RANKL, OPG, TRAIL, KRas, and c-Fos expression in relation to central lymph node metastases in papillary thyroid carcinoma.

PURPOSE: RANKL, OPG and TRAIL have long been pursued in cancer. Mutated KRas proteins and c-Fos overexpression - well-recognized oncogenic events - have been conceived as coordinators of RANKL, OPG and TRAIL pathways. Considering the paucity in the relevant literature, the purpose of the present study was to investigate whether the expression of these molecules configures a distinct papillary thyroid carcinoma (PTC) subgroup with adverse clinicopathological characteristics. METHODS: RANKL, OPG, TRAIL, KRas, and c-Fos immunohistochemical expression in relation to clinicopathological characteristics of PTC was assessed retrospectively in paraffin-embedded PTC specimens from 114 patients who underwent total thyroidectomy with simultaneous central lymph node dissection (CLND). RESULTS: Expression of RANKL, OPG, TRAIL, Kras and c- Fos was revealed in 78.6, 63.2, 61.4, 47.4, and 73.7% of PTC, respectively. As predominant KRas-expressing PTC histotype emerged the classical PTC (cPTC), comprising 66.7% of PTC. A significant correlation was demonstrated of RANKL, OPG, and TRAIL expression with central lymph node metastasis CLNM (p=0.007, p<0.001, and p=0.002, respectively), concerning especially cPTC as regards to RANKL (p=0.027) and OPG (p=0.006), and both cPTC (p=0.043) and follicular variant of PTC (FVPTC) (p=0.049) with regard to TRAIL. OPG expression associated significantly with multifocality (p=0.045). Multivariable-adjusted logistic regression models characterized TRAIL as independent predictor of CLNM (OR=10.335, 95% CI: 1.23-86.87). CLNM correlated significantly with six pairs of coexpressions: TRAIL-KRas (p=0.011), TRAIL-c-Fos (p=0.006), OPG-c-Fos (p=0.024), RANKL-TRAIL (p<0.001), RANKL-OPG (p<0.001), TRAIL- OPG (p<0.001). CONCLUSION: The present study suggested for the first time that OPG, RANKL, TRAIL expressions, either alone or in concert involving c-Fos and KRas expression, are related to CLNM. Further research is warranted to elucidate whether the examined molecules can be endorsed as indicators of aggressive PTC behavior and guide a personalized therapeutic intervention.

Phenotypic and functional alterations of primary human PBMCs induced by HCV non-enveloped capsid-like particles uptake.

Hepatitis C virus non-enveloped particles circulate in the serum of HCV-infected patients and are believed to be involved in viral persistence. It was previously demonstrated that recombinant HCVne particles can efficiently enter T cells. In this study we investigated the effect of this entry on the phenotype and function of PBMCs, focused on the CD4+ and CD8+ T-cells. We have generated recombinant HCVne in the absence of other viral proteins. PBMCs from healthy donors were sampled after incubation either with HCVne or the control at different time points. Levels of expression of CD107a, CD25, CTLA-4, and T regulatory cells were estimated and cytokine expression and secretion were also monitored. Peripheral T cells expressed elevated CD127. The intracellular expression of the inhibitory marker CTLA-4 (CD152) increased significantly on peripheral T cells at late hours post-treatment, compared to the respective non-treated group. Despite the fact that there was an initial immune response due to HCVne uptake, T cells were driven to a partial exhausted phenotype. A significant induction of CD4+CD25+(hi)CD127-regulatory T cells at late hours was observed. Consistently, Foxp3+CD4+ T cells were also increased. In parallel, a significant transcriptional activation and increased secretion of IL-2, IL-10, and IFN-γ, was recorded. Moreover, mRNA transcription of TGF-ß was considerably elevated. HCVne particles have the potential to shape the immune response by modifying specific phenotypic and functional markers mainly on CD4+ T cells and driving them to partial exhaustion as well as to Treg expansion.

Metzenbaum-assisted liver resection: a safe and effective liver resection technique.

