An automated Monte Carlo QC system for volumetric modulated arc therapy: Possibilities and challenges.

PURPOSE: To develop and implement an automated Monte Carlo (MC) system for patient specific VMAT quality control in a patient geometry that generates treatment planning system (TPS) compliant DICOM objects and includes a module for 3D analysis of dose deviations. Also, the aims were to recommend diagnose specific tolerance criteria and an evaluation procedure. METHODS: The EGSnrc code package formed the basis for development of the MC system. The workflow consists of a number of modules connected to a TPS by means of manual DICOM exports and imports which were executed sequentially without user interaction. DVH comparison was performed in the TPS. In addition, MC- and TPS dose distributions were analysed by applying the normalized dose difference (NDD) formalism. NDD failure maps and a pass rate for a certain threshold were obtained. 170 clinical plans (prostate, thorax, head-and-neck and gynecological) were selected for analysis. RESULTS: Agreement within 1.5% was found between clinical- and MC data for the mean dose to the target volumes and within 3% for parameters more sensitive to the shape of the DVH e.g. D98% PTV. Regarding the NDD analysis, tolerance criteria 2%/3 mm were established for prostate plans and 3%/3 mm for the rest of the cases. CONCLUSIONS: An automated MC system was developed and implemented. Evaluation procedure is recommended with NDD-analysis as a first step. For pass rate < 95%, the evaluation continues with comparison of DVH parameters. For deviations larger than 2%, a visual inspection of the clinical- and MC dose distributions is performed.

Impaired intention-to-treat survival after listing for liver transplantation in children with biliary atresia compared to other chronic liver diseases: 20 years' experience from the Nordic countries.

Biliary atresia (BA) is the most common indication for LT in children. We investigated whether this diagnosis per se, compared to other chronic liver diseases (OCLD), had an influence on patient survival. Data from 421 Scandinavian children, 194 with BA and 227 with OCLD, listed for LT between 1990 and 2010 were analyzed. The intention-to-treat survival and influencing risk factors were studied. Patients with BA had higher risk of death after listing than patients with OCLD. The youngest (<1 year) and smallest (<10 kg) children with the highest bilirubin (>510 µmol/L), highest INR (>1.6), and highest PELD score (>20) listed during 1990s had the worst outcome. Given the same PELD score, patients with BA had higher risk of death than patients with OCLD. For adolescents, low weight/BMI was the only prognostic marker. Impaired intention-to-treat survival in patients with BA was mainly explained by more advanced liver disease in younger ages and higher proportion of young children in the BA group rather than diagnosis per se. PELD score predicted death, but seemed to underestimate the severity of liver disease in patients with BA. Poor nutritional status and severe cholestasis had negative impact on survival, supporting the "sickest children first" allocation policy and correction of malnutrition before surgery.

Monte Carlo optimization of total body irradiation in a phantom and patient geometry.

The objective of this work is to apply a Monte Carlo (MC) accelerator model, validated by experimental data at isocentre distances, to a large-field total body irradiation (TBI) technique and to develop a strategy for individual patient treatment on the basis of MC dose distributions. Calculations are carried out using BEAMnrc/DOSXYZnrc code packages for a 15 MV Varian accelerator. Acceptable agreement is obtained between MC data and measurements in a large water phantom behind a spoiler at source-skin distances (SSD) = 460 cm as well as in a CIRS® thorax phantom. Dose distributions in patients are studied when simulating bilateral beam delivery at a distance of 480 cm to the patient central sagittal plane. A procedure for individual improvement of the dose uniformity is suggested including the design of compensators in a conventional treatment planning system (TPS) and a subsequent update of the dose distribution. It is demonstrated that the dose uniformity for the simple TBI technique can be considerably improved. The optimization strategy developed is straightforward and suitable for clinics where the TPS available is deficient to calculate 3D dose distributions at extended SSD.

Elemental versus polymeric enteral nutrition in paediatric Crohn's disease: a multicentre randomized controlled trial.

