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Background: A textbook outcome (TO) is a composite indicator covering the entire intervention process in order to reflect the "ideal" intervention and be a surrogate for patient important outcomes. Selective internal radiation therapy (SIRT) is a complex multidisciplinary and multistep intervention facing the challenge of standardization. This expert opinion-based study aimed to define a TO for SIRT of hepatocellular carcinoma., Methods: This study involved two steps: (1) the steering committee (4 interventional radiologists) first developed an extensive list of possible relevant items reflecting an optimal SIRT intervention based on a literature review and (2) then conducted an international and multidisciplinary survey which resulted in the final TO. This survey was online, from February to July 2021, and consisted three consecutive rounds with predefined settings. Experts were identified by contacting senior authors of randomized trials, large observational studies, or studies on quality improvement in SIRT. This study was strictly academic., Results: A total of 50 items were included in the first round of the survey. A total of 29/40 experts (73%) responded, including 23 interventional radiologists (79%), three nuclear medicine physicians (10%), two hepatologists, and one oncologist, from 11 countries spanning three continents. The final TO consisted 11 parameters across six domains ("pre-intervention workup," "tumor targeting and dosimetry," "intervention," "post- 90 Y imaging," "length of hospital stay," and "complications"). Of these, all but one were applied in the institutions of > 80% of experts., Conclusions: This multidimensional indicator is a comprehensive standardization tool, suitable for routine care, clinical round, and research., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The goal of tissue decellularization is to efficiently remove unwanted cellular components, such as DNA and cellular debris, while retaining the complex structural and molecular milieu within the extracellular matrix (ECM). Decellularization protocols to date are centered on customized tissue-specific and lab-specific protocols that involve consecutive manual steps which results in variable and protocol-specific ECM material. The differences that result from the inconsistent protocols between decellularized ECMs affect consistency across batches, limit comparisons between results obtained from different laboratories, and could limit the transferability of the material for consistent laboratory or clinical use. The present study is the first proof-of-concept towards the development of a standardized protocol that can be used to derive multiple ECM biomaterials (powders and hydrogels) via a previously established automated system. The automated decellularization method developed by our group was used due to its short decellularization time (4 hours) and its ability to reduce batch-to-batch variability. The ECM obtained using this first iteration of a unified protocol was able to produce ECM hydrogels from skin, lung, muscle, tendons, cartilage, and laryngeal tissues. All hydrogels formed in this study were cytocompatible and showed gelation and rheological properties consistent with previous ECM hydrogels. The ECMs also showed unique proteomic composition. The present study represents the first step towards developing standardized protocols that can be used on multiple tissues in a fast, scalable, and reproducible manner.

Background & Aims: Policy changes in the United States have lengthened overall waiting times for patients with hepatocellular carcinoma (HCC). We investigated temporal trends in utilization of locoregional therapy (LRT) and associated waitlist outcomes among liver transplant (LT) candidates in the United States., Methods: Data for primary adult LT candidates listed from 2003 to 2018 who received HCC exception were extracted from the Organ Procurement and Transplantation Network database. Explant histology was examined, and multivariable competing risk analysis was used to evaluate the association between LRT type and waitlist dropout., Results: There were 31,609 eligible patients with at least 1 approved HCC exception, and 34,610 treatments among 24,145 LT candidates. The proportion with at least 1 LRT recorded increased from 42.3% in 2003 to 92.4% in 2018. Chemoembolization remains the most frequent type, followed by thermal ablation, with a notable increase in radioembolization from 3% in 2013 to 19% in 2018. An increased incidence of LRT was observed among patients with tumor burden beyond Milan criteria, higher α-fetoprotein level, and more compensated liver disease. Receipt of any type of LRT was associated with a lower risk of waitlist dropout; there was no significant difference by number of LRTs. In inverse probability of treatment weighting-adjusted analysis, radioembolization or ablation as the first LRT was associated with a reduced risk of waitlist dropout compared with chemoembolization., Conclusions: In a large nationwide cohort of LT candidates with HCC, LRT, and in particular radioembolization, increasingly was used to bridge to LT. Patients with greater tumor burden and those with more compensated liver disease received more treatments while awaiting LT. Bridging LRT was associated with a lower risk of waitlist dropout., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The cellular composition of barrier epithelia is essential to organismal homoeostasis. In particular, within the small intestine, adult stem cells establish tissue cellularity, and may provide a means to control the abundance and quality of specialized epithelial cells. Yet, methods for the identification of biological targets regulating epithelial composition and function, and of small molecules modulating them, are lacking. Here we show that druggable biological targets and small-molecule regulators of intestinal stem cell differentiation can be identified via multiplexed phenotypic screening using thousands of miniaturized organoid models of intestinal stem cell differentiation into Paneth cells, and validated via longitudinal single-cell RNA-sequencing. We found that inhibitors of the nuclear exporter Exportin 1 modulate the fate of intestinal stem cells, independently of known differentiation cues, significantly increasing the abundance of Paneth cells in the organoids and in wild-type mice. Physiological organoid models of the differentiation of intestinal stem cells could find broader utility for the screening of biological targets and small molecules that can modulate the composition and function of other barrier epithelia., (© 2022. The Author(s).)

