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Leonidas G Koniaris

Publications and source records attributed to Leonidas G Koniaris.

At least 19 recordsLinked to original sources
PubMed2007

Retroperitoneal and truncal sarcomas: prognosis depends upon type not location.

BACKGROUND: Prognostication of truncal and retroperitoneal soft tissue sarcomas has traditionally been predicated on tumor location and grade. OBJECTIVE: To compare outcomes for patients with retroperitoneal or truncal sarcomas. METHODS: Retrospective analysis of a prospective cancer data registry from 1977 to 2004 was performed and outcomes were determined. RESULTS: The study group numbered 312 patients (median age 58 years, 54% male, 56% Caucasian, 14% black, 29% Hispanic). The most common tumor types were liposarcoma (35.9%), leiomyosarcoma (30.1%), and malignant fibrous histiocytoma (MFH) (19.5%). Tumor distributions were retroperitoneal (38.9%), pelvic (24.7%), abdominal (18.6%) and thoracic (17.9%). Median overall survival was 74 months. Operative resection was undertaken in 89.4% of cases and multiple surgeries (range 2-5) in 42.2%. Negative resection margins were obtained in 72.7% of patients. Univariate analysis comparing retroperitoneal versus truncal location demonstrated no significant differences in survival. Survival was improved in lower grade tumors (P < 0.02). Liposarcoma and fibrosarcoma were associated with improved survival (P < 0.0001). Multivariate analysis of pre-treatment variables showed increasing age, grade, histopathology (leiomyosarcoma and MFH) and metastasis to be associated with worse outcomes. Multivariate analysis of the treatment variables showed that surgery and negative resection margins were associated with improved survival (P < 0.001). No advantage for chemoradiotherapy could be demonstrated. CONCLUSIONS: Successful operative resection can confer prolonged disease-free survival and cure for truncal and retroperitoneal sarcomas. Histological subtype, not location, is predictive of long-term survival. Future studies should focus on histological subtype rather than tumor location for truncal and retroperitoneal sarcomas.

Adult↗
PubMed2006

Decreased aquaporin expression leads to increased resistance to apoptosis in hepatocellular carcinoma.

Cells undergoing apoptosis are characterized by decreased cell size due to changes in intracellular ion concentration and rapid, aquaporin (AQP)-dependent water movement out of the cell, events required for the activation of pro-apoptotic enzymes. The current study demonstrates AQP 8 and 9 expression is significantly decreased in hepatocellular carcinoma (HCC) versus normal liver. Isolation of hepatic tumor cells (H4IIE) and hepatocytes confirmed a lack of water movement across the H4IIE cell membrane via AQPs and identified an inherent resistance of H4IIE cells to apoptotic stimuli. In contrast, hepatocytes rapidly responded to osmotic challenge through AQP-dependent water movement and underwent cell death following apoptotic stimulation.

Animals↗
PubMed2006

Molecular pathogenesis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common life-threatening malignancies in the world. This cancer generally arises within the boundaries of well-defined causal factors, of which viral hepatitis infection, aflatoxin exposure, chronic alcohol abuse, and nonalcoholic steatohepatitis are the major risk factors. Despite the identification of these etiological agents, hepatocarcinogenesis remains poorly understood. The molecular mechanisms leading to the development of HCC appear extremely complex and only recently have begun to be elucidated. Currently, surgical resection or liver transplantation offer the best chance of cure for the patient with HCC; however, these therapies are hindered by inability of many of these patients to undergo liver resection, by tumor recurrence and by donor shortages. A lack of suitable therapeutic strategies has led to a greater focus on prevention of HCC using antiviral agents and vaccination. Overall, the current outlook for patients with HCC is bleak; however, a better understanding of the molecular and genetic basis of this cancer should lead to the development of more efficacious therapies.

Animals↗
PubMed2006

Inflammatory myofibroblastic tumors.