AIM: To compare the efficacy and safety of an elemental and a polymeric diet as the primary therapy for active Crohn's disease in children. METHODS: In a randomized, non-blind, multicentre, controlled trial in Sweden, 16 children with Crohn's disease received Elemental 028 Extra (E028E) and 17 Nutrison Standard (NuS). Remission rates (Paediatric Crohn's Disease Activity Index (PCDAI) < 10 or a PCDAI decrease of 40% or 15 points of initial level) were compared at 6 wk. RESULTS: There was no significant difference between the two groups in remission rate at 6 wk (intent-to-treat analysis): E028E 11/16 (69%) and NuS 14/17 (82%) (p = 0.438). There was no difference in the decrease in PCDAI and CDAI between patients treated with E028E and those treated with NuS from 0 to 6 wk. Patients treated with NuS gained significantly more weight than patients treated with E028E (+2.5 kg; 95% CI 0.9, 4.1; p = 0.004), this difference remained when adjusting for maximum caloric intake per kilogram bodyweight (+2.9 kg; 95% CI 1.4, 4.5; p = 0.001). Concomitant disease, complications and side effects were seen in 5/33 patients (pyelonephritis, pneumonia, intraabdominal abscess, perianal abscess and borborygmi). CONCLUSION: E028E and NuS did not differ in terms of remission rate. Patients treated with NuS gained more weight than patients with E028E. Polymeric diet may be superior to elemental diet in the treatment of paediatric Crohn's disease where the primary aim is to increase the patient's weight.

[Liver transplantation--from experiment to routine care. Experiences from the first 500 liver transplantations in Gothenburg]. / Levertransplantation--från experiment till rutinsjukvård. Erfarenheter från de första 500 levertransplantationerna i Göteborg.

During a fifteen-year period, 500 liver transplantations have been performed at Sahlgrenska University Hospital in Göteborg. The results have improved, and factors influencing outcome are discussed. A one-year survival rate over 90% and a 5-year survival rate close to 80% can now be expected for most indications. Long-term complications as well as special problems occurring in different groups of recipients are discussed. New indications for liver transplantation such as liver metastasis of endocrine tumors are described. This article also describes our experience of in situ splitting and living-related liver transplantation as well as other innovations such as cavoportal hemitransposition and multivisceral transplantation.

Anti-MUC-1 immunoliposomal doxorubicin in the treatment of murine models of metastatic breast cancer.

The fate of breast cancer patients is dependent upon elimination or control of metastases. We studied the effect of antibody-targeted liposomes containing entrapped doxorubicin (DXR) on development of tumours in two models of breast cancer, pseudometastatic and metastatic, in mice. The former used the mouse mammary carcinoma cell line GZHI, which expresses the human MUC-1 gene (L. Ding, E.N. Lalani, M. Reddish, R. Koganty, T. Wong, J. Samuel, M.B. Yacyshyn, A. Meikle, P.Y.S. Fung, J. Taylor-Papadimitriou, B.M. Longenecker, Cancer Immunol. Immunother. 36 (1993) 9--17). GZHI cells seed into the lungs of Balb/c mice following intravenous injection. The latter used the 4T1-MUC1 cell line, a MUC-1 transfectant of the mouse mammary carcinoma cell line 4T1, which metastasizes from a primary mammary fatpad (mfp) implant to the lungs (C.J. Aslakson, F.R. Miller, Cancer Res. 52 (1992) 1399--1405). B27.29, a monoclonal antibody against the MUC-1 antigen, was used to target sterically stabilized immunoliposomes (SIL[B27.29]) to tumour cells. In vitro, SIL[B27.29] showed high specific binding to both GZHI and 4T1-MUC1 cells. The IC(50) of DXR-loaded SIL[B27.29] was similar to that of free drug for GZHI cells. In the pseudometastatic model, mice treated with a single injection of 6 mg DXR/kg in DXR-SIL[B27.29] at 24 h after cell implantation had longer survival times than those injected with non-targeted liposomal drug. In the metastatic model, severe combined immune deficiency mice given weekly injectionsx3 of 2.5 mg DXR/kg encapsulated in either targeted or non-targeted liposomes were almost equally effective in slowing growth of the primary tumour and reducing development of lung tumours. Surgical removal of the primary tumour from mfp, followed by various chemotherapy regimens, was attempted, but removal of the primary tumour was generally incomplete; tumour regrowth occurred and metastases developed in the lungs in all treatment groups. DXR-SL reduced the occurrence of regrowth of the primary tumour, whereas neither targeted liposomal drug or free drug prevented regrowth. We conclude that monoclonal antibody-targeted liposomal DXR is effective in treating early lesions in both the pseudometastatic and metastatic models, but limitations to the access of the targeted liposomes to tumour cells in the primary tumour compromised their therapeutic efficacy in treating the more advanced lesions.