AIM: We hereby present and evaluate a technique for hepatic parenchymal transection based on the application of Metzenbaum scissors and clips during liver ischemia. METHODS: Our technique was retrospectively evaluated in 32 noncirrhotic, noncholestatic patients with intrahepatic cholangiocarcinoma and 32 patients with hepatocellular carcinoma (23 of whom cirrhotic, 71.9%). Patient data were retrieved from our Hepatobiliary Surgery Database. Type and duration of vascular clamping, blood transfusion requirements, marginal status and immediate postoperative complications were analyzed. RESULTS: Twenty-seven extended (>4 liver segments; 42.2%) and 37 nonextended (≤4 liver segments; 57.8%) liver resections were analyzed. Warm liver ischemia duration was 14 (interquartile range: 11-17.8) min. Thirty-three patients (51.6%) were transfused with a median of 2 (1.5-3) units of packed red blood cells. Tumor-free margins were achieved in 90.6% of cases (n = 58). The overall morbidity rate was 18.8% with a 4.7% mortality rate. Our technique allowed for excellent identification and safe dissection and preservation, or ligation of major liver vessels. CONCLUSIONS: The proposed technique is simple, fast, safe and with low cost. It is associated with limited postoperative complications while from an oncologic standpoint it enables the surgeon to achieve a high percentage of tumor-free margins while protecting major vascular structures.

Immunotherapy of gastric cancer: Present status and future perspectives.

In this editorial, we comment on the article entitled "Advances and key focus areas in gastric cancer immunotherapy: A comprehensive scientometric and clinical trial review (1999-2023)," which was published in the recent issue of the World Journal of Gastroenterology. We focused on the results of the authors' bibliometric analysis concerning gastric cancer immunotherapy, which they analyzed in depth by compiling the relevant publications of the last 20 years. Before that, we briefly describe the most recent data concerning the epidemiological parameters of gastric cancer (GC) in different countries, attempting to give an interpretation based on the etiological factors involved in the etiopathogenesis of the neoplasm. We then briefly discuss the conservative treatment (chemotherapy) of the various forms of this malignant neoplasm. We describe the treatment of resectable tumors, locally advanced neoplasms, and unresectable (advanced) cases. Special attention is given to modern therapeutic approaches with emphasis on immunotherapy, which seems to be the future of GC treatment, especially in combination with chemotherapy. There is also a thorough analysis of the results of the study under review in terms of the number of scientific publications, the countries in which the studies were conducted, the authors, and the scientific centers of origin, as well as the clinical studies in progress. Finally, an attempt is made to draw some con-clusions and to point out possible future directions.

Combination treatment of inflammatory bowel disease: Present status and future perspectives.

The treatment of patients with inflammatory bowel disease (IBD), especially those with severe or refractory disease, represents an important challenge for the clinical gastroenterologist. It seems to be no exaggeration to say that in these patients, not only the scientific background of the gastroenterologist is tested, but also the abundance of "gifts" that he should possess (insight, intuition, determination, ability to take initiative, etc.) for the successful outcome of the treatment. In daily clinical practice, depending on the severity of the attack, IBD is treated with one or a combination of two or more pharmaceutical agents. These combinations include not only the first-line drugs (e.g., mesalazine, corticosteroids, antibiotics, etc) but also second- and third-line drugs (immunosuppressants and biologic agents). It is a fact that despite the significant therapeutic advances there is still a significant percentage of patients who do not satisfactorily respond to the treatment applied. Therefore, a part of these patients are going to surgery. In recent years, several small-size clinical studies, reviews, and case reports have been published combining not only biological agents with other drugs (e.g., immunosuppressants or corticosteroids) but also the combination of two biological agents simultaneously, especially in severe cases. In our opinion, it is at least a strange (and largely unexplained) fact that we often use combinations of drugs in a given patient although studies comparing the simultaneous administration of two or more drugs with monotherapy are very few. As mentioned above, there is a timid tendency in the literature to combine two biological agents in severe cases unresponsive to the applied treatment or patients with severe extraintestinal manifestations. The appropriate dosage, the duration of the administration, the suitable timing for checking the clinical and laboratory outcome, as well as the treatment side-effects, should be the subject of intense clinical research shortly. In this editorial, we attempt to summarize the existing data regarding the already applied combination therapies and to humbly formulate thoughts and suggestions for the future application of the combination treatment of biological agents in a well-defined category of patients. We suggest that the application of biomarkers and artificial intelligence could help in establishing new forms of treatment using the available modern drugs in patients with IBD resistant to treatment.

Early-onset gastrointestinal cancer: An epidemiological reality with great significance and implications.