INTRODUCTION: Inflammatory myofibroblastic tumors (IMT) while uncommon may arise within numerous organs. Historically, the literature regarding IMT has been confined to small one organ case series, with few reviews encompassing multiple anatomic sites, and little data regarding adjuvant treatment. METHODS: A review of patients with IMT treated at two large academic medical centers over a 15-year period was undertaken. Patient demographics, pathologic diagnoses, and pertinent clinical data were obtained. RESULTS: Forty-four cases of pathologically confirmed IMT were identified. Tumor locations included multiple anatomic sites. Therapies included complete resection, incomplete resection, observation, or chemotherapy, and/or radiation. Five patients underwent adjuvant chemotherapy and/or radiation therapy following surgery (14%) for local aggressiveness of the tumor, invasion, positive margins, or location of tumor that was not amenable to surgical resection. A second, concomitant, histologically distinct, neoplasm was identified in five cases. Of the patients who underwent treatment three local recurrences were noted (8%) and occurred in patients with partial resection without adjuvant chemo- or radiotherapy. CONCLUSIONS: Inflammatory myofibroblastic tumors may be a locally aggressive and destructive neoplasm. Tumor recurrence is unusual following complete surgical resection or organ-preserving combined modality therapy.

Adolescent↗
PubMed2006

Hepatectomy enables prolonged survival in select patients with isolated noncolorectal liver metastasis.

OBJECTIVE: This study was done to determine the benefit of undergoing liver resection for noncolorectal metastasis. METHODS: A single-institution retrospective review of all patients (n = 95) who underwent hepatic resection for a noncolorectal liver metastasis from 1990 to 2005 was performed. Primary outcomes measure was months of patient survival after liver resection. RESULTS: Median patient age was 58 years (range 19 to 83 years). There were 37 men (38.9%) and 58 women (61.1%). The 30-day postoperative mortality rate was 2.1%, and postoperative complications developed in 15.8% of patients. Mean hospital stay was 7 days (range 4 to 25 days). Median time of survival from date of liver resection was 36 months, and 5-year survival rate was 34.9%. Primary tumor sites were identified as foregut or gastrointestinal in 16.8% and nongastrointestinal in 83.2%. Patients with a nonforegut primary tumor had a median survival time twice as long as those with foregut primaries (49 months versus 20 months, p < 0.001). Multiple liver metastases were an independent prognostic factor for worse outcomes with a hazard ratio of 3.3 (p = 0.007). No treatment-dependent variables (initial treatment modality, extent of liver resection, margins, complications) were found on multivariable analysis to be important prognostic factors. CONCLUSIONS: In select patients with any of a variety of malignancies metastatic to the liver, prolonged survival can result from liver resection, especially in those with a single, resectable tumor from a nongastrointestinal primary site.

Adult↗
PubMed2006

Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair.

Interleukin-6 (IL-6) is an important mediator of liver regeneration and repair that is also elevated in chronic liver diseases, including fatty liver of obesity and cirrhosis. IL-6 has been reported both to delay and accelerate liver regeneration. We examined the effects on liver injury and regeneration of a continuous administration of exogenous IL-6 to mice by injection of an IL-6-expressing CHO-cell line in athymic nude mice and by osmotic mini-pump delivery of recombinant murine IL-6. Short-term IL-6 administration (1-2 days) accelerated early recovery of liver mass, whereas more long-term administration (5-7 days) markedly impaired liver regeneration. Similarly, short-term IL-6 treatment increased hepatic resistance to the lethal effects of the Fas agonist Jo-2, but on more prolonged IL-6 exposure the Jo-2 resistance vanished. IL-6 administration initially induced expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL, correlating with protection against Fas-mediated cell death. More prolonged IL-6 administration, however, resulted in marked induction of the pro-apoptotic protein Bax. This result coincided with increased activation of the type II or intrinsic, mitochondrial path to cell death, manifested by increased caspase-9 activation and increased cytochrome c release after Jo-2 exposure. These data demonstrate that IL-6 can function acutely to improve hepatic regeneration and repair, but that more chronic exposure not only abolishes the protective effects of IL-6, but actually sensitizes the liver to injury and death. In conclusion, elevated IL-6 in certain chronic liver diseases contributes to an increased likelihood of liver failure after injury.