It is estimated that almost one-third of the United States population will be affected by a vocal fold (VF) disorder during their lifespan. Promising therapies to treat VF injury and scarring are mostly centered on VF tissue engineering strategies such as the injection of engineered biomaterials and cell therapy. VF tissue engineering, however, is a challenging field as the biomechanical properties, structure, and composition of the VF tissue change upon exposure to mechanical stimulation. As a result, the development of long-term VF treatment strategies relies on the characterization of engineered tissues under a controlled mechanical environment. In this review, we highlight the importance of bioreactors as a powerful tool for VF tissue engineering with a focus on the current state of the art of bioreactors designed to mimic phonation in vitro. We discuss the influence of the phonatory environment on the development, function, injury, and healing of the VF tissue and its importance for the development of efficient therapeutic strategies. A concise and comprehensive overview of bioreactor designs, principles, operating parameters, and scalability are presented. An in-depth analysis of VF bioreactor data to date reveals that mechanical stimulation significantly influences cell viability and the expression of proinflammatory and profibrotic genes in vitro . Although the precision and accuracy of bioreactors contribute to generating reliable results, diverse gene expression profiles across the literature suggest that future efforts should focus on the standardization of bioreactor parameters to enable direct comparisons between studies. Impact statement We present a comprehensive review of bioreactors for vocal fold (VF) tissue engineering with a focus on the influence of the phonatory environment on the development, function, injury, and healing of the VFs and the importance of mimicking phonation on engineered VF tissues in vitro . Furthermore, we put forward a strong argument for the continued development of bioreactors in this area with an emphasis on the standardization of bioreactor designs, principles, operating parameters, and oscillatory regimes to enable comparisons between studies.

There is currently no consensus regarding preferred clinical outcome measures following image-guided tumor ablation or clear definitions of oncologic end points. This consensus document proposes standardized definitions for a broad range of oncologic outcome measures with recommendations on how to uniformly document, analyze, and report outcomes. The initiative was coordinated by the Society of Interventional Oncology in collaboration with the Definition for the Assessment of Time-to-Event End Points in Cancer Trials, or DATECAN, group. According to predefined criteria, based on experience with clinical trials, an international panel of 62 experts convened. Recommendations were developed using the validated three-step modified Delphi consensus method. Consensus was reached on when to assess outcomes per patient, per session, or per tumor; on starting and ending time and survival time definitions; and on time-to-event end points. Although no consensus was reached on the preferred classification system to report complications, quality of life, and health economics issues, the panel did agree on using the most recent version of a validated patient-reported outcome questionnaire. This article provides a framework of key opinion leader recommendations with the intent to facilitate a clear interpretation of results and standardize worldwide communication. Widespread adoption will improve reproducibility, allow for accurate comparisons, and avoid misinterpretations in the field of interventional oncology research. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Liddell in this issue.

Surgical meshes are commonly used to repair defects and support soft tissues. Macrophages (Mφs) are critical cells in the wound healing process and are involved in the host response upon foreign biomaterials. There are various commercially available permanent and absorbable meshes used by surgeons for surgical interventions. Polypropylene (PP) meshes represent a permanent biomaterial that can elicit both inflammatory and anti-inflammatory responses. In contrast, poly-4-hydroxybutyrate (P4HB) based meshes are absorbable and linked to positive clinical outcomes but have a poorly characterized immune response. This study evaluated the in vitro targeted transcriptomic response of human Mφs seeded for 48 h on PP and P4HB surgical meshes. The in vitro measured response from human Mφs cultured on P4HB exhibited inflammatory and anti-inflammatory gene expression profiles typically associated with wound healing, which aligns with in vivo animal studies from literature. The work herein provides in vitro evidence for the early transcriptomic targeted signature of human Mφs upon two commonly used surgical meshes. The findings suggest a transition from an inflammatory to a non-inflammatory phenotype by P4HB as well as an upregulation of genes annotated under the pathogen response pathway.

