Alexander Julianov

Decrease in intrahepatic CD56+ lymphocytes in gastric and colorectal cancer patients with liver metastases

Gulubova M, Manolova I, Kyurkchiev D, Julianov A, Altunkova I. Decrease in intrahepatic CD56+ lymphocytes in gastric and colorectal cancer patients with liver metastases. APMIS 2009; 117: 870–9.

Relation between transforming growth factor-β1 expression, its receptor and clinicopathological factors and survival in HER2-negative gastric cancers

ZusammenfassungHINTERGRUND: Das Magenkarzinom ist in vielen Ländern noch immer die am häufigsten vorkommende Neoplasie. Es werden daher neben den als prognostische Marker bekannten klinisch pathologischen Faktoren, neue – davon unabhängige – Parameter untersucht. Ziel der Studie war die Untersuchung einer Expression des TGF-β1, sowie des TGF-β1-II Rezeptors (TGF-β1-RII) in HER-2-negativen Magenkarzinomen. Weiters wurde untersucht, ob eine Korrelation dieser Parameter mit klinisch-pathologischen Risiko- bzw. Prognosefaktoren des Magenkarzinoms besteht. PATIENTEN UND METHODEN: Gewebeproben von 42 Patienten, die einer kurativen Magen Resektion wegen eines Magenkarzinoms unterzogen worden waren, wurden immunhistochemisch auf das Vorliegen von HER2/neu, TGF-β1 und TGF-β1RII untersucht. Die Expression der Proteine wurde mit klinisch-pathologischen Parametern der Patienten korreliert und auf ihre prognostische Bedeutung ausgewertet. ERGEBNISSE: Alle untersuchten Proben waren HER2/neu negativ. Die Analyse des TGF-β1 ergab eine immunhistochemische Anfärbung vor allem im Zytoplasma und an der Membran. Unsere Ergebnisse zeigten, dass 80 % der intestinalen Magenkarzinom Proben eine TGF-β1 Expression aufwiesen, während das nur bei 43 % der Proben des diffusen Typs der Fall war. Auch die Tumoren mit niedriger oder mäßiger Differenzierung waren in Bezug auf TGF-βRII immunhistochemisch positiv (p = 0,041). Schließlich wurde eine mediane Überlebenszeit von 37,03 Monaten erhoben. Die Patienten mit TGF-β1 Expression hatten im Vergleich zu den Patienten, bei denen keine Expression von TGF-β1 nachgewiesen werden konnte (p = 0,034) eine schlechtere Prognose nach der chirurgischen Therapie. SCHLUSSFOLGERUNGEN: Wir konnten zeigen dass der Nachweis einer TGF-β1 Expression im Gewebe von Magen Tumoren, die einen HER2nez/negativen Status aufweisen, prognostisch ungünstig ist. Die für TGF-β1 and TGF-βRII erhobenen Ergebnisse zeigten eine Korrelation mit klinisch pathologischen Parametern. Der histologische Typ und der Differenzierungsgrad korrelierte mit dem Nachweis von TGF-β1. TGF-β1 positive Patienten hatten eine vergleichsweise kürzere Überlebenszeit als die TGF-β1 negativen Patienten.SummaryBACKGROUND: Gastric cancer is still the most prevalent neoplasia in many countries. Therefore, besides the clinicopathological factors known to be prognostic markers, new independent parameters are being investigated. This study was to investigate the expression of transforming growth factor – β1 (TGF-β1) and transforming growth factor – β1 receptor II (TGF-β1RII) in HER2/neu negative gastric carcinomas and to explore the correlations, the clinicopathological characteristics and prognosis of gastric carcinoma. PATIENTS AND METHODS: Surgical specimens from 42 patients with gastric cancer were examined for the presence of HER2/neu, TGF-β1 and TGF-β1RII by immunohistochemistry. The correlation between expression of the proteins and patient clinicopathological parameters was evaluated and the prognostic significance of TGF-β1 and of receptor expression was assessed. RESULTS: All specimens demonstrated HER2/neu-negative status. TGF-β1 analyses exhibited predominantly cytoplasmic and membranous immunostaining. We found that 80% of intestinal gastric cancer specimens have TGF-β1 expression, while in the diffuse type they are 43%. Also the tumors with low and moderate differentiation were positive for TGF-βRII (p = 0.041). Finally we found that median survival period of the patients was 37.03 months and the patients with TGF-β1 expression had worse prognosis after surgical therapy compared to those without expression of TGF-β1 (p = 0.034). CONCLUSIONS: We have shown that TGF-β1 expression in gastric tumor tissue with HER2/neu-negative status is of prognostic relevance in gastric cancer. The data for TGF-β1 and TGF-βRII expression showed association with clinicopathological parameters, and more precisely with the differentiation and histology type and TGF-β1-positive patient had a shorter overall survival compared with TGF-β1-negative patients.