Animals↗
PubMed2006

Is adjuvant 5-FU-based chemoradiotherapy for resectable pancreatic adenocarcinoma beneficial? A meta-analysis of an unanswered question.

The objective of this study was to determine the effect, if any, on survival of adjuvant 5-FU-based chemoradiotherapy following pancreaticoduodenectomy for pancreatic carcinoma. A systematic review of the published literature was undertaken. Survival estimates were derived from published reports. Five prospective studies (4 level I, 1 level II) with a total of 607 (229 surgery only; 378 surgery-adjuvant) patients followed for survival met selection criteria. Two-year survival ranged from 15%-37% in the surgery only group and 37%-43% in the surgery and adjuvant groups. The survival advantage (absolute difference) ranged from 3%-27% and no individual study achieved statistical significance (5%). Although clinical heterogeneity existed in surgery-alone control groups with regard to trial date, no statistical heterogeneity was detected (P = 0.459, chi2 test), allowing pooling of survival data. Using a fixed effects model, the summary estimate showed an absolute 2-year survival benefit with adjuvant therapy of 12% (95% CI, 3%-21%, P = 0.011). Trials after 1997 (n = 3) indicated a survival benefit of 8% to patients receiving adjuvant therapy (95% CI, -3-18%, P = 0.145). The result was not statistically significant, and there was no evidence of heterogeneity (P = 0.626, chi2 test). Summary estimates were unchanged when the analysis was performed with a random effects model. 5-FU based chemotherapy with radiotherapy given after resection imparts a small overall survival benefit of 2 years. The benefit of 5-FU-based adjuvant therapy, however, has declined in recent years, and its significance remains unproven in the context of current diagnostic and surgical practice.

Antimetabolites, Antineoplastic↗
PubMed2006

Current incidence and outcomes of gastrointestinal mesenchymal tumors including gastrointestinal stromal tumors.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) have been recognized as the most common mesenchymal tumors of the gastrointestinal tract. The most effective treatment for unresectable tumors is imatinib mesylate, based on two phase II trials. Because no phase III clinical trial has been undertaken, we sought to determine both current population-based incidence and whether improved outcomes noted in both individual centers and clinical trials have also been observed in a large prospective cancer registry earlier and after the introduction of imatinib. STUDY DESIGN: The 13-center cumulative tumor registry (April 2005 release) from the Surveillance, Epidemiology, and End Results (SEER) database was queried from 1992 to 2002 to determine incidence and associated outcomes for patients diagnosed with GIST. Confirmations of incidence trends using the incident Florida Cancer Data System (FCDS, 2005 release) were also determined. RESULTS: A 25-fold age-adjusted increase in incidence of GIST, from 0.028 per 100,000 in 1992 to 0.688 per 100,000 in 2002, was observed. This increase is mostly because smooth-muscle tumors have been reclassified as GISTs, but it also represents a 50% increase in population- and age-adjusted gastrointestinal mesenchymal tumor diagnosis since 1992. Despite rising GIST incidence rates, there has been a marked improvement in survival since 2000, coinciding with the introduction of the tyrosine kinase inhibitor imatinib into clinical practice. CONCLUSIONS: The diagnosis of GIST has dramatically increased since 1992. Survivals have greatly improved since 2000, when imatinib mesylate was FDA approved.

