Zsolt Simonka

Release of TGFβig-h3 by gastric myofibroblasts slows tumor growth and is decreased with cancer progression

Tumor progression has been linked to changes in the stromal environment. Myofibroblasts are stromal cells that are often increased in tumors but their contribution to cancer progression is not well understood. Here, we show that the secretomes of myofibroblasts derived from gastric cancers [cancer-associated myofibroblasts (CAMs)] differ in a functionally significant manner from those derived from adjacent tissue [adjacent tissue myofibroblasts (ATMs)]. CAMs showed increased rates of migration and proliferation compared with ATMs or normal tissue myofibroblasts (NTMs). Moreover, conditioned medium (CM) from CAMs significantly stimulated migration, invasion and proliferation of gastric cancer cells compared with CM from ATMs or NTMs. Proteomic analysis of myofibroblast secretomes revealed decreased abundance of the extracellular matrix (ECM) adaptor protein like transforming growth factor-β-induced gene-h3 (TGFβig-h3) in CAMs, which was correlated with lymph node involvement and shorter survival. TGFβig-h3 inhibited IGF-II-stimulated migration and proliferation of both cancer cells and myofibroblasts, and suppressed IGF-II activation of p42/44 MAPkinase; TGFβig-h3 knockdown increased IGF-II- and CM-stimulated migration. Furthermore, administration of TGFβig-h3 inhibited myofibroblast-stimulated growth of gastric cancer xenografts. We conclude that stromal cells exert inhibitory as well as stimulatory effects on tumor cells; TGFβig-h3 is a stromal inhibitory factor that is decreased with progression of gastric cancers.

NHE1 activity contributes to migration and is necessary for proliferation of human gastric myofibroblasts

Myofibroblasts play central roles in wound healing, deposition of the extracellular matrix and epithelial function. Their functions depend on migration and proliferation within the subepithelial matrix, which results in accelerated cellular metabolism. Upregulated metabolic pathways generate protons which need to be excreted to maintain intracellular pH (pHi). We isolated human gastric myofibroblasts (HGMs) from surgical specimens of five patients. Then we characterized, for the first time, the expression and functional activities of the Na+/H+ exchanger (NHE) isoforms 1, 2 and 3, and the functional activities of the Na+/HCO3− cotransporter (NBC) and the anion exchanger (AE) in cultured HGMs using microfluorimetry, immunocytochemistry, reverse transcription polymerase chain reaction and immunoblot analysis. We showed that NHE1–3, NBC and AE activities are present in HGMs and that NHE1 is the most active of the NHEs. In scratch wound assays we also demonstrated (using the selective NHE inhibitor HOE-642) that carbachol and insulin like growth factor II (IGF-II) partly stimulate migration of HGMs in a NHE1-dependent manner. EdU incorporation assays revealed that IGF-II induces proliferation of HGMs which is inhibited by HOE-642. The results indicate that NHE1 is necessary for IGF-II-induced proliferation response of HGMs. Overall, we have characterized the pHi regulatory mechanisms of HGMs. In addition, we demonstrated that NHE1 activity contributes to both IGF-II- and carbachol-stimulated migration and that it is obligatory for IGF-II-induced proliferation of HGMs.

Na+/Ca2+ exchangers regulate the migration and proliferation of human gastric myofibroblasts

Gastrointestinal myofibroblasts are contractile, electrically nonexcitable, transitional cells that play a role in extracellular matrix production, in ulcer healing, and in pathophysiological conditions they contribute to chronic inflammation and tumor development. Na+/Ca2+ exchangers (NCX) are known to have a crucial role in Ca2+ homeostasis of contractile cells, however, no information is available concerning the role of NCX in the proliferation and migration of gastrointestinal myofibroblasts. In this study, our aim was to investigate the role of NCX in the Ca2+ homeostasis, migration, and proliferation of human gastrointestinal myofibroblasts, focusing on human gastric myofibroblasts (HGMs). We used microfluorometric measurements to investigate the intracellular Ca2+ and Na+ concentrations, PCR analysis and immunostaining to show the presence of the NCX, patch clamp for measuring NCX activity, and proliferation and migration assays to investigate the functional role of the exchanger. We showed that 53.0±8.1% of the HGMs present Ca2+ oscillations, which depend on extracellular Ca2+ and Na+, and can be inhibited by NCX inhibitors. NCX1, NCX2, and NCX3 were expressed at both mRNA and protein levels in HGMs, and they contribute to the intracellular Ca2+ and Na+ homeostasis as well, regardless of the oscillatory activity. NCX inhibitors significantly blocked the basal and insulin-like growth factor II-stimulated migration and proliferation rates of HGMs. In conclusion, we showed that NCX plays a pivotal role in regulating the Ca2+ homeostasis, migration, and proliferation of HGMs. The inhibition of NCX activity may be a potential therapeutic target in hyperproliferative gastric diseases.