Hepatic artery aneurysm causing obstructive jaundice.

Hepatic artery aneurysms (HAA) are rare and represent 14-20% of all visceral artery aneurysms. The vast majority of HAA are single and are located extrahepatically and nowadays about half of the HAA are iatrogenic, as a consequence of the widespread use of interventional diagnostic and therapeutic biliary procedures. Abdominal trauma, infection, inflammation and atherosclerosis are other common predisposing factors. Most of the HAA are asymptomatic, and 60-80% of the patients are diagnosed when the aneurysm has complicated with rupture and bleeding, obstructive jaundice due to external bile duct compression or rupture of the HAA into the biliary tree with clots occluding the lumen. We present a case of HAA presented with obstructive jaundice. Irrespective of clinical presentation the diagnosis of HAA is always based on imaging studies.

Immunohistochemical detection of collagen type III and IV in relation with transformation of Ito cells in liver sinusoids of patients with reactive biliary hepatitis.

Reactive biliary hepatitis is a defined morphological entity, which is a result of chronic diseases of the gall bladder, biliary ducts or pancreas. The aim of the present study was to describe the morphology of reactive biliary hepatitis and its significance for progression of liver fibrosis, and in particular Ito cell (fat storing cell) transformation and occurrence of collagen type III and IV in the liver. Liver tissue from 19 patients with reactive biliary hepatitis was investigated light microscopically and immunohistochemically. Histologically, the liver showed features of mild to severe portal and lobular inflammation. The number of Ito cells increased periportally and pericentrally. Deposition of collagen type III and IV was increased in portal tracts, septa and perisinusoidal spaces, mainly in periportal zones of the lobules. Ultrastructurally, collagen type III immunoreactive fibrillar networks were found to be increased in the space of Disse around transitional cells. Collagen type IV immunoreactive deposits were detected around newly proliferating bile ducts in portal stroma and in the space of Disse. Ito cells were mainly transformed into transitional and myofibroblast-like cells. We discuss here the role of Ito cells and certain cytokines in the process of fibrosis of the liver in the course of reactive biliary hepatitis. It is proposed that bile acid retention in bile ducts during non-specific reactive inflammation or a gut endotoxin may cause transformation of Ito cells and increased collagen type III and IV in this type of hepatitis.

Relationship of TGF-β1 and Smad7 expression with decreased dendritic cell infiltration in liver gastrointestinal cancer metastasis

Immune responses and their modulation within the liver are critical to the outcome of liver malignancies. In late‐stage tumors, secreted TGF‐β promotes oncogenic functions and can confer tolerogenicity to some immune cells like DCs. The TGF‐β signaling pathway is involved in the control of several biological processes, including immunosurveillance. The aim of the present study was to assess CD1a+ and CD83+ DCs and to evaluate the impact of TGF‐β pathway on DCs maturation and distribution in the liver metastases from gastric and colorectal tumors. The percentage of CD83+ DCs in the liver tissue, surrounding metastasis and in the metastasis‐free liver was measured by flow cytometry, and TGF‐β levels were assessed in the tissue supernatant from the peritumoral liver after mononuclear cell isolation and in the sera of the same patients. CD1a+ and CD83+ DCs were observed in the tumor stroma and border. Out of 73 patients, there was cytoplasmic reactivity: of TGF‐β1 in 37 (50.7%); of Smad4 in 62 (84.9%); of Smad7 in 46 (63%), and of TGFβRII in 39 (53.4%) of the metastases. The TGF‐β1 expression in tumor cell cytoplasm correlated with low CD1a+ and low CD83+ DCs infiltration. The tissue levels of TGF‐β1, measured by ELISA in the supernatant were significantly increased in metastases than in normal liver. Using a two‐color FACS analysis, we found that the percentage of HLA‐DR+ CD83+ DCs in metastases was significantly decreased as compared with metastasis‐free liver tissue. In conclusion, the positive and negative correlations between the mediators from the TGF‐β pathway implied the existence of imbalance and suppression of this cytokine activity. The presence of increased TGF‐β expression by immunohistochemistry in tumor cells was confirmed by detection of increased TGF‐β tissue level in the supernatant from the tissue homogenate. The observation of low numbers of CD1a+ and CD83+ DCs in tumor stroma correlated with TGF‐β overexpression in tumor cells, a fact that well documents the immunosuppressive role of TGF‐β in metastasis development. The increased percentage of CD83+ DCs in the peritumoral tissue supposes that there could be active recruitment or local differentiation of DCs in the metastasis border, but inside the tumor the immune cells recruitment and activity are suppressed by TGF‐β and by other cytokines.

Percutaneous Radiofrequency Ablation as First-Line Treatment in Patients With Early Colorectal Liver Metastases Amenable to Surgery: Is It Justified?