Antineoplastic Agents↗
PubMed2006

507 Warren-Zeppa distal splenorenal shunts: a 34-year experience.

OBJECTIVE: To define the long-term characteristics, prognostic factors, and outcomes of patients undergoing selective splenorenal shunting procedures for portal hypertension-induced recurrent upper gastrointestinal bleeding. MATERIALS AND METHODS: A retrospective evaluation of a prospectively collected data set. RESULTS: From June 1971 through May 2005, 507 Warren-Zeppa shunts were performed at a single institution. Indications included: alcoholic cirrhosis, 52.6%; viral cirrhosis, 21.8%; cryptogenic cirrhosis, 8.4%; autoimmune cirrhosis, 5.8%; and other causes, 6.3%. Median survival was 81 months (5-year survival, 58.9%; 10-year survival, 34.4%; 20-year survival, 12.5%). patients with portal vein thrombosis and biliary cirrhosis demonstrated better survival than others (P = 0.03), while patients with alcoholic cirrhosis trended toward worse survival than those with nonalcoholic causes (P = 0.11). Multivariate analysis of preoperative risk factors found body hair loss (hazard ratio, 17.3; P > 0.005), preoperative encephalopathy (hazard ratio, 1.93; P > 0.003), diuretic use (hazard ratio, 1.43; P > 0.003), and age (hazard ratio, 1.02 per year of age; P > 0.051) were independent predictors of poor long-term survival. Multivariate analysis of operative factors demonstrated blood loss <500 mL was predictive of up to a 4-fold improved long-term survival (hazard ratio, 3.95; P < 0.013). Postoperative complications included: recurrent bleeding, 12%; ascites, 17.5%; and encephalopathy, 13.9%. Multivariate analysis of postoperative factors prospectively collected in 130 patients found that alcoholic recidivism (hazard ratio, 2.66; P > 0.001) was the only independent predictor of poor prognosis. CONCLUSIONS: The Warren-Zeppa shunt provides long-term survival and control of bleeding in most patients with portal hypertension. Excellent long-term survival can be obtained in properly selected patients with portal hypertension and relatively spared hepatic function.

Adolescent↗
PubMed2005

The discovery of insulin: the Rochester, New York, connection.

The discovery of insulin in Toronto by Dr. Frederick G. Banting and colleagues has been well chronicled. The story of how insulin therapy was introduced into the United States has been less detailed. The first patient to be treated with insulin in the United States resided in Rochester, New York, a city with a then newly developed medical school that had also tried to recruit Dr. Banting. A series of letters from that period provides a description of the course of a juvenile patient with diabetes before and after the use of insulin as a therapeutic agent.

Diabetes Mellitus, Type 1↗
PubMed2005

Growth differentiation factor-15: induction in liver injury through p53 and tumor necrosis factor-independent mechanisms.

Expression of macrophage inhibitory cytokine-1 (MIC-1), a divergent transforming growth factor-beta family member, and its murine ortholog, growth/differentiation factor-15 (GDF-15), is induced in hepatocytes by surgical and chemical injury and heat shock. Here, we demonstrate that the regulation of GDF-15/MIC-1 expression may be evolutionarily conserved because MIC-1 was induced in diseased human livers. Gdf15 induction was independent of protein synthesis, a hallmark of immediate-early gene regulation. Although tumor necrosis factor (TNF) induced GDF-15 expression, injury-elicited Gdf15 expression was not reduced in mice deficient for both TNF receptor subtypes. Furthermore, although the stress sensor p53 is known to induce GDF-15/MIC-1 expression, injury-elicited Gdf15 expression was unchanged in p53 null mice. Our results demonstrate that GDF-15 induction is an immediate early response to liver injury that can occur through TNF and p53 independent pathways.

Animals↗
PubMed2005

Embolization as first-line therapy for diverticulosis-related massive lower gastrointestinal bleeding: evidence from a meta-analysis.

The study goal was to determine which etiologies of lower gastrointestinal bleeding (LGIB) may best be treated with superselective embolization. A meta-analysis was undertaken of 25 identified publications reporting the use of embolization and an unpublished series of 12 consecutive patients with LGIB from the authors' institution. Six published series and the authors' series met selection criteria for further analysis. Multiple regression analysis demonstrated no significant difference in pooled outcomes when varying the included study, age, or embolization method on the outcome of rebleeding. The pooled odds ratio for arteriovenous dysplastic lesions and other diseases was 3.53 compared with rebleeding after localization and embolization for diverticular disease (95% confidence interval odds ratio, 1.33, 9.41; P < 0.01). Embolization for diverticular bleeding was successful in 85% of patients. In contrast, rebleeding after embolization for nondiverticular bleeding occurred in greater than 40% of patients and over a more protracted period. Embolization for LGIB is most effective for the treatment of diverticular bleeding. Caution should be used when applying embolization therapy for nondiverticular causes due to the considerably higher associated failure rate. An inpatient observation period of 2 days is suggested following embolization for diverticular bleeding.