A low-level expression of human MUC1 mucin enhances lethality of murine tumor cells.

We report here the development of a mouse mammary adenocarcinoma cell line containing full-length human MUC1 cDNA that can be more lethal than the parental cell line. The metastatic murine mammary adenocarcinoma cell line 410.4 was transfected with cDNA coding for a 42-tandem-repeat version of human MUC1. Two cell lines were selected, one for stable, high expression in vitro of cell-surface MUC1 (GZHi) and one for stable, low expression in vitro of cell-surface MUC1 (GZLo). Following subcutaneous challenge of CB6F1 mice with various doses of tumor cells, GZHi tumors showed loss of MUC1 expression; negligible amounts of serum MUC1 mucin were detected and the mice survived longer than mice challenged with GZLo or wild-type (410.4) tumor cells. Mice challenged with GZLo tumor cells had shorter survival times than mice challenged with either GZHi or 410.4 tumor cells. GZLo-challenged mice that showed rapidly increasing serum MUC1 mucin levels several weeks prior to death had a shorter survival than mice without detectable rising MUC1 serum levels. Surprisingly, SCID-BEIGE mice challenged with GZLo cells also survived for a shorter time than those challenged with either GZHi or 410.4 cells. This suggests that MUC1 mucin may also enhance the aggressiveness of GZLo tumors by non-immune mechanisms.

MUC1 synthetic peptide inhibition of intercellular adhesion molecule-1 and MUC1 binding requires six tandem repeats.

We reported recently that breast cancer-associated MUC1 is a ligand for intercellular adhesion molecule-1 (ICAM-1; L. H. Regimbald et al., Cancer Res., 56: 4244-4249, 1996). We report here the results of a competitive indirect binding assay to detect the molecular requirements for binding between ICAM-1 and MUC1. The assay involved inhibition of the binding of recombinant human ICAM-1 to a murine breast adenocarcinoma cell line transfected with human MUC1. The addition of a library of human MUC1 synthetic peptides ranging from 9 to 24 amino acids (aa) showed minimal or no inhibition. However, a 120-aa peptide that corresponds to six tandem repeats of the human mucin MUC1 was as effective an inhibitor as purified tumor MUC1 and MUC1 epitope (PDTRPAP)-specific antibody (B27.29). We conclude that the number of MUC1 tandem repeats necessary for an ordered tertiary structure (D. Fontenot et al., Cancer Res., 53: 5386-5394, 1993) is also important for ICAM-1 recognition. These findings are similar to those described recently for MUC1 induction of T-cell anergy (B. Agrawal et al., Nat. Med., 4: 43-49, 1998). This suggests that the anergy induction by MUC1 may be due to ICAM-1 binding by MUC1.

Expression of MUC1 mucin on activated human T cells: implications for a role of MUC1 in normal immune regulation.

MUC1 mucin is expressed by normal and malignant epithelial cells and is thought to function through cell-cell interactions and transmembrane signal transduction events. Secreted cancer-associated MUC1 is immunosuppressive and inhibits human T-cell proliferation. We report here that newly synthesized MUC1 is expressed on the surface of mitogen-activated human T cells and is also found in soluble form in the supernatants from cultures of mitogen-activated human T cells. After removal of the mitogenic stimulus from the T-cell cultures, MUC1 expression is downregulated. The addition of anti-MUC1 monoclonal antibody to mitogen-activated cultures partially inhibits the T-cell proliferative response. These data suggest that MUC1 serves an immunodulatory function for human T lymphocytes.

