incluyó a 30 pacientes saudíes con OA de rodilla que fueron operados por RTR (desde junio de 2014 hasta diciembre de 2015) en el Departamento de Ortopedia, Facultad de Medicina, King Abdulaziz University, Arabia Saudita. Los datos clínicos y radiológicos de los pacientes se obtuvieron de las fichas hospitalarias. Se realizó examen patológico de la superficie articular superior de la tibia extirpada y cóndilos femorales. Se utilizó el análisis Chi-cuadrado de Pearson para probar las diferencias entre las variables en los factores de riesgo asociados. El número de mujeres era mayor que los hombres. El 60 % de los pacientes eran mayores de 60 años [edad media, 59,2 (mujeres) y 61,7 (hombres) años]. Todos los pacientes superaron la obesidad clase 1, siendo las mujeres más obesas que los hombres. El examen patológico de la superficie articular superior de la tibia y los cóndilos femorales mostraron lesiones con puntaje alto, que fue más evidente en mujeres que en hombres. Los hallazgos radiológicos mostraron que la mayoría de las lesiones eran de alto grado. Los hallazgos de este estudio ayudarán a comprender la patogenia de la OA y mejorarán la toma de decisiones sobre el tratamiento relevante para el RTR en la OA de rodilla en Arabia Saudita y en otros lugares.

Increased COX-2 Immunostaining in Urothelial Carcinoma of the Urinary Bladder Is Associated with Invasiveness and Poor Prognosis.

BACKGROUND: Urothelial carcinoma of the urinary bladder (UCB) is the commonest bladder tumor. Cyclooxygenase-2 (COX-2) mediates angiogenesis, cell survival/proliferation, and apoptosis. This study investigates the relation of COX-2 immunostaining in UCB to clinicopathological parameters in Saudi Arabia. METHODS: The study population includes 123 UCB and 25 urothelial mucosae adjacent to UCB. UCB samples were collected before any local or systemic therapy. Tissue microarrays were designed and constructed, and TMA blocks were sliced for further immunohistochemical staining. Immunohistochemical staining was done using a mouse anti-human COX-2 monoclonal antibody. A cutoff point of 10% was chosen as the threshold to determine low and high COX-2 immunostaining. RESULTS: COX-2 immunostaining is higher in UCB than in the adjacent urothelium (p = 0.033). High COX-2 immunostaining is associated with high-grade UCB (p = 0.013), distant metastasis (p = 0.031), lymphovascular invasion (p = 0.008), positive muscle invasion (p = 0.017), pT2 and above (p = 0.003), and high anatomical stages (stage II and above). High COX-2 immunostaining is an independent predictor of higher tumor grade (p < 0.001), muscle invasion (p = 0.015), advanced pathological T (p = 0.014), lymphovascular invasion (p = 0.011), and distant metastasis (p = 0.039). High COX-2 immunostaining is associated with lower overall survival rate (p = 0.019). CONCLUSION: COX-2 immunostaining is associated with the invasiveness of UCB which may be used as an independent prognostic marker. COX-2 may be a significant molecule in the initiation and progression of UCB. Molecular and clinical investigations are required to explore the molecular downstream of COX-2 in UCB and effectiveness of COX-2 inhibitors as adjuvant therapy along with traditional chemotherapy.

Low expression of MUC2 is associated with longer disease-free survival in patients with colorectal carcinoma.

BACKGROUND/AIM: The objective of this study was to investigate the relationship between MUC2 immunostaining and clinicopathological characteristics in a subset of colorectal carcinomas (CRCs). MATERIALS AND METHODS: A total of 128 CRCs, 50 local nodal metastases, and 42 normal colonic mucosae were retrieved from the archives at the Department of Pathology at King Abdulaziz University, Jeddah, Saudi Arabia. Immunohistochemistry was performed using anti-MUC2 antibody. A cut-off of 25% of positive immunostaining was used to define low and high immunostaining. Statistical tests were used to determine the association of MUC2 with clinicopathological characteristics and survival. RESULTS: MUC2 immunostaining was observed in 66.7% in normal colonic mucosa. Low MUC2 immunostaining was higher in primary CRC (P = 0.003) and nodal metastasis (80%) (P < 0.001). There was significant association of low MUC2 immunostaining in CRC with age group below 60 years (P = 0.05) and occurrence of lymphovascular invasion (P = 0.034). Other clinicopathological parameters were not correlated with MUC2 immunostaining. Regression analysis revealed that low MUC2 immunostaining was an independent predictor of lymphovascular invasion (P = 0.041). In the Kaplan-Meier survival analysis, there was a significant longer disease-free survival in patients with low MUC2 immunostaining (P = 0.045). However, there was no association between MUC2 immunostaining and overall survival (P = 0.601). CONCLUSION: MUC2 immunostaining may have distinct clinical significance and provide valuable information and could be considered as an important independent prognostic factor while planning the adjuvant therapy in CRC. In future perspective, characterization of MUC2 immunostaining on a large number of cases and molecular studies may be needed.