Adult↗
PubMed2005

A technique for emergency liver packing.

Control of liver hemorrhage may present a daunting clinical scenario. Use of liver packing techniques is highly effective to control bleeding but can result in significant recurrent bleeding with pack removal. Such bleeding is particularly a problem when large portions of the hepatic parenchymal surface and Glisson's capsule have been disrupted. We describe, herein, our approach to hepatic packing in scenarios where a large component of hepatic capsular disruption has occurred. Use of a non-stick bowel bag is employed on the disrupted liver surface, which, when removed, will not result in liver rebleeding. This technique has been used successfully in the management of five cases of severe liver injury with extensive capsular disruption. Familiarity with such an approach may facilitate management of similar liver injuries.

Adult↗
PubMed2005

Interleukin-6 inhibits cell proliferation in a rat model of hepatocellular carcinoma.

BACKGROUND: Interleukin-6 (IL-6) plays a critical role in normal hepatic growth and liver regeneration. The aims of the present study are to determine the expression of components of IL-6 signaling in an in vivo model of hepatocellular carcinoma (HCC) and address the role of IL-6 signaling in the progression of HCC. METHODS: An in vivo rat HCC model was established and IL-6 receptor (IL-6R) and downstream signaling pathway expression and activity were determined in HCC and normal liver specimens. Tumorigenic HCC cells from resected HCC samples and normal hepatocytes were then isolated and cultured in the presence and absence of recombinant human IL-6 (rhIL-6). RESULTS: HCC specimens demonstrated decreased IL-6Ralpha/gp130 expression as compared with the normal liver. In contrast, HCC samples had significantly increased IL-6 messenger RNA expression and signal transducers and activators of transcription (STAT)3 activity. Using in vitro cell cultures, we demonstrated that IL-6 stimulated STAT3 and extracellular regulated kinase (ERK) activity in both HCC cells and isolated hepatocytes. However, while STAT3 activation profiles were similar, IL-6 stimulated ERK activity in a biphasic manner in HCC cells and a monophasic, sustained ERK activation in hepatocytes. In HCC cells, a significant induction of cyclin-dependent kinase (CDK) inhibitors, p21(waf1/cip1) and p27(Kip1) occurred, an effect that was not observed in normal hepatocytes. Finally, we established that IL-6 acted to inhibit serum-stimulated DNA synthesis and cell mitogenesis in HCC cells in vitro. CONCLUSIONS: These data demonstrate altered expression of components of IL-6 signaling in HCC in vivo. IL-6 treatment of HCC cells inhibits serum-stimulated mitogenesis, possibly via differences in activation profiles of intracellular signaling pathways and their effect on CDK inhibitor expression/activity.

Animals↗
PubMed2005

Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury.

The immunoregulatory cytokine macrophage inhibitory cytokine-1 (MIC-1), a divergent TGF-beta family member, and its murine ortholog, growth/differentiation factor-15 (GDF-15) are induced in hepatocytes by surgical and chemical injury and heat shock. To better understand the in vivo role this factor plays in organ injury, we examined the regulation of GDF-15 in murine models of kidney and lung injury. We demonstrate herein induction of GDF-15/MIC-1 after surgical, toxic/genotoxic, ischemic, and hyperoxic kidney or lung injury. Gdf15 induction was independent of protein synthesis, a hallmark of immediate-early gene regulation. Although TNF induced GDF-15 expression, injury-elicited Gdf15 expression was not reduced in mice deficient for both TNF receptor subtype. Furthermore, although the stress sensor p53 is known to induce GDF-15/MIC-1 expression, injury-elicited Gdf15 expression was unchanged in p53-null mice. Our results demonstrate that GDF-15 induction after organ injury is a hallmark of many tissues. These data demonstrate that GDF-15/MIC-1 is an early mediator of the injury response in kidney and lung that might regulate inflammation, cell survival, proliferation, and apoptosis in a variety of injured tissues and disease processes.

Animals↗