Relevance of BRAF Subcellular Localization and Its Interaction with KRAS and KIT Mutations in Skin Melanoma.

Although skin melanoma (SKM) represents only one-quarter of newly diagnosed skin malignant tumors, it presents a high mortality rate. Hence, new prognostic and therapeutic tools need to be developed. This study focused on investigating the prognostic value of the subcellular expression of BRAF, KRAS, and KIT in SKM in correlation with their gene-encoding interactions. In silico analysis of the abovementioned gene interactions, along with their mRNA expression, was conducted, and the results were validated at the protein level using immunohistochemical (IHC) stains. For IHC expression, the encoded protein expressions were checked on 96 consecutive SKMs and 30 nevi. The UALCAN database showed no prognostic value for the mRNA expression level of KRAS and BRAF and demonstrated a longer survival for patients with low mRNA expression of KIT in SKMs. IHC examinations of SKMs confirmed the UALCAN data and showed that KIT expression was inversely correlated with ulceration, Breslow index, mitotic rate, and pT stage. KRAS expression was also found to be inversely correlated with ulceration and perineural invasion. When the subcellular expression of BRAF protein was recorded (nuclear vs. cytoplasmatic vs. mixed nucleus + cytoplasm), a direct correlation was emphasized between nuclear positivity and lymphovascular or perineural invasion. The independent prognostic value was demonstrated for mixed expression of the BRAF protein in SKM. BRAF cytoplasmic predominance, in association with KIT's IHC positivity, was more frequently observed in early-stage nonulcerated SKMs, which displayed a low mitotic rate and a late death event. The present study firstly verified the possible prognostic value of BRAF subcellular localization in SKMs. A low mRNA expression or IHC cytoplasmic positivity for KIT and BRAF might be used as a positive prognostic parameter of SKM. SKM's BRAF nuclear positivity needs to be evaluated in further studies as a possible indicator of perineural and lymphovascular invasion.

SOX11, SOX10 and MITF Gene Interaction: A Possible Diagnostic Tool in Malignant Melanoma.

Malignant melanoma (MM) is a highly heterogenic tumor whose histological diagnosis might be difficult. This study aimed to investigate the diagnostic and prognostic utility of the conventional pan-melanoma cocktail members (HMB-45, melan-A and tyrosinase), in conjunction with SOX10 and SOX11 immunohistochemical (IHC) expression. In 105 consecutive cases of MMs and 44 of naevi, the IHC examination was performed using the five-abovementioned markers, along with microphthalmia transcription factor (MITF), S100, and Ki67. Correlation with the clinicopathological factors and a long-term follow-up was also done. Survival analysis was performed with Kaplan-Meier curves and compared with TCGA public datasets. None of the 44 naevi expressed SOX11, but its positivity was seen in 52 MMs (49.52%), being directly correlated with lymphovascular invasion, the Ki67 index, and SOX10 expression. HMB-45, SOX10, and tyrosinase, but not melan-A, proved to differentiate the naevi from MMs successfully, with high specificity. Triple MITF/SOX10/SOX11 co-expression was seen in 9 out of 15 negative conventional pan-melanoma-cocktail cases. The independent prognostic value was proved for the conventional pan-melanoma cocktail (triple positivity for HMB-45, melan-A, and tyrosinase) and, independently for HMB-45 and tyrosinase, but not for melan-A, SOX10, or SOX11. As consequence, to differentiate MMs from benign naevi, melan-A should be substituted by SOX10 in the conventional cocktail. Although the conventional pan-melanoma cocktail, along with S100 can be used for the identification of melanocytic origin of tumor cells and predicting prognosis of MMs, the conventional-adapted cocktail (triple positivity for HMB-45, SOX10, and tyrosinase) has a slightly higher diagnostic specificity. SOX11 can be added to identify the aggressive MMs with risk for lymphatic dissemination and the presence of circulating tumor cells.

Upper Gastrointestinal Tract Hemorrhage: Unexpected Discovery.