Decellularized extracellular matrix (ECM) scaffolds derived from tissues and organs are complex biomaterials used in clinical and research applications. A number of decellularization protocols have been described for ECM biomaterials derivation, each adapted to a particular tissue and use, restricting comparisons among materials. One of the major sources of variability in ECM products comes from the tissue source and animal age. Although this variability could be minimized using established tissue sources, other sources arise from the decellularization process itself. Overall, current protocols require manual work and are poorly standardized with regard to the choice of reagents, the order by which they are added, and exposure times. The combination of these factors adds variability affecting the uniformity of the final product between batches. Furthermore, each protocol needs to be optimized for each tissue and tissue source making tissue-to-tissue comparisons difficult. Automation and standardization of ECM scaffold development constitute a significant improvement to current biomanufacturing techniques but remains poorly explored. This study aimed to develop a biofabrication method for fast and automated derivation of raw material for ECM hydrogel production while preserving ECM composition and controlling lot-to-lot variability. The main result was a closed semibatch bioreactor system with automated dosing of decellularization reagents capable of deriving ECM material from pretreated soft tissues. The ECM was further processed into hydrogels to demonstrate gelation and cytocompatibility. This work presents a versatile, scalable, and automated platform for the rapid production of ECM scaffolds.

Background: This study undertook to assess usability, 24-h glycemic profiles, and safety of an investigational basal/bolus insulin delivery device (IDD) providing rapid-acting or regular human insulin (RHI) for people with type 2 diabetes (T2D) transitioning from multiple daily insulin injections (MDIs). Methods: This prospective, single-center, open-label two-period study enrolled adults with T2D and glycated hemoglobin (HbA1c) 7%-11% (53-97 mmol/M). Participants continued the usual MDI therapy during a 2- to 3-day in-clinic MDI period and then within 7 days were switched to the IDD, using current insulin dose, for a 6-day in-clinic IDD period, with blinded continuous glucose monitoring throughout the in-clinic periods. Results: We enrolled 21 participants (mean ± standard deviation age 57 ± 8 years; HbA1c 8.2% ± 0.9% [66 ± 9.8 mmol/M]) using U-100 insulin lispro ( n  = 11) or who switched to U-100 RHI ( n  = 10). Glycemic measures improved from the MDI to IDD period, including fasting blood glucose (BG), 141.2 ± 38.3 mg/dL (7.8 ± 2.1 mmol/L) versus 121.2 ± 35.0 mg/dL (6.7 ± 1.9 mmol/L; P  = 0.002), respectively; 24-h mean BG, 137.0 ± 20.5 mg/dL (7.6 ± 1.1 mmol/L) versus 125.0 ± 16.5 mg/dL (6.9 ± 0.9 mmol/L; P  = 0.004); and time in range (at 70-180 mg/dL; 3.9-10 mmol/L), 81.0% ± 14.4% versus 87.5% ± 10.6% ( P  = 0.008). No significant differences between MDIs and IDD use were recorded for time <70 mg/dL (1.6% ± 2.7% vs. 3.1% ± 2.7%, P  = 0.08), CV%, or mean of daily differences. Mean amplitude of glycemic excursions was significantly lower with the IDD ( P  = 0.011). There were no significant differences between insulin lispro and RHI for any glycemic measure. No serious adverse events were recorded. Conclusions: In the context of this exploratory study, the IDD was safe and effective to administer insulin lispro and RHI for adults with T2D.