Liposomal formulations of synthetic MUC1 peptides: effects of encapsulation versus surface display of peptides on immune responses.

Synthetic human MUC1 peptides are important candidates for therapeutic cancer vaccines. To explore whether a human MUC1 peptide BP25 (STAPPAHGVTSAPDTRPAPGSTAPP) can be rendered immunogenic by incorporation in liposomes, the effects of physical association of the peptide with liposomes on immune responses were investigated. Lipid conjugated and nonconjugated MUC1 peptides were incorporated in liposomes with a composition of distearoylphosphatidylcholine/cholesterol/dimyristoylphosphatidylglyc erol (3:1:0.25, molar ratio) containing monophosphoryl lipid A (1% w/w of the total lipids). Liposomes were characterized for peptide retention by HPLC and for surface peptide display of MUC1 epitopes by flow cytometry. C57BL/6 mice were immunized with lipopeptide alone, peptide mixed with peptide-free liposomes, and peptide associated with liposomes in entrapped or surface-exposed forms. T cell proliferative responses, cytokine patterns, and antibody isotypes were studied. Results showed that immune responses were profoundly influenced by the liposome formulations. Physically associated, either encapsulated or surface-exposed, peptide liposomes elicited strong antigen-specific T cell responses, but not lipopeptide alone or peptide mixed with peptide-free liposomes. Analysis of the cytokines secreted by the proliferating T cells showed a high level of IFN-gamma and undetectable levels of IL-4, indicating a T helper type 1 response. Thus, physical association of the peptide with liposomes was required for T cell proliferative responses, but the mode of association was not critical. On the other hand, the nature of the association significantly affected humoral immune responses. Only the surface-exposed peptide liposomes induced MUC1-specific antibodies. A domination of anti-MUC1 IgG2b over IgG1 (94 versus 6%) was observed. Our results support the hypothesis that different immune pathways are stimulated by different liposome formulations. This study demonstrated that a liposome delivery system could be tailored to induce either a preferential cellular or humoral immune response.

Immunogenicity and antitumor activity of a liposomal MUC1 peptide-based vaccine.

A human MUC1-transfected mouse mammary adenocarcinoma cell line (GZHI) was used to develop both subcutaneous and intravenous tumor models. A vaccine formulation comprised of a 24 mer (human MUC1) synthetic peptide encapsulated with monophosphoryl lipid A adjuvant (MPLA) in multilamellar liposomes was tested for immunogenicity and anti-tumor activity. A low dose of the human MUC1 peptide (5 microg) administered in liposomes provided excellent protection of mice in both tumor challenge models. The protective antitumor activity mediated by the liposome formulation correlated with anti-MUC1-specific T-cell proliferation, gamma-interferon (IFN-gamma) production and IgG2a anti-MUC1 antibodies, suggesting a type 1 (T1) T-cell response. In contrast, lack of protection in mice immunized with negative control vaccines correlated with IgG1 anti-MUCI antibody formation, low or no anti-MUC1 IgG2a and low antigen-specific T-cell proliferation, consistent with a type 2 (T2) T-cell response to the tumor.

Cancer-associated MUC1 mucin inhibits human T-cell proliferation, which is reversible by IL-2.

A number of adenocarcinomas abundantly express and secrete underglycosylated MUC1 mucin. Underglycosylation exposes tandem repeat peptide sequences on cancer-associated MUC1 mucin that are normally cryptic. High levels of MUC1 mucin are correlated with a poor prognosis and immunosuppression in adenocarcinoma patients. In this report we show that cancer-associated MUC1 mucin, affinity-purified from ascites fluids of cancer patients, and synthetic tandem repeats of MUC1 mucin core peptide can suppress human T-cell proliferative responses. This MUC1 mucin-induced suppression of T-cell responses can be reversed by the addition of exogenous IL-2 or anti-CD28 monoclonal antibody. These results are consistent with other studies showing that lymphocytes present in the vicinity of tumor cells are anergic and can be reactivated with exogenous interleukin-2. Overcoming MUC1 mucin-induced immunosuppression with IL-2 combined with active specific immunotherapy might be an effective immunotherapeutic strategy against human adenocarcinomas.