Pica is a serious condition that is characterized by ingesting inedible things which can prove to be fatal (glass, pebbles, etc.) We present the case of a 64-year-old male patient who is admitted to the emergency room with the following complaints: upper GI tract bleeding manifested through hematemesis and melena, epigastric pain, lack of bowel movements. A contrast computed tomograohy is performed showing the presence of a hyper-dense stomach content, gastric wall thickening, abdominal fluid but with no signs of intestinal occlusion. A laparotomy is performed and ollowing an anterior gastrotomy a large quantity of pebbles is found along with a hemorrhagic and stenotic tumor of the lesser curvature. Taking into account the intraoperative aspect the decision was made to perform an end-to-side stapled esophago-jejunal anastomosis on an omega loop with a Braun entero-entero anastomosis following total gastric resection and D1 lymphadenectomy. Postoperative course is uneventful. A barium swallow carried out on the 10th day following surgery shows a functional anastomosis without leakage. On day 11, the patient is discharged. Pica is usually discovered by accident, most frequently on the operating table which is why thorough preoperative examination and investigations are required.

Multimacronodular pulmonary tuberculosis (bacteriologically negative) confirmed histologically.

Background: Pulmonary tuberculosis can be confirmed by positive bacteriology of sputum, bronchial aspirate or by biopsies (microscopy and/ or culture) or by histopathological examination highlighting specific tuberculous granulomas. When microscopy is repeatedly negative during noninvasive methods, lung biopsy by thoracoscopy is needed for confirmation and differential diagnosis. Case presentation: A 40-year-old female patient (nonsmoker, diabetic, with previous exposure to chemicals) was admitted to the hospital for weight loss, dry cough, loss of appetite, pallor, and fatigue. Chest-X-ray and thoracic CT revealed multiple irregular macronodules with various shapes, randomly spread across the lungs. Bacteriology for acid fast bacilli (AFB) from six spontaneous sputum was negative. Bronchoscopy showed an acute bronchitis. Bronchial aspirate was negative for tumor cells and AFB. Several biopsies from bronchial wall showed unspecific changes. The molecular biology tests for specific nucleic acids detection (Polymerase Chain Reaction) or positron-emission-tomography (to differentiate benign nodules from malign ones) were not accessible. Multiple biopsies from lung parenchyma and pleura were obtained using thoracoscopy. Histopathology revealed multiple specific tuberculous granulomas. The complex antituberculous treatment (9 months) has led to the total cure of the disease and resorption of the nodules. The patient's last visit (after 2 years) showed no clinical/imagistic or bacteriologic relapse of the disease. Conclusion: Tuberculosis may present in the form of multiple macronodules spread randomly across the lung parenchyma. Thoracoscopy coupled with multiple large lung biopsies are recommended for diagnosis of multinodular lung lesions, especially when common bacteriology/cytology from bronchoscopic aspiration failed to achieve diagnosis. Histological exam from thoracoscopic biopsies allows differential diagnosis between entities that have macronodular features: tuberculosis, primitive lung cancer, lymphomas, metastatic disease or invasive fungal disease.

Significant Shrinkage of Multifocal Liver Metastases and Long-Term Survival in a Patient With Rectal Cancer, After Trans-Arterial Chemoembolization (TACE): A Case Report.

In this paper, we present the successful therapeutic approach of unresectable liver metastases in a patient with rectal cancer.A 63-year-old male underwent endoscopic polypectomy followed by rectosigmoid resection for an adenocarcinoma of the rectum diagnosed in pT2N0 stage. The angio-computed tomography (CT) revealed four metastatic hepatic nodules ranging from 12 to 130 mm in diameter. After one cure of trans-arterial chemoembolization (TACE) with lipiodol and 5-fluorouracil, combined with FOLFOX4 + capecitabine systemic chemotherapy, the diameter of all hepatic nodules decreased to half size, at 6 months after TACE. Further curative surgical hepatic metastasectomy was done and complete pathologic response was obtained. The patient is free of recurrences and metastases after 26 months of follow-up.This representative case shows that an efficient trans-disciplinary approach could lead to successful therapeutic management even in patients with advanced-staged colorectal carcinomas.

