The SAGES Fundamental Use of Surgical Energy program (FUSE): history, development, and purpose.

BACKGROUND: Adverse events due to energy device use in surgical operating rooms are a daily occurrence. These occur at a rate of approximately 1-2 per 1000 operations. Hundreds of operating room fires occur each year in the United States, some causing severe injury and even mortality. The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) therefore created the first comprehensive educational curriculum on the safe use of surgical energy devices, called Fundamental Use of Surgical Energy (FUSE). This paper describes the history, development, and purpose of this important training program for all members of the operating room team. METHODS: The databases of SAGES and the FUSE committee as well as personal photographs and documents of members of the FUSE task force were used to establish a brief history of the FUSE program from its inception to its current status. RESULTS: The authors were able to detail all aspects of the history, development, and national as well as global implementation of the third SAGES Fundamentals Program FUSE. CONCLUSIONS: The written documentation of the making of FUSE is an important contribution to the history and mission of SAGES and allows the reader to understand the idea, concept, realization, and implementation of the only free online educational tool for physicians on energy devices available today. FUSE is the culmination of the SAGES efforts to recognize gaps in patient safety and develop state-of-the-art educational programs to address those gaps. It is the goal of the FUSE task force to ensure that general FUSE implementation becomes multinational, involving as many countries as possible.

Safety and outcome of combined liver and pancreatic resections.

BACKGROUND: In Western countries, combined liver and pancreatic resections (CLPR) are performed rarely because of the perceived high morbidity and mortality rates. This study evaluated the safety and outcomes of CLPR at a tertiary European centre for hepatopancreatobiliary surgery. METHODS: A review of two prospectively maintained databases for pancreatic and liver resections was undertaken to identify patients undergoing CLPR between January 1994 and January 2012. Clinicopathological and surgical outcomes were analysed. Univariable and multivariable analyses for postoperative morbidity were performed. RESULTS: Fifty consecutive patients with a median age of 58 (range 20-81) years underwent CLPR. Indications for surgery were neuroendocrine carcinoma (16 patients), biliary cancer (15), colonic cancer (5), duodenal cancer (1) and others (13). The type of pancreatic resection included pancreaticoduodenectomy (30), distal pancreatectomy (17), spleen-preserving distal pancreatectomy (2) and total pancreatectomy (1). Twenty-three patients had associated major hepatectomies, 27 underwent minor liver resections and 11 had associated vascular resections. Mortality and morbidity rates were 4 and 46 per cent respectively. Univariable and multivariable analysis showed no differences in postoperative morbidity in relation to extent of liver resection or type of pancreatic resection. Use of preoperative chemotherapy was the only independent risk factor associated with postoperative morbidity (P = 0.021). CONCLUSION: CLPR can be performed with fairly low morbidity and mortality rates. Postoperative outcomes were not affected by the extent of liver resection or the type of pancreatic resection. Patients receiving chemotherapy should be evaluated carefully before surgery is considered.

Flt3 ligand promotes the generation of a distinct CD34(+) human natural killer cell progenitor that responds to interleukin-15.

Interleukin-15 (IL-15) is produced by human bone marrow (BM) stromal cells and can induce CD34(+) hematopoietic progenitor cells (HPCs) to differentiate into CD56(+)CD3(-) natural killer (NK) cells in the absence of stromal cells. IL-15 mediates its effects by signaling through the beta and gammac chains of the IL-2/15 receptor (R). The c-kit ligand (KL), also produced by stromal cells, enhances the expansion of NK cells from CD34(+) HPCs in the presence of IL-15, but alone has no ability to differentiate NK cells. Mice deficient in KL do not appear to have a quantitative deficiency in NK cells, suggesting that other stromal cell factors may contribute to NK cell expansion. Flt3 ligand (FL) is also produced by BM stromal cells and has homology with KL. Furthermore, mice with a targeted disruption of the FL gene have reduced numbers of NK cells. We evaluated here the effects of FL on human NK cell development and expansion from CD34(+) HPCs. Like KL, FL significantly enhanced the expansion of NK cells from CD34(+) HPCs in the presence of IL-15, compared with IL-15 alone. However, FL alone had no effect on NK cell differentiation. We therefore explored the mechanism by which FL promotes IL-15-mediated NK cell development. FL was found to induce IL-2/15Rbeta (CD122) expression on CD34(bright) HPCs. The CD34(bright) CD122(+) cell coexpressed CD38, but lacked expression of CD7, CD56, NK cell receptors (NKRs), or cytotoxic activity in the absence of IL-15. Using limiting dilution analysis in the presence of IL-15 alone, we demonstrated that the FL-induced CD34(bright)CD122(+) HPCs had an NK cell precursor frequency 20- to 60-fold higher than the CD34(dim/neg)CD122(-) HPCs and 65- to 235-fold higher than fresh CD34(+) HPCs. KL had similar effects as FL, but induced a significantly lower percentage of CD34(bright)CD122(+) cells (P

Medullary carcinoma of the thyroid: prognostic factors and treatment recommendations.