Fascin expression in urinary bladder urothelial carcinoma correlates with unfavourable prognosis.

BACKGROUND: Urinary bladder crothelial carcinoma (UCB) is the most common urinary bladder neoplasm. The present study aims at investigating immunostaining of fascin in UCB in relation to clinicopathologiccriteria in Saudi Arabia. METHODS: This study utilised 122 UCB and 25 apparently normal urothelium archival pathologic samples prior to local or systemic therapy. Tissue microarrays were constructed and the generated TMA blocks were used for Immunohistochemical staining. The mouse anti-fascin monoclonal antibody was used. A 25% was used to specify low and high fascin immunostaining. RESULTS: Fascin immunostaining was detected in UCB and apparently normal urothelium. High immunostaining was statistically less frequent than low fascin immunostaining (P≤0.001). In UCB, high fascin immunostaining was associated with older patients (P=0.005) and local disease recurrence (P=0.002). High fascin immunostaining was an independent predictor of local disease recurrence (P=0.002) and associated with poor overall survival (P=0.027). CONCLUSION: High fascin immunostaining in UCB was associated with adverse prognostic factors and may be used as an independent prognostic marker. Fascin was detected in apparently normal urothelium and may contribute to UCB carcinogenesis. Further investigations (molecular and clinical) are required to understand the molecular interaction of fascin with UCB and its possible therapeutic applications.

Primary Myeloid Sarcoma of the Breast: A Case Report and Review of Literature.

Myeloid sarcoma (MS) of the breast is uncommon. We report this case of a 29-year-old female presented with a breast lump that was diagnosed as hamartoma by radiology. The lump was removed surgically. Pathological examination revealed a malignant tumor composed of immature cells with eosinophilic cytoplasm and single or multiple nucleoli, diffusely infiltrating the mammary parenchyma and sparing a few ducts and lobules. Immunostaining revealed positivity for leukocytic common antigen, myeloperoxidase, and CD68, and focally positive for CD34 and CD117. The final diagnosis was released as primary MS of the breast. The patient was treated with radiotherapy and chemotherapy. Three consecutive bone marrow biopsies were negative for neoplastic infiltration.

Immunohistochemical staining of cytokeratin 20 and cytokeratin 7 in colorectal carcinomas: Four different immunostaining profiles.

Background/Aim: Aberrant expression of CK20/CK7 is reported in a percentage of colorectal carcinomas (CRC); however, its relation to clinicopathological variables and survival data is still unclear. The objective of this study is to explore patterns of CK20/CK7 immunostaining in CRC and to analyse the diagnostic, prognostic, and predictive role of patterns of CK20/CK7 immunostaining. Materials and Methods: A total of 144 CRC cases were retrieved from the archives at the Department of Pathology, King Abdulaziz University, Jeddah, Saudi Arabia. Immunohistochemistry was performed using antibody to CK7 and CK20. Immunostaining was defined as low and high by using the extent of staining. The association of CK7 and CK20 with clinicopathological characteristics and survival. Results: CK20 was expressed in a higher percentage of CRC and nodal metastasis than CK7. No difference in CK7 and CK20 immunostaining in primary and metastasis carcinomas was found. Four patterns of CK20/CK7 were identified; CK20+/CK7- (60.4%), CK20+/CK7+ (2.1%), CK20-/CK7- (35.4%), and CK20-/CK7+ (2.1%). There was no statistically significant correlation between CK20/CK7 immunohistochemical profile and clinicopathological characteristics, prognosis, and survival was determined. Conclusions: Our results may support the heterogeneity of CRC. CRC showed four different subclasses following patterns of relative CK20/CK7 immunostaining. A considerable number of CRC expressed aberrant immune profile of CK20/CK7, which should be considered during diagnosing CRC in metastatic regions. Further studies on larger cohorts correlating different immunohistochemical cytokeratin profiles to molecular subtypes of CRC are recommended for better understanding of pathogenesis and behaviour of CRC.

The incidence of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion in Saudi adult patients with renal cancer: a retrospective tissue microarray analysis.

Renal cell carcinoma (RCC) is the most common renal tumour. RCC with Xp11.2 translocation/TFE3 (transcription factor E3) gene fusions (Xp11.2 RCC) is positive for immunostain labelling by TFE3 antibody. This tumour is rarely described in adults. This study aims to evaluate the frequency of RCC with Xp11.2 in a subset of Saudi adult patients with RCC. 112 RCCs diagnosed in 1995-2016 were retrieved from the Department of Pathology at King Abdulaziz University and King and Faisal Specialist Hospital and Research Centre, Saudi Arabia. Tissue microarrays were constructed and TFE3 immunostaining was performed. TFE3 immunostaining was considered positive when diffuse strong nuclear immunostaining was detected. TFE3 immunostaining-positive tumours were confirmed by fluorescence in situ hybridisation. 4.5% of RCCs were shown to be Xp11.2 RCC by TFE3 immunostaining. TFE3-positive tumours have a papillary configuration, nested pattern, or both. Positive tumours show male predominance, more occurrences in middle age, high grade, and large-sized tumours with necrosis. Two tumours were FISH-positive. Xp11.2 RCC is rare in Saudi adult patients. Xp11.2 RCCs tend to be large sized and higher grade. TFE3 immunostaining should be considered in RCC that are histologically suggestive to confirm the diagnosis of Xp11.2.

p16 protein is upregulated in a stepwise fashion in colorectal adenoma and colorectal carcinoma.