The effects of laparoscopic Nissen fundoplication on Barrett's esophagus: Long-term results

Abstract Objective. The aim of our study was to conduct a retrospective investigation of the efficacy of laparoscopic Nissen fundoplication in patients with Barretts esophagus. Material and methods. A total of 78 patients with Barretts esophagus underwent surgery. Patients were divided into three groups on the basis of the preoperative endoscopic biopsies: a non-intestinal group (n = 63) with fundic or cardiac metaplasia, an intestinal group (n = 18) with intestinal metaplasia, and a dysplastic group (n = 7) with low-grade dysplasia. Clinical follow-up was available in the case of 64 patients at a mean of 42 ± 16.9 months after surgery. Results. Check-up examination revealed total regression of Barretts metaplasia in 10 patients. Partial regression was seen in 9 cases, no further progression in 34 patients, and progression into cardiac or intestinal metaplasia in 11 patients. No cases of dysplastic or malignant transformation were registered. Where we observed the regression of BE, among the postoperative functional examinations results of manometry (pressure of lower esophageal sphincter) and pH-metry were significantly better compared with those groups where no changes occurred in BE, or progression of BE was found. Discussion. Our results highlight the importance of the cases of fundic and cardiac metaplasia, which can also transform into intestinal metaplasia. Conclusions. Antireflux surgery can appropriately control the reflux disease in a majority of the patients who had unsuccessful medical treatment, and it may inhibit the progression and induce the regression of Barretts metaplasia in a significant proportion of these patients.

Successful endoscopic clipping in the early treatment of spontaneous esophageal perforation

Barogenic esophageal injury or Boerhaave syndrome is an esophageal perforation entailing very high mortality and morbidity. Endoscopic techniques have been introduced in the treatment of various types of esophageal perforation. This report describes the first patient who underwent a successful endoscopic clipping involving sealing of a transpleural esophageal rupture within 24 hours of the onset of symptoms.

Role of laparoscopic surgery in the treatment of ulcerative colitis; short- and mid-term results

Abstract Objectives. Laparoscopy is used more widely for the surgery of ulcerative colitis. The objective of this study was a comparison of the surgical and 3-year follow-up results of patients treated with conventional and minimally invasive methods. Materials and methods. A total of 45 patients received surgery for ulcerative colitis, 16 as emergency and 29 as elective cases. Laparoscopy was used in 23 and a conventional method in 22 cases. No difference was found between the two groups from the aspects of American Society of Anesthesiologists physical status (ASA) class, mean body mass index (BMI) and age. There were 4 emergency cases in the laparoscopy group, and 12 in the open group. Nineteen elective surgeries were performed in the laparoscopy group, and 10 in the open group. Results. There was no significant difference between the groups as concerns the length of hospital or intensive care unit (ICU) stay, the time to bowel function recovery, but the duration of open surgery was significantly shorter. There was no difference between the groups in the rate of early postoperative complications, whereas among potential late complications, the rates of intestinal obstruction (8.7% vs. 45%) and a septic condition (0% vs. 27%) were significantly lower in the laparoscopy group. There was a significant improvement in the quality of life after surgery in both groups, and better cosmetic results were observed in the laparoscopy group. Conclusion. Laparoscopy can be used for ulcerative colitis both emergency and elective cases, it provides a good quality of life and the mid-term rate of complications is lower as compared with open surgery.

Learning curve after rapid introduction of laparoscopic appendectomy: are there any risks in surgical resident participation?