Rapid induction of primary human CD4+ and CD8+ T cell responses against cancer-associated MUC1 peptide epitopes.

Antigen-specific MHC class II- and class I-restricted helper and cytotoxic T cell responses are important anti-cancer immune responses. MUC1 mucin is a potentially important target for immunotherapy because of its high expression on most human adenocarcinomas. MUC1 peptide-specific type 1 T cell responses were generated in vitro using human peripheral blood lymphocytes (PBL), incubated with liposomes containing synthetic MUC1 lipopeptide antigen. Only two weekly stimulations with the liposomal MUC1 formulation led to the generation of potent anti-MUC1-specific T cell proliferation as well as class I-restricted cytotoxic responses. Thus the use of PBL pulsed with liposome-encapsulated antigen provides an effective approach of rapidly generating effective antigen-presenting cell (APC) function as well as antigen specific T cells in vitro. It may be feasible to use this technology for the rapid and effective generation of APC and/or T cells as cellular vaccines for adenocarcinomas.

The incidence of neurovascular complications following axillary brachial plexus block using a transarterial approach. A prospective study of 1,000 consecutive patients.

BACKGROUND AND OBJECTIVES: The present study was performed at the Crystal Clinic Surgery Center, an outpatient free-standing surgicenter specializing in orthopedic surgery, to determine the incidence of both neurologic and vascular sequelae associated with exclusive use of a transarterial approach to axillary brachial plexus block in order to assess the technique's safety and efficacy. METHODS: The prospective consecutive study involved 1,000 adult patients scheduled for surgery using axillary brachial plexus block. The transarterial approach was performed on all patients using a medium-bevel 24-gauge Jelco 1-5-inch needle. Data tabulated included the incidence of neurovascular complications and the outcome of successful axillary brachial plexus anesthesia. RESULTS: Two patients presented with a sensory paresthesia (0.2%) in the distribution of the ulnar nerve and the musculocutaneous nerve that most likely occurred during supplementation of an incomplete block. Three patients presented with upper-arm myalgias (0.3%) related to tourniquet injury. After the operation, two patients developed reflex sympathetic dystrophy, which responded to stellate ganglion blocks. Vascular complications, including transient arterial spasm in 10 of 996 (1%), unintentional intravascular injection in 2 of 996 (0.2%), and small (0-2 cm) hematoma formation in 2 of 996 (0.2%), were recognized but did not require any intervention other than close observation. The study revealed a complete block in 88.8% of cases, an incomplete block requiring supplemental local anesthesia in 10% of cases, and a complete block failure in 1.2%. CONCLUSIONS: This study demonstrated the safety and efficacy of the transarterial technique in achieving brachial plexus block.

Does pregnancy immunize against breast cancer?

Multiparity has been linked with protection against breast cancer. T cells from biparous women, but not T cells from nulliparous women or men, specifically proliferated in response to core peptide sequences of a human breast cancer-associated mucin (MUC-1). Two of the nulliparous women were retested during the first trimester of their first pregnancy, and their T cells proliferated specifically in response to MUC-1 mucin. These observations support the hypothesis that there is a natural immunization against MUC-1 peptide epitopes during pregnancy which provides some protection against the development of breast cancer. These data also suggest that certain MUC-1 synthetic peptides might be effective components of "vaccines" for therapy or prevention of breast cancer.

Uvular necrosis following endotracheal intubation.

Uvular necrosis as a potential source of infection is a poorly detected complication that should be considered as part of the differential diagnosis of postoperative sore throat. We report a unique case of uvular necrosis following endotracheal intubation. The patient complained of a severe sore throat and foreign body sensation 48 hours following surgery.