Gastrointestinal stromal tumors: review on morphology, diagnosis and management.

Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. Major advances in their definition and classification and the understanding of their molecular mechanisms have recently been made. These advances have become a model of targeted therapy in oncology. The diagnosis of GISTs relies on histological arguments--proliferation of spindle-shaped cells in 70% of cases, of epithelioid cells in 20%, histological variants are rare--, and on immunohistochemical arguments--expression of CD117 in 95%, usually associated with CD34 expression in 70% of cases. Most GISTs are associated with molecular abnormalities in low target genes: KIT and PDGFRA. The differential diagnosis of GISTs includes the other mesenchymal tumors of the gastrointestinal tract, such as leiomyomas, leiomyosarcomas, schwannomas and intra-abdominal fibromatosis. The evaluation of the prognosis is essential and is based on a simple algorithm using two histoprognostic parameters, tumor size and mitotic index. The treatment of localized GISTs is surgical resection and that of advanced or unresecable GISTs is based on the use of targeted therapy, imatinib, which is a pharmacological antagonist of the c-kit protein. Proper understanding and utilization of the diagnostic criteria and classification of GISTs by pathologists are essential for good patient management.

[The importance of the I-colic time in colorectal cancer with synchronous hepatic metastases. Specifics of surgical strategy]. / Importanta timpului I-colic în cancerul colo-rectal cu metastaze hepatice sincrone. Particularitati de tactica chirurgicala.

AIM: This paper proposes the presentation of a decision-making algorithm in colorectal cancer with synchronous hepatic metastases, as stressing the importance of I-colic time in obtaining the R0 desideratum. MATERIAL AND METHOD: There is no worldwide consensus regarding the surgical attitude in metastatic colorectal cancer. There are some predominantly conservative attitudes which use stenting and neoadjuvant chemotherapy followed by periodical re-evaluation or more aggressive surgical treatment. In the pertinent literature, emphasis is on surgery in two stages, on the separation of the colic stage from the hepatic one, the majority proposing stage one cholic and stage two hepatic, thus there are also situations in which the liver may be dealt with from the first intention. RESULTS: We propose to present, taking the examples from clinical cases, the main techniques of dealing with the cases of metastatic colorectal cancer, stressing personal attitude: aggressive surgery in a short step, which is either radical or creates the conditions for a step II radical one. CONCLUSION: In our vision the liver is the key to the surgical treatment in metastatic colorectal cancer and we must take into account from the first step through interventions with radical intent any time it is possible or through other operations: ligature of portal branch, partial hepatectomies, unilateral local destruction, preparing the way to radical step II.

[Vascular exclusion of the liver: surgical technique and initial clinical experience]. / Excluzia vasculara a ficatului (EVF): tehnica chirurgicala si experienta clinica initiala.

The intraoperative hemorrhage is the most life threatening complication during a liver resection, reason why the intraoperative vascular control represents one of the key points in the liver resection. This work presents the liver vascular exclusion without caval occlusion technique and also studies the first cases operated in University Surgery Clinic Nr. 1, Targu Mures, Romania. LVE consists of an association between hilum occlusion by Pringle manoeuvre and selective clampage of the three hepatic veins. Once achieved, the technique allows resection without blood lose and no special cautions, a continue clampage of 60-90 minutes being useful for the reconstruction of the possibly harmed or resected structures during the hepatectomy. The indications of the technique are voluminous center located liver tumors, multiple liver tumors, tumors in contact with hepatic veins or with hilum bifurcation. University Surgery Clinic Nr. 1 Targu Mures's experience in this technique began in 2005 consists in 8 cases. Preoperative diagnosis were: 2 right liver voluminous benign tumors (hemangiomas), 5 cases of colo-rectal metastasis and one resection for metastases of gastro-intestinal stromal tumor. Postsurgery evolution was very good with an average hospitalisation of 6 days. Mortality rate and morbidity were zero. We strongly recommend the use of LVE technique for selected cases of difficult liver resection, LVE being one of the most advanced techniques of liver resection.