Purpose: Peptide receptor radionuclide therapy (PRRT) and radioembolization are increasingly used in neuroendocrine neoplasms patients. However, concerns have been raised on cumulative hepatotoxicity. The aim of this sub-analysis was to investigate hepatotoxicity of yttrium-90 resin microspheres radioembolization in patients who were previously treated with PRRT., Methods: Patients treated with radioembolization after systemic radionuclide treatment were retrospectively analysed. Imaging response according to response evaluation criteria in solid tumours (RECIST) v1.1 and clinical response after 3 months were collected. Clinical, biochemical and haematological toxicities according to common terminology criteria for adverse events (CTCAE) v4.03 were also collected. Specifics on prior PRRT, subsequent radioembolization treatments, treatments after radioembolization and overall survival (OS) were collected., Results: Forty-four patients were included, who underwent a total of 58 radioembolization procedures, of which 55% whole liver treatments, at a median of 353 days after prior PRRT. According to RECIST 1.1, an objective response rate of 16% and disease control rate of 91% were found after 3 months. Clinical response was seen in 65% (15/23) of symptomatic patients after 3 months. Within 3 months, clinical toxicities occurred in 26%. Biochemical and haematological toxicities CTCAE grade 3-4 occurred in ≤ 10%, apart from lymphocytopenia (42%). Radioembolization-related complications occurred in 5% and fatal radioembolization-induced liver disease in 2% (one patient). A median OS of 3.5 years [95% confidence interval 1.8-5.1 years] after radioembolization for the entire study population was found., Conclusion: Radioembolization after systemic radionuclide treatments is safe, and the occurrence of radioembolization-induced liver disease is rare., Level of Evidence: 4, case series.

An online survey was conducted to assess the perspectives and use of diabetes technologies by a sample of U.S. primary care physicians (PCPs) and endocrinologists to optimize intensive insulin therapy in patients with type 2 diabetes. Overall, endocrinologists reported using diabetes technologies more frequently than PCPs for patients with type 2 diabetes requiring basal-bolus insulin therapy. PCPs and endocrinologists who were highly focused on diabetes management with insulin therapy reported using insulin delivery devices (insulin pumps and wearable tube-free patches) when patients are not achieving their A1C target while taking basal plus three or more prandial injections of insulin daily., (© 2019 by the American Diabetes Association.)

This article reports on a survey conducted at four diabetes-related annual conferences in 2017 and 2018 to obtain input from the medical community regarding the most important features of insulin delivery devices to address the unmet needs of people with type 2 diabetes who require basal/bolus insulin therapy. The overall patterns of responses compiled from 742 participating health care providers, each voting for three of eight proposed features of insulin delivery devices, were mostly similar numerically at each conference. The features garnering the top three percentages of votes ( n = 2,226) averaged for all four conferences were tube-free patch (14.7%), reduced number of insulin injections (14.7%), and dose capture report (14.2%). Four other features received almost as many votes: flexible dosing (14.0%), patient lifestyle app (13.3%), wireless controller (12.7%), and interconnected glucose monitoring (12.6%). This survey provided valuable information that can aid the development of future insulin delivery devices., (© 2019 by the American Diabetes Association.)

The TheraSphere Global Dosimetry Steering Committee was formed in 2017 by BTG International to review existing data and address gaps in knowledge related to dosimetry. This committee is comprised of health care providers with diverse areas of expertise and perspectives on radiation dosimetry. The goal of these recommendations is to optimize glass microspheres radiation therapy for hepatocellular carcinoma while accounting for variables including disease presentation, tumour vascularity, liver function, and curative/palliative intent. The recommendations aim to unify glass microsphere users behind standardized dosimetry methodology that is simple, reproducible and supported by clinical data, with the overarching goal of improving clinical outcomes and advancing the knowledge of dosimetry.

IN BRIEF The number of medications used to treat diabetes has increased dramatically in the past 15 years. With so many options that have shown significant A1C improvement, it is important to consider side effects, precautions, and additional benefits these agents may offer. This article is a review of some of the most compelling literature available on the nonglycemic benefits of sulfonylureas, thiazolidinediones, biguanides, glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase 4 inhibitors, and sodium-glucose cotransporter 2 inhibitors. Other classes of antihyperglycemic agents, such as dopamine agonists, meglitinides, and amylin agonists, are not discussed in this article.

Purpose: Radioembolization of liver metastases of neuroendocrine neoplasms (NEN) has shown promising results; however, the current literature is of limited quality. A large international, multicentre retrospective study was designed to address several shortcomings of the current literature., Materials: 244 NEN patients with different NEN grades were included., Methods: Primary outcome parameters were radiologic response 3 and 6 months after treatment according to RECIST 1.1 and mRECIST. Secondary outcome parameters included clinical response, clinical and biochemical toxicities., Results: Radioembolization resulted in CR in 2%, PR in 14%, SD in 75% and PD 9% according to RECIST 1.1 and