1. Hemandas AK, Abdelrahman T, Flashman KG, et al. Laparoscopic colorectal surgery produces better outcomes for high risk cancer patients compared to open surgery. Ann Surg. 2010;252(1): 84–89. 2. Fearon KC, Ljungqvist O, Von Meyenfeldt M, et al. Enhanced recovery after surgery: a consensus review of clinical care for patients undergoing colonic resection. Clin Nutr. 2005;24(3): 466–477. 3. King PM, Blazeby JM, Ewings P, et al. Randomized clinical trial comparing laparoscopic and open surgery for colorectal cancer within an enhanced recovery programme. Br J Surg. 2006;93(3): 300–308. 4. MacKay G, Ihedioha U, McConnachie A, et al. Laparoscopic colonic resection in fast-track patients does not enhance short-term recovery after elective surgery. Colorectal Dis. 2007;9: 368–372. 5. Basse L, Jakobsen DH, Bardram L, et al. Functional recovery after open versus laparoscopic colonic resection: a randomized, blinded study. Ann Surg. 2005;241:3:416–423. 6. Oncological clinical Trials of office (OCTO). Conventional versus laparoscopic surgery for colorectal cancer within an enhanced programme. Available at: http://www.octo-oxford.org.uk/alltrials/trials/ EnROL.html. Accessed April 12, 2011.

A five-year disease-free survival after combined hepatectomy and radiofrequency ablation of large hepatocellular carcinoma adjacent to vena cava

Destroying the hepatic tumor located close to the large vessels is a major limiting factor of radiofrequency ablation (RFA) that is difficult to overcome. A long-term disease-free survival after combined hepatectomy and radiofrequency ablation of a large hepatic tumor adjacent to vena cava has not been previously published. We report a patient with a 23-cm large hepatocellular carcinoma occupying the left lateral segments and a 6-cm contralateral intrahepatic metastasis in Couinaud segments VII–VIII adjacent to the retrohepatic IVC, treated with a combination of resection of the larger tumor and intraoperative radiofrequency ablation of the paracaval tumor under intermittent total vascular exclusion of the right hemiliver. After five years of follow up the patient is disease free. This case demonstrates the importance of vascular control for eliminating the heat sink effect of caval blood flow during RFA of liver tumors adjacent to inferior vena cava.

Transforming growth factor-β1 gene promoter -509C/T polymorphism in association with expression affects colorectal cancer development and depends on gender

It is widely known that sporadic colorectal cancer (CRC) is age-related diseases with higher incidence rate among men. Transforming growth factor-β1 (TGF-β1) is a major immune regulatory cytokine with a great impact and dual role in gastrointestinal carcinogenesis. In this context, the aim of the study was to explore the role of circulating TGF-β1 and the -509C/T functional promoter polymorphism (rs1800469) within the TGF-β1 gene (TGFB1) in the susceptibility, progression, and prognosis of CRC among Bulgarian male and female patients. Patients with sporadic CRC and healthy controls were genotyped by polymerase-chain reaction–restriction fragment length polymorphism. Serum TGF-β1 levels before and after curative surgery were determined by ELISA. Total RNA was extracted from paired tumor, normal mucosa and distant metastasis samples and was used for quantitative detection of TGFB1 mRNA by TaqMan qPCR.We observed that TGF-β1 serum levels depend on the -509C/T genotype in combination with gender. TGF-β1 serum levels in CRC patients were decreased compared to controls, but statistical significance was reached only for men. In the stratified analysis by gender and genotype, a significant association was found for the CC genotype. Overall, our results indicate that the -509C allele increased the cancer risk, particularly for advanced stages (OR = 1.477; p = 0.029). The results from the relative mRNA quantification showed a significant upregulation of TGFB1 in distant metastases compared to primary tumor tissues and higher TGFB1 mRNA levels in men (RQ = 4.959; p = 0.022). In conclusion, we present data that diminished circulating TGF-β1 due to the CC genotype could be a possible risk factor for tumor susceptibility and progression. This association is more pronounced in males than in females. Colorectal cancer tissue expression of TGFB1 gene mRNA correlates with tumor progression and metastasis.

Hepatectomy for liver metastases from squamous cell laryngeal cancer. Is it worthy

Patients with liver metastases from squamous cell head and neck cancer (SCHNC) are usually treated with chemotherapy and are not evaluated for eventual liver-directed treatment. However, the potential benefits from liver surgery for the patients with hepatic-only metastases from SCHNC generally remain undefined. We report a patient with late liver-only metastases from squamous cell glottic cancer treated with resection of the liver metastases followed by adjuvant platinum-based chemotherapy plus cetuximab. The patient died 25 months after resection of the hepatic metastases from widespread hepatic and pulmonary recurrence. The literature data as well as this case demonstrates the capability of liver surgery to prolong survival in patients with hepatic metastases from SCHNC.