BACKGROUND/AIMS: p16 is tumor suppressor gene acting as a cell cycle regulator. The present study was conducted to compare p16 expression in normal, dysplastic, and malignant colonic mucosae, and to explore its relation to clinicopathological variables and follow-up data in colorectal carcinoma (CRC). PATIENTS AND METHODS: Tissue microarrays were performed from 25 normal colonic mucosae, 41 colonic adenomas, and 191 CRC, with corresponding 50 nodal metastases. Immunohistochemistry was performed using anti-p16 antibody, sections were scored, and statistical analysis was performed. K-ras mutation detection was also performed. RESULTS: Immunoexpression of p16 was significantly higher in CRC than in adenomas (P = 0.033) and normal colonic mucosa (P = 0.005). There was no statistically significant difference between p16 expression in CRC and nodal metastasis. There was no significant association between p16 immunoexpression in CRC and all clinicopathological data and survival probability. K-ras mutations were detected in 34% of CRC. However, there was no correlation between K-ras status and p16 expression (P = 0.325). CONCLUSION: Absence of p16 expression is correlated to a benign course of CRC adenomas. p16 has a key role in CRC progression and can be used as a marker for colorectal adenoma. On the other hand, it has no role as a predictive and/or prognostic factor in CRC. Further extended studies are required to explore the role of p16 as indicator of premalignant lesions in the colon and to test its relation with CRC histological grade, as well as to test its value as a new therapeutic target.

c-MET immunostaining in colorectal carcinoma is associated with local disease recurrence.

BACKGROUND: Increased mesenchymal-epithelial transition factor gene (c-MET) expression in several human malignancies is related to increased tumour progression. The aim of the present study is to explore the relationship between immunohistochemical expression of c-MET in colorectal carcinoma (CRC) and the clinicopathological characteristics and follow up data, to compare the expression of c-MET in primary CRC and its metastasis in lymph nodes and to test its validity as independent prognostic factor. METHODS: Hundred and thirty-five archival CRC and nodal metastases samples were collected from King Abdulaziz University Hospital, Saudi Arabia. Tissue microarrays were constructed and immunohistochemistry was done to detected c-MET protein expression. Appropriate statistical analysis was performed. RESULTS: High c-MET immunostaining was significantly associated with tumour size larger than 5 cm (p < 0.003) and in left colon subsite (p < 0.05). There was no significant correlation between c-MET protein expression and age, sex, degree of differentiation, tumour invasion, presence of nodal metastasis, lymphovascular invasion, status of surgical resection margin, or presence of distant metastasis. Furthermore, no association between c-MET protein expression and disease free survival. High protein expression of c-MET is associated with the incidence of local disease recurrence (p < 0.012). CONCLUSION: c-MET is a new promising target that may help in understanding the pathogenesis of CRC, and to be used as independent prognostic biomarker to predict local disease recurrence in CRC. Further molecular in vitro and in vivo studies are required to pursue c-MET as potential molecular marker of metastases and test the possibility of its incorporation as a new targeted therapeutic target.

Overexpression of PAK-1 is an independent predictor of disease recurrence in colorectal carcinoma.

BACKGROUND: Colorectal carcinoma (CRC) is a significant cause of major morbidity and mortality. PAK-1 is a protein that regulates cytoskeletal dynamics and cell motility. The purpose of the present study is to investigate the relationship between PAK-1 immunoexpression and CRC progression and its validity as an independent prognostic factor. PATIENTS AND METHODS: Paraffin blocks of 103 primary CRCs and 37 nodal metastases were retrieved and tissue microarrays were constructed. Immunohistochemistry was performed using anti-PAK-1 antibody. Immunostaining was scored and results were analysed in relation to clinicopathological parameters. RESULTS: PAK-1 was overexpressed in primary CRC (P<0.001). No difference between low and high expression in nodal metastasis (P=0.139). There was no difference between PAK-1 immunoexpression in primary and nodal metastasis (P=0.275). High PAK-1 immunoexpression was associated with disease recurrence (P=0.03). However, there was no association with most clinicopathological parameters. PAK-1 overexpression was detected as an independent predictor of disease recurrence (P=0.05). No association was found between PAK-1 immunoexpression and disease free survival (log-rank =1.287, P=0.257). CONCLUSION: PAK-1 overexpression may be involved in CRC progression and could be considered an independent predictor of disease recurrence. Further in vivo and in vitro molecular studies are needed to investigate the role of PAK-1 in colorectal carcinogenesis.