BACKGROUND: Because medullary thyroid carcinoma accounts for only 7% of all thyroid malignancies, data to support treatment strategies are scarce. METHODS: We retrospectively reviewed treatment and outcome in 34 patients with MTC treated at Roswell Park between 1961 and 1995. Univariate analysis was performed using the variables age, sex, tumor size, N stage, and M stage. RESULTS: Median survival was 4.7 years, with 51% and 32% of patients alive at 5 and 15 years, respectively. Nodal metastases were seen in 76% and distant metastases in 67% of all patients. More than 60% of the patients with nodal metastases survived longer than 10 years. Once diagnosed with distant metastases, 90% of the patients died within 5 years. Local failure rate with lobectomy was 44%, compared to 10% after total thyroidectomy (P < .02). Age, extrathyroid extension, and M stage portend a poor outcome. Nodal status had no statistically significant impact on survival. CONCLUSION: Survival with tumors confined to the thyroid gland is independent of nodal status. Long-term survival in patients with distant metastases is rare. This study underscores the role of total thyroidectomy in the initial treatment and the need to develop effective adjuvant therapy for MTC.

Differentiated thyroid carcinoma: risk group assignment and management controversies.

In this review, we provide a framework for clinical decision-making in the treatment of differentiated thyroid cancer. The clinical discussion and treatment recommendations are relevant to an adult population (> 16 years of age). The natural history, pathogenesis, diagnostic tools, and treatment controversies in the management of this disease are explored. The roles of radioiodine therapy and thyroid-stimulating hormone (TSH) suppression and the treatment of locoregional disease are reviewed. This discussion provides a comprehensive assessment of management and treatment issues in differentiated thyroid cancer.

Anal canal and perianal epidermoid cancers.

Squamous cell carcinoma of the anal canal serves as a paradigm for the successful application of multimodality treatment of solid tumors. Since 1974, multimodality treatment with combined radiation and chemotherapy has become the standard. The compelling advantage of sphincter preservation and the substantial survival benefit compared with surgery alone prompted investigators to adopt chemoradiation treatment. Several questions regarding the optimal radiation dose and chemotherapy in initial as well as salvage therapy remain, and only recently have results of several prospective randomized studies become available to address some of these unresolved issues. We reviewed the clinical aspects and historical treatment results of anal canal and perianal epidermoid cancers in light of the results of these modern trials. Current management strategies are redefined, and future directions of clinical studies are outlined.

Aberrant biliopancreatic duct. A probable cause of acute pancreatitis?

Abnormal biliopancreatic ducts are very uncommon in adults with the exception of those associated with abnormalities of either the pancreatic or the bile ducts. The case presented herein is unique in that a biliopancreatic connection occurred proximal to the papilla of Vater and the patient was symptomatic because of the aberrant connection. The surgical therapy consisted of cholecystectomy and ligation of the aberrant duct, with complete relief of severe, debilitating symptoms. This interesting clinical observation is discussed in the light of Opie's theory of biliary reflux into the pancreatic duct as a pathogenetic mechanism for acute pancreatitis.

Differential oncolytic effect of NK-enriched subsets in long-term interleukin-2 cultures.

The aim of this study was to characterize the oncolytic efficacy of human natural killer (NK) cell subsets generated from highly NK-enriched population in long-term IL-2 cultures. NK cells cultured for 3 weeks with interleukin-2 (IL-2) were separated into several subsets using two color fluorescence-activated cell sorting and CD2, CD8, CD16, and CD56 monoclonal antibodies. These individual NK cell subsets were then tested for cytotoxicity against various tumor target cell lines, including K-562, Daudi, and Ovcar-3. The CD16+/CD56+ NK cell subset was superior in its cytotoxic activity against all targets in comparison to the CD16-/CD56+ subset. Within CD16 population, CD16+CD2+ NK cells were most potent; however CD16+/CD2- subset was also cytotoxic, indicating that CD2 molecule is important, but not necessary for NK cell cytotoxic function. CD16+/CD8+ and CD16+/CD8- subsets showed variance in cytolytic efficacy, depending on the tumor target tested. Highest cytotoxicity against K-562 was observed in the CD16+/CD8+ population, while the CD16+/CD8- subset manifested highest cytotoxic activity against Daudi. No significant differences within these NK cell subsets were observed against Ovcar-3 targets. These data indicate that NK cell subsets are not equally oncolytic, and that the oncolytic effect may be tumor dependent.