During the last few years, epidemiological data from many countries suggest that the incidence and prevalence of many cancers of the digestive system are shifting from the older to the younger ages, the so-called "early-onset cancer". This is particularly evident in colorectal cancer and secondarily in other malignant digestive neoplasms, mainly stomach and in a lesser degree pancreas, and biliary tract. It should be emphasized that data concerning digestive neoplasms, except for those referring to the colon and stomach, could be characterized as rather insufficient. The exact magnitude of the shift in younger ages is expected to become clearer shortly, as long as relevant epidemiological data from many parts of the world would be available. The most important question concerns the etiology of this phenomenon, since its magnitude cannot be explained solely by the better diagnostic methodology and the preventive programs applied in many countries. The existing data support the assumption that a number of environmental factors may play a primary role in influencing carcinogenesis, sometimes from childhood. Changes that have appeared in the last decades related mainly to eating habits, consistency of gut microbiome and an increase of obese people interacting with genetic factors, ultimately favor the process of carcinogenesis. Even these factors however, are not entirely sufficient to explain the age-related changes in the frequency of digestive neoplasms. Studies of the individual effect of each of the already known factors or factors likely to be involved in the etiology of this phenomenon and studies using state-of-the-art technologies to accurately determine the degree of the population exposure to these factors are required. In this article, we attempt to describe the epidemiological data supporting the age-shifting of digestive malignancies and their possible pathogenesis. Finally, we propose some measures regarding the attitude of the scientific community to this alarming phenomenon.

Enteral Nutrition in Operated-On Gastric Cancer Patients: An Update.

It is well established that the preoperative nutritional status of gastric cancer (GC) patients significantly affects the prognosis of the operated patients, their overall survival, as well as the disease-specific survival. Existing data support that preoperative assessment of nutritional status and early correction of nutritional deficiencies exert a favorable effect on early postoperative outcomes. A variety of relevant indices are used to assess the nutritional status of GC patients who are candidates for surgery. The guidelines of almost all international organizations recommend the use of oral enteral nutrition (EN). Oncologically acceptable types of gastrectomy and methods of patient rehabilitation should take into account the expected postoperative nutritional status. The majority of data support that perioperative EN reduces complications and hospital stay, but not mortality. Oral EN in the postoperative period, albeit in small amounts, helps to reduce the weight loss that is a consequence of gastrectomy. Iron deficiency with or without anemia and low serum levels of vitamin B12 are common metabolic sequelae after gastrectomy and should be restored. EN also significantly helps patients undergoing neoadjuvant or adjuvant antineoplastic therapy. The occurrence of the so-called "postgastrectomy syndromes" requires dietary modifications and drug support. This review attempts to highlight the benefits of EN in GC patients undergoing gastrectomy and to emphasize the type of necessary nutritional management, based on current literature data.

Co-culture of primary human tumor hepatocytes from patients with hepatocellular carcinoma with autologous peripheral blood mononuclear cells: study of their in vitro immunological interactions.

BACKGROUND: Many studies have suggested that the immune response may play a crucial role in the progression of hepatocellular carcinoma (HCC). Therefore, our aim was to establish a (i) functional culture of primary human tumor hepatocytes and non-tumor from patients with hepatocellular carcinoma (HCC) and (ii) a co-culture system of HCC and non-HCC hepatocytes with autologous peripheral blood mononuclear cells (PBMCs) in order to study in vitro cell-to-cell interactions. METHODS: Tumor (HCC) and non-tumor (non-HCC) hepatocytes were isolated from the liver resection specimens of 11 patients operated for HCC, while PBMCs were retrieved immediately prior to surgery. Four biopsies were obtained from patients with no liver disease who had surgery for non malignant tumor (normal hepatocytes). Hepatocytes were either cultured alone (monoculture) or co-cultured with PBMCs. Flow cytometry measurements for MHC class II expression, apoptosis, necrosis and viability (7AAD) were performed 24 h, 48 h and 72 h in co-culture and monocultures. RESULTS: HCC and non-HCC hepatocytes exhibited increased MHC-II expression at 48h and 72h in co-culture with PBMCs as compared to monoculture, with MHC II-expressing HCC hepatocytes showing increased viability at 72 h. PBMCs showed increased MHC-II expression (activation) in co-culture with HCC as compared to non-HCC hepatocytes at all time points. Moreover, CD8+ T cells had significantly increased apoptosis and necrosis at 48h in co-culture with HCC hepatocytes as compared to monocultures. Interestingly, MHC-II expression on both HCC and non-HCC hepatocytes in co-culture was positively correlated with the respective activated CD8+ T cells. CONCLUSIONS: We have established an in vitro co-culture model to study interactions between autologous PBMCs and primary HCC and non-HCC hepatocytes. This direct interaction leads to increased antigen presenting ability of HCC hepatocytes, activation of PBMCs with a concomitant apoptosis of activated CD8+ T cells. Although, a partially effective immune response against HCC exists, still tumor hepatocytes manage to escape.

Review of the molecular profile and modern prognostic markers for gastric lymphoma: how do they affect clinical practice?

Primary gastric lymphoma is a rare cancer of the stomach with an indeterminate prognosis. Recently, a series of molecular prognostic markers has been introduced to better describe this clinical entity. This review describes the clinical importance of several oncogenes, apoptotic genes and chromosomal mutations in the initiation and progress of primary non-Hodgkin gastric lymphoma and their effect on patient survival. We also outline the prognostic clinical importance of certain cellular adhesion molecules, such as ICAM and PECAM-1, in patients with gastric lymphoma, and we analyze the correlation of these molecules with apoptosis, angiogenesis, tumour growth and metastatic potential. We also focus on the host-immune response and the impact of Helicobacter pylori infection on gastric lymphoma development and progression. Finally, we explore the therapeutic methods currently available for gastric lymphoma, comparing the traditional invasive approach with more recent conservative options, and we stress the importance of the application of novel molecular markers in clinical practice.

Novel tumour-specific promoters for transcriptional targeting of hepatocellular carcinoma by herpes simplex virus vectors.

BACKGROUND: Hepatocellular carcinoma (HCC) is a cancer of poor prognosis, with limited success in patient treatment, which it makes an excellent target for gene therapy and viral oncolysis. Accordingly, herpes virus simplex type-1 (HSV-1) is one of the most promising viral platforms for transferring therapeutic genes and the development of oncolytic vectors that can target, multiply in, and eradicate hepatoma cells via their lytic cycle. Enhanced efficacy and specificity of HSV-1-based vectors towards HCC may be achieved by using HCC-specific gene promoters to drive selective viral gene expression and accomplish conditional replication and/or to control the expression of therapeutic genes. However, careful verification of promoter function in the context of the replication-competent HSV-1 vectors is required. The present study aimed to identify novel HCC-specific promoters that could efficiently direct transgene expression to HCC cells and maintain their activity during active viral replication. METHODS: Publicly available microarray data from human HCC biopsies were analysed in order to detect novel candidate genes induced primarily in HCC compared to normal liver. HCC specificity and promoter activity were evaluated by RT-PCR and chromatin immunoprecipitation. Additionally, transcriptional activity of promoters was further evaluated in the context of HSV-1 genome, using luciferase assays in cultured cells and animal models. RESULTS: Eight HCC-specific genes were characterised in this study: Angiopoietin-like-3, Cytochrome P450, family 2, subfamily C, polypeptide 8, Vitronectin, Alcohol dehydrogenase 6-class V, Apolipoprotein B, Fibrinogen beta chain, Inter-alpha-globulin-inhibitor H3 and Inter-alpha-globulin-inhibitor H1. Specific HCC expression and active gene transcription were confirmed in human liver and non-liver cell lines and further evaluated in primary neoplastic cells from hepatitis C and B virus (HCV- and HBV)-associated HCC patients. High promoter activity and specificity in the presence of HSV-1 infection and from within the viral genome, was validated, both in vitro and in vivo. CONCLUSIONS: We identified and experimentally characterized novel hepatoma-specific promoters, which were valuable for cancer-specific gene therapy, using HSV-1 vectors.

Administration of human protein C improves survival in an experimental model of sepsis.

OBJECTIVE: Study the effect of human protein C (PC) concentrate administration on organ damage and survival in septic rats. DESIGN: Animal study. SETTING: University laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Cecal ligation and puncture (CLP) was performed in 210 rats. Rats were randomly assigned to receive either human protein C (PC) IV 1, 7, and 13 hrs after CLP (CLP+PC) or placebo (CLP). Septic animals were again randomized in a survival group (CLP: n = 50 and CLP+PC: n = 40) that was monitored for 60 hrs and time groups (CLP: n = 60 and CLP+PC: n = 60) that were killed at 6, 12, 24, 36, 48, and 60 hrs after CLP. Brain, heart, lung, liver, kidney, gastric, and colon tissue were removed and postfixed in paraffin sections. MEASUREMENTS AND MAIN RESULTS: PC infusion increased PC serum levels in early sepsis (median 7.25) compared with late sepsis (median 2, p = .001). Activated protein C/a1-antitrypsin complex levels in the CLP+PC group were significantly increased in late sepsis (60 hrs after CLP) compared with early sepsis (6, 12, and 24 hrs after CLP, p = .009, p = .004, and p = .008, respectively) and to late septic CLP and normal rats (p = .005 and p = .007, respectively). Their IL-6 and tumor necrosis factor a plasma levels were decreased (by 27% and 25%, respectively) at 6 hrs compared with placebo (p = .008 and p = .016). Their serum PC levels were also decreased in CLP+PC survivors compared with nonsurvivors of the same group (median = 1.5 vs. median = 7, p = .001). Apoptosis was reduced in brain (10% vs. 77.8%, p < .001), stomach (66.7% vs. 100%, p < .002) and intestine (33.3% vs. 85.2%, p < .001) compared with placebo. Finally, the survival of septic rats treated with human PC was significantly increased compared with placebo (75% vs. 54%, p = .033). CONCLUSIONS: Human Protein C administration increased survival in septic rats, decreased plasma inflammatory cytokines levels and tissue injury in vital organs.

Multicentric evaluation of a clinical and prognostic scoring system predictive of survival after resection of intrahepatic cholangiocarcinomas.

OBJECTIVE: To develop a clinical and prognostic scoring system predictive of survival after resection of intrahepatic cholangiocarcinomas (ICC). PATIENTS: Two hundred and one consecutive ICC patients (83 from Essen, Germany, 54 from New York, USA and 64 from Chiba, Japan). The scoring systems were developed utilizing the data set from Essen University and then applied to the data sets from Mount Sinai Medical Center and Chiba University for validation. Eighteen potential prognostic factors were evaluated. Statistical analysis included multivariable regression analyses with the Cox proportional hazard model, power analysis, internal validation with structural equation modelling bootstrapping and external validation. The prognostic scoring model was based mainly in pathological and demographical variables, whereas the clinical scoring model was based mainly in radiological and demographical variables. RESULTS: Gender (P=0.0086), UICC stage (P=0.0140) and R-class (P=0.0016) were predictive of survival for the prognostic scoring model, while gender (P=0.0023), CA 19-9 levels (P=0.0153) and macrovascular invasion (P=0.0067) were predictive of survival for the clinical scoring model. Prognostic points were assigned as follows: female:male=1:2 points, UICC (I-II):UICC (III-IV)=1:2 points and R0:R1=1:2 points. Clinical points were allocated as follows: female:male=1:2 points, CA 19-9 (<100 U/ml):CA 19-9 (> or =100 U/ml)=1:2 points and no macrovascular invasion:macrovascular invasion=1:2 points. Prognostic groups with 3-4, 5 and 6 points (P=0.000001) and clinical groups with 3-4 and 5-6 points (P=0.0103) achieved statistically significant difference. CONCLUSIONS: We propose a clinical and prognostic scoring system predictive of long-term survival after surgical resections for ICC.

Prospective appraisal of a 2-day training course on laparoscopic sleeve gastrectomy: the ELTC experience.

BACKGROUND: The increasing role of laparoscopic sleeve gastrectomy (LSG) in the treatment of morbid obesity dictates the need for greater acquaintance with this type of surgery. This study was designed to evaluate the impact of a 2-day LSG course and a 4-day laparoscopic bariatric mini-training program on the knowledge and training gained by participating surgeons. METHODS: A total of 73 trainees (31 residents and 42 surgeons) completed a question survey immediately after completion of the respective courses. Questions probed demographic data, training experience before and after course completion, evaluation of course content, and operative experience. RESULTS: All residents and four of the general surgeons found the laparoscopic bariatric mini-training program to be of value with respect to future professional orientations. Seven surgeons started performing LSGs, while another five surgeons decided to occupy themselves with various types of laparoscopic bariatric procedures. The most useful parts of the course included the identification and treatment of complications, the use of new instrumentation, and surgical demonstrations (video or live), as decided by more than 80% of the participants. On a 1-5 scale, the presentation of novel knowledge was evaluated to be ≥ 3 by all participants. CONCLUSION: The 2-day LSG course offered participants high-quality novel knowledge and excellent training quality, and exerted impact on their personal career.

Surgical resection for advanced gallbladder carcinoma. The Mount Sinai experience.

BACKGROUND/AIMS: Advanced gallbladder cancer (GC) carries dismal prognosis, due to its extent at diagnosis and the low R0 resection performance rate. METHODOLOGY: Thirty-two GC patients referred to our Department with an intention to treat between 1993 and 2005. All patients had advanced T stage (> or = T3). Pathological findings, surgical procedures and survival data were analyzed. RESULTS: Seventeen radical procedures (16 hepatectomies and 1 cholecystectomy with common bile duct resection), 4 palliative procedures (12.5%) and 11 surgical explorations (34.4%) were performed (53.1%, resectability rate). Hepatectomies were performed with 0% mortality, 11.8% morbidity and 94.1% resectability rate. The respective 1-, 3- and 5- year survival rates were 71.4%, 28.6% and 14.3%. Radical lymph node dissection (p = 0.03), absence of perineural tumor invasion (p = 0.03) and patients' age <70 years (p < 0.01) were non-independently associated with favorable prognosis in the hepatectomy-treated group of GC patients. CONCLUSIONS: GC patients with stage > or = IIA should be treated with hepatectomy combined with radical lymphadenectomy in order to achieve better staging and disease control. Incorporating the caudate lobe, more than 4 liver segments, or part of the extrahepatic biliary tree in the resection specimen in selected patients, might help eliminate perineural metastatic spread and achieve improved overall survival.

Apoptotic death of renal tubular cells in experimental sepsis.

BACKGROUND AND PURPOSE: Renal dysfunction attributable to sepsis was long considered a result of hemodynamic instability and subsequent local ischemia. Recent data show that apoptosis may be implicated also. The purpose of this study was to evaluate the role of apoptosis and the expression of the bax, bcl-2, caspase-8, and cytochrome c proteins in the renal parenchymal cells of rats with sepsis. METHODS: Sepsis was induced using cecal ligation and puncture (CLP) in 62 male Wistar rats, which were euthanized 6, 12, 24, 36, 48, or 60 h later. Ten sham-treated animals served as a control group. Another group of 50 animals were subjected to CLP and then supervised for 60 h. Renal apoptosis was evaluated using light and transmission electron microscopy, in situ nick-end labeling (TUNEL), and flow cytometry using 7-amino-actinomycin D (7-AAD). Caspase-mediated apoptosis was assessed using M30 antibody. The expression of the apoptosis-regulator proteins B-cell lymphoma 2 (bcl-2), bcl-2-associated x protein (bax), caspase-8, and cytochrome c was detected immunohistochemically. RESULTS: Sepsis increased inflammatory infiltration (p < 0.001) and necrosis (p < 0.001) in renal parenchyma. Apoptosis was significantly more common than in the kidneys of control animals (p = 0.02). Nuclei stained by the TUNEL technique were predominant in the tubular cells of non-survivors (p = 0.05). The time distribution of all types of cell death was increased significantly 6 h after the induction of sepsis, and declined subsequently. Caspase-generated cytokeratin 18 (CK18) new epitope (M30) was significantly more abundant in the kidneys of animals with sepsis than in control rats, with peaks at 6 h and 60 h post-procedure (p < 0.001). In addition, cells initiating apoptosis were significantly more common at 6 h than at 48 h post-CLP (p = 0.014). Caspase-8 protein immunodetection followed the same time pattern as cell death, increasing as early as 6 h post-CLP and decreasing thereafter (p = 0.013). Bax protein expression was elevated significantly early in the course of sepsis (p = 0.037), whereas the other members of the mitochondrial-dependent pathway remained constant. Animals dying from sepsis had a significantly greater prevalence of bax- (p = 0.037) and caspase-8- (p = 0.031) immunoreactive renal cells. CONCLUSION: Apoptosis in renal tissue was significantly more common in animals with sepsis than in controls. The time distribution of cell death markers showed a consistent pattern, making early sepsis the likely initiator of the apoptotic events.

Undifferentiated Adipose Tissue Stem Cell Transplantation Promotes Hepatic Regeneration, Ameliorates Histopathologic Damage of the Liver, and Upregulates the Expression of Liver Regeneration- and Liver-Specific Genes in a Rat Model of Partial Hepatectomy.

OBJECTIVE: Adipose tissue stem cells (ADSCs) present a promising therapeutic method to alleviate liver failure (LF). The purpose of this prospective study was to evaluate the efficacy of undifferentiated ADSC transplantation on liver regeneration and on the expression of liver regeneration- and liver-specific genes, following 60% partial hepatectomy (PHx). METHODS: Sixty female rats were subjected to PHx and were transplanted with 106 or 2 × 106 ADSCs, either into the portal vein (PV) or into the hepatic parenchyma. Animals of the control group were not transplanted and served as controls. Animals were sacrificed on the 4th, the 7th, or the 15th postoperative day (POD). RESULTS: The transplanted ADSCs were successfully engrafted into the liver parenchyma and ameliorated the histopathologic damage on the 7th and 15th POD. All transplanted animals demonstrated a significantly higher liver regeneration rate on the 4th and 7th POD, compared with the control group. The expression of hepatocyte growth factor, α-fetoprotein, tyrosine aminotransferase, hepatocyte nuclear factor 4a, and cytochrome P450 1A2 was significantly upregulated, compared with the control group. CONCLUSIONS: Although undifferentiated, ADSC transplantation significantly enhanced the liver regeneration process. These findings may be proven clinically valuable, especially in cases of acute LF.

Bilateral synchronous breast carcinomas followed by a metastasis to the gallbladder: a case report.

BACKGROUND: Breast cancer is usually associated with metastases to lungs, bones and liver. Breast carcinoma metastasizing to the gallbladder is very rare. CASE PRESENTATION: A 59-year-old woman presented with bilateral synchronous breast lesions. A palpable, retroareolar solid lesion of diameter equal to 5 cm was present in the right breast, and a newly developed, non-palpable lesion with microcalcifications (diameter equal to 0.7 cm) was present in the upper outer quadrant of the left breast. Modified radical mastectomy was performed on the right breast and lumpectomy after hook-wire localization was performed on the left breast, combined with lymph node dissection in both sides. The pathological examination revealed invasive lobular carcinoma grade II in the right breast and invasive ductal carcinoma grade I in the left breast. Chemotherapy, radiation therapy, trastuzumab and letrozole were appropriately administered. At her 18-month follow-up, the patient was free of symptoms; the imaging tests (chest CT, abdominal U/S, bone scan), biochemical tests, blood cell count and tumor markers were also normal. At the 20th month after surgery however, the patient developed symptoms of cholecystitis and underwent cholecystectomy. The histopathological examination revealed metastasis of the lobular carcinoma to the gallbladder. CONCLUSION: This extremely rare case confirms on a single patient the results of large series having demonstrated the preferential metastasis of lobular breast cancer to the gallbladder. Symptoms of cholecystitis should not be neglected in such patients, as they might indicate metastasis to the gallbladder.

Mesenchymal Stem Cells Transplantation following Partial Hepatectomy: A New Concept to Promote Liver Regeneration-Systematic Review of the Literature Focused on Experimental Studies in Rodent Models.

Mesenchymal stem cells (MSCs) are an attractive source for regenerative medicine because they are easily accessible through minimally invasive methods and have the potential to enhance liver regeneration (LG) and improve liver function, following partial hepatectomy (PH) and acute or chronic liver injury. A systematic review of the literature was conducted for articles published up to September 1st, 2016, using the MEDLINE database. The keywords that were used in various combinations were as follows: "Mesenchymal stem cells", "transplantation", "stem cells", "adipose tissue derived stem cells", "bone marrow-derived stem cells", "partial hepatectomy", "acute liver failure", "chronic liver failure", "liver fibrosis", "liver cirrhosis", "rats", "mice", and "liver regeneration". All introduced keywords were searched for separately in MeSH Database to control relevance and terminological accuracy and validity. A total of 41 articles were identified for potential inclusion and reviewed in detail. After a strict selection process, a total of 28 articles were excluded, leaving 13 articles to form the basis of this systematic review. MSCs transplantation promoted LG and improved liver function. Furthermore, MSCs had the ability to differentiate in hepatocyte-like cells, increase survival, and protect hepatocytes by paracrine mechanisms. MSCs transplantation may provide beneficial effects in the process of LG after PH and acute or chronic liver injury. They may represent a new therapeutic option to treat posthepatectomy acute liver failure.

Real-time ultrasound-guided catheterisation of the internal jugular vein: a prospective comparison with the landmark technique in critical care patients.

INTRODUCTION: Central venous cannulation is crucial in the management of the critical care patient. This study was designed to evaluate whether real-time ultrasound-guided cannulation of the internal jugular vein is superior to the standard landmark method. METHODS: In this randomised study, 450 critical care patients who underwent real-time ultrasound-guided cannulation of the internal jugular vein were prospectively compared with 450 critical care patients in whom the landmark technique was used. Randomisation was performed by means of a computer-generated random-numbers table, and patients were stratified with regard to age, gender, and body mass index. RESULTS: There were no significant differences in gender, age, body mass index, or side of cannulation (left or right) or in the presence of risk factors for difficult venous cannulation such as prior catheterisation, limited sites for access attempts, previous difficulties during catheterisation, previous mechanical complication, known vascular abnormality, untreated coagulopathy, skeletal deformity, and cannulation during cardiac arrest between the two groups of patients. Furthermore, the physicians who performed the procedures had comparable experience in the placement of central venous catheters (p = non-significant). Cannulation of the internal jugular vein was achieved in all patients by using ultrasound and in 425 of the patients (94.4%) by using the landmark technique (p < 0.001). Average access time (skin to vein) and number of attempts were significantly reduced in the ultrasound group of patients compared with the landmark group (p < 0.001). In the landmark group, puncture of the carotid artery occurred in 10.6% of patients, haematoma in 8.4%, haemothorax in 1.7%, pneumothorax in 2.4%, and central venous catheter-associated blood stream infection in 16%, which were all significantly increased compared with the ultrasound group (p < 0.001). CONCLUSION: The present data suggest that ultrasound-guided catheterisation of the internal jugular vein in critical care patients is superior to the landmark technique and therefore should be the method of choice in these patients.

Molecular markers (PECAM-1, ICAM-3, HLA-DR) determine prognosis in primary non-Hodgkin's gastric lymphoma patients.

AIM: To investigate the prognostic significance of PECAM-1, ICAM-3 and HLA-DR antigens in patients with primary non-Hodgkin's gastric lymphoma. METHODS: We immunohistochemically studied PECAM-1, ICAM-3 and HLA-DR antigen expression in 36 B-cell MALT-type primary gastric lymphoma patients. Ten non-malignant and ten healthy gastric tissue specimens were used as controls. Clinicopathological and survival data were correlated with the staining results. RESULTS: HLA-DR antigen expression was detected in 33 gastric lymphoma patients (91.7%) and 6 non-malignant patients (54.5%). PECAM-1 stained tumor cells of 10 patients (27.8%), endothelial cells of 9 patients (25%) and inflammatory infiltrate of 4 patients (40%) with benign gastric disease. ICAM-3 expression was observed on the tumor cells of 17 patients (47.2%), while 5 non-malignant patients (50%) were stained positive as well. None of the healthy controls was stained for any of the genes studied. In the multivariate analysis, HLA-DR antigen and PECAM-1 were proved to be statistically significant independent prognostic factors associated with a favourable and an unfavourable prognosis respectively (P=0.009 and P=0.003). In the univariate analysis, PECAM-1(+)/ICAM-3(-) and HLA-DR(-)/ICAM-3(-) patients exhibited a significantly decreased overall survival compared to those with the exactly opposite gene expression patterns (P=0.0041 and P=0.0091, respectively). Those patients who were HLA-DR(+)/ICAM-3(+)/PECAM-1(-) (n=8) had a significantly higher survival rate compared to the rest of the group (n=24) (P=0.0289). CONCLUSION: PECAM-1, ICAM-3 and HLA-DR are representative markers of tumor expansion potential and host immune surveillance respectively. Their combined use may help us to identify high-risk patients who could benefit from more aggressive therapeutic protocols.