BackgroundWith the spread of the minimally invasive technique, laparoscopic appendectomy (LA) is performed with increasing frequency with excellent results. The method provides surgical residents with an excellent opportunity to learn basic laparoscopic skills and prepares them for more complex interventions.MethodsWe evaluated the results of 600 laparoscopic appendectomies performed by 5 surgical residents (Group A) and 5 consultant surgeons (Group B) between 2006 and 2009. Comparing the two groups based on patient demographics, duration of surgery, operation time depending on the severity of inflammation, intraoperative blood loss, conversion rate, hospital stay in days, and postoperative complications. We also assessed the extent to which the minimum of 20 surgeries to be performed in the learning curve period as recommended by the EAES corresponds to our experience. SPPS 20 was used for the statistical analysis.ResultsSix hundred laparoscopic appendectomies were performed in the study period (Group A: n = 319; Group B: n = 281). A significant difference was found between the two groups in duration of surgery during the learning curve period and when comparing the duration of LA surgeries in the learning curve period with the duration of later surgeries in both groups. The operation time in case of more severe inflammation also showed a significant difference when comparing with simple appendicitis operation time.ConclusionsThe rapid introduction of laparoscopy involves few risks, the surgery is also performed with sufficient safety by surgical residents, and it provides them with an excellent opportunity to learn the basic laparoscopy skills.

Laparoscopic Splenectomy Is a Safe Method in Cases of Extremely Large Spleens

INTRODUCTION The aim of this study was to assess if there is a relationship between the outcome of laparoscopic splenectomy (LS) procedures and the size of the spleen, the learning curve, or the method of specimen retrieval. PATIENTS AND METHODS Between January 1, 2002 and December 31, 2013, 70 LS procedures were performed at our department. Based on the weight of the removed spleen, patients were divided into three groups: Group 1, <350 g (n=32); Group 2, 350-1000 g (n=15); and Group 3, >1000 g (n=7). The role of the learning curve was also analyzed with the first 20 surgeries considered as the learning period. The specimen was retrieved with morcellation through the lateral port site in 54 cases, whereas in 11 cases, the large spleen was retrieved through a Pfannenstiel incision. RESULTS The mean duration of surgery was 122 minutes. When considered by spleen weight, durations for Groups 1-3 were 117, 128, and 134 minutes, respectively. When considered by the learning curve, durations for learning and later periods were 149 and 111 minutes, respectively (P=.002). After the learning period, larger spleens were removed (208 versus 519 g; P=.02), and there were fewer conversions. The mean postoperative hospital stay was 5.1 days. In the 11 cases where the specimen was retrieved through a Pfannenstiel incision, the mean duration of surgery was 108 minutes, and the mean spleen weight was 1032 g. CONCLUSIONS Our study supports that the proposal that LS is safe and has numerous advantages, even in the case of massive splenomegaly. Our results were mainly affected by the spleen size and the learning curve.

Apocrine Encapsulated Papillary Carcinoma of the Breast: The First Reported Case with an Infiltrative Component

Apocrine encapsulated papillary carcinoma (EPC) of the breast is a rare neoplasm, and only 10 cases have been reported in the literature to date. Although EPC by definition lacks a peripheral myoepithelial layer, all previously published apocrine EPC cases were clinically indolent and lacked a conventional invasive component. Herein, we report the 11th case of apocrine EPC, which had a conventional invasive carcinoma component and provides evidence of the malignant potential of this entity. We postulate that apocrine EPC is most likely a morphological variant of conventional EPC, with the same unpredictable malignant potential as non-apocrine cases.

Associations Between a Sedentary Lifestyle and Negative Mood State and the Risk of Breast Cancer

Objective: The highly stressful nature of the diagnosis and treatment of breast cancer and the painful surgical procedures lead to a series of psychological problems among patients. Our primary aim was to examine the effect of pre- and postoperative psychological characteristics on postoperative pain, quality of life, and survival among women with breast cancer. Our secondary aim was to determine whether physical activity and positive emotions would decrease the size of the tumor among women with breast cancer. Methods: The study involved 90 breast cancer patients from the surgery clinic at the University of Szeged, Hungary. We tested patients with a combination of five instruments, before and after surgery: Spielberger’s State and Trait Anxiety Scale, Beck’s Depression Scale, Functional Assessment of Cancer Therapy—Breast Cancer Scale (FACT-B), Perceived Stress Scale (PSS-10), and Visual Analog Pain Scale (VAS). Futhermore, we assessed the physical activity of patients. Results: Anxiety disorders were present in 52% of women, 35% of the patients suffered from depression. Patients with higher perceived stress and anxiety had higher postoperative pain after surgery, which were associated with lower emotional, functional, and physical well-being and social support. Patients with lower physical activity had higher anxiety, depression, and perceived stress levels. Physical activity has been strongly linked to improved quality of life and decreased tumor size. Discussion: It seems that physical inactivity might reduce the chance for survival in women with breast cancer. Futhermore, the rates of psychosocial distress are very high. Our data present a challenge to clinical services to provide a comprehensive range of support services to reduce distress.