Generation of MHC-nonrestricted and restricted oncolytic subsets from human bone marrow.

We analyzed the cytotoxicity and characterized the phenotype of oncolytic bone marrow (BM) lymphocyte subsets generated in vitro by interleukin-2 (IL-2) and stimulator cells (SC). Two irradiated B-lymphoblastoid cell lines (Daudi and EBV-transformed BSM) and fresh human acute myelogenous leukemia (AML) were used as SC. Stimulation with Daudi and IL-2 resulted in a substantial increase in cytotoxic activity (100- to 1000-fold) against a broad range of tumor targets, and total cellular expansion was higher compared to stimulation with IL-2 alone. The most prominent increase was observed in the CD16+ and CD56+/CD3- natural killer (NK) cell subset; however, a significant increase was also observed in CD56+/CD3+ T cells. Functional analysis of Daudi- and IL-2-generated subsets using fluorescence-activated cell sorting (FACS) revealed that most of the lytic activity was mediated by NK cells. Significant potentiation of oncolytic activity and cell growth was also seen in the cultures stimulated with BSM or fresh AML and IL-2. The highest oncolytic activity in the latter cultures was mediated primarily by CD8+, CD3+, and CD56- T cells, although NK cells also participated in cytotoxic activity. The T cell-mediated cytotoxicity was restricted by the major histocompatibility complex (MHC), since most cytotoxicity could be blocked by HLA I antibodies. Additionally, we observed that optimum stimulation of cytotoxicity required effector cell-stimulator cell contact. These data indicate that depending on the tumor used for stimulation, different lymphocyte subsets may be generated in IL-2 cultures. These different approaches may be useful in both specific and nonspecific immunotherapy.

Antitumor activity, growth, and phenotype of long-term IL-2 cultures of human NK and T lymphocytes.

We have studied growth, function, and phenotype of purified NK and T cells in long-term cultures and compared these parameters to those of conventionally prepared interleukin-2-activated lymphocytes with killer cell activity (LAK). Enrichment of NK and T cells was achieved by Percoll density gradient. Growth was analyzed by cell counts and [3H]TdR uptake. Cytotoxicity and tumor-binding efficacy were assessed in a 3-h 51Cr and single cell agarose assay, respectively, against K-562, Daudi, human ovarian cell line Ovcar-3, and fresh leukemic blasts. We found that long-term proliferation and lytic activity were highest in NK-enriched and lowest in T-enriched cultures. Conventional LAK cultures generated medium cytotoxicity levels. Lytic activity declined within 3 weeks in cultures not enriched for NK cells, while NK-enriched cultures showed high levels of cytotoxicity up to 6 weeks. No change was found in binding activity within 3 weeks with the exception of T cell-enriched fraction. A number of changes in the phenotypic patterns was observed in IL-2 cultures; the CD56+/CD3-/+ and CD56+/CD8+ subset increased in most cultures, whereas the CD56-/CD3+ subset decreased over time. The highly enriched NK cell culture maintained its NK cell phenotype over 5-6 weeks. We also delineated the most cytotoxic lymphocyte subset in long-term IL-2 cultures by complement dependent cytotoxic assays and fluorescence-activated cell sorting (FACS). Lytic activity in conventional LAK as well as in T and NK cell-enriched IL-2 cultures was mediated primarily by CD56+, CD16+, CD3- NK cells. The clinical implication of these studies is discussed.

Feeder cells enhance oncolytic and proliferative activity of long-term human bone marrow interleukin-2 cultures and induce different lymphocyte subsets.

The effect of feeder cells on oncolytic activity of lymphocyte subsets and their growth was evaluated in long-term human bone marrow interleukin-2 (IL-2) cultures. Two B-lymphoblastoid cell lines (Daudi and Epstein-Barr-virus-transformed BSM) and two human leukemias, AML-M5, were used as feeder cells. The most prominent effects were seen in cultures stimulated with Daudi cells. In these cultures, cytotoxic activity was 100-1000 times increased against a broad range of target cells and the total cellular expansion was more than 40 times higher than in control cultures. This Daudi-related effect appeared to be mediated by natural killer (NK) cells, since cellular expansion occurred mostly in the CD16+ and CD56+ CD3- NK cell subset. In cultures stimulated with BSM and acute myelogenous leukemia (AML) feeder cells, the increase in proliferation was similar, but the enhancement of cytotoxicity, even though significant, was less prominent. Although all feeder cells were effective in stimulation of bone marrow reactivity, the highest cytotoxicity was always observed with feeder cells autologous to the targets, indicating some degree of specificity. This was especially evident in cultures stimulated with autologous versus allogeneic AML feeder cells. In contrast to Daudi-stimulated IL-2 cultures, in which the highest expansion of CD3- CD56+ NK cells was observed, in BSM and AML cultures, the CD3+ CD56+/-T cell subsets were more prolific. This indicates that the response and phenotypic heterogeneity of bone marrow cultures depends on the type of feeder cells used. This observation indicates that the preferential stimulation of a pertinent lymphocyte subset for therapeutic purposes may be possible.

Lytic units reconsidered: pitfalls in calculation and usage.

51Chromium release-derived cytotoxicity data yield curvilinear plots when the x axis displays the effector:target ratio and the y axis displays the percentage of cytotoxicity. To facilitate data analysis, several biomathematical models (simple linear regression, exponential fit, and Von Krogh) have been used to express these cytotoxicity curves as a single numerical value, termed the lytic unit. Other than using raw cytotoxicity data, the lytic unit has been the most common method of data presentation in human and animal tumor immune studies involving natural killer cells, lymphokine-activated killer cells, and cytotoxic T cells. Unfortunately, the models for determining lytic unit values incorporate assumptions and methods of calculation that can result in inaccurate model-predicted cytotoxicity in comparison with the actual observed cytotoxicity data. Even when the model is accurate in predicting cytotoxicity values (i.e., the nonlinear regression-calculated three-parameter Von Krogh model), comparisons between donors of minimally different or highly different cytotoxicity are still fraught with potential error due to statistically verifiable violations of assumptions of parallelism. Although more cumbersome, donor cytotoxicity comparisons using a range of effector:target ratios are not subject to the above problems. Researchers may therefore want to reconsider the use of lytic units when evaluating and reporting cytotoxicity data.

Immunologic and clinical aspects of natural killer cells in human leukemia.

We have studied peripheral-blood, splenic and bone marrow natural killer (NK) activity in patients with leukemia. These studies demonstrated that leukemic patients displayed defective NK activity in all of these tissues. However, NK defect could be corrected by culture of effector cells with interleukin-2 (IL-2). The phenotypic analysis of IL-2 cultures showed clearly the heterogeneity of lymphocyte subsets. The characterization studies demonstrated that CD56+, CD3- NK cells manifested most potent lysis of leukemia, CD56+, CD3+ T cells mediated some, but low, antileukemia activity and CD56-, CD3+ T lymphocytes were devoid of cytotoxicity.

A parametric study of the force/moment systems produced by T-loop retraction springs.

This study considers the effects of several parameters on the force/moment systems produced by T-loop retraction springs. The springs are studied by using the finite element method and by experimentally measuring the forces and moments from the various designs. The results show that varying the spring height can produce larger moment to force ratios as the height increases. Changes in the preactivation bends result in unsymmetric moment characteristics and also produce large intrusive/extrusive forces. The addition of helices at the bends did little to alter the springs' mechanical characteristics.

A mathematical model for metastatic growth illustrated by in vivo and in vitro growth of a transplantable mammary carcinoma in mice.

We analysed the growth pattern of metastases in C3H-mice produced by i.v. injection (tail vein) of tumor cell suspensions of mammary carcinoma HB. Although the ordinary Gompertz equation generally corresponds well to tumor growth in animals and men, we found it inadequate to describe the growth of lung metastases in our model. The morphometric analysis and growth kinetics (LI/GF) of the metastases show a biphasic pattern. The first phase is characterized by a strictly avascular growth and nutrition by diffusion, the second phase is initiated by tumor angiogenesis. To analyze these observations we developed a new mathematical equation which fits particularly well to the metastatic growth curve. We conclude that the present model is appropriate for the analysis of tumor angiogenesis, especially to study factors, which influence the development of a tumor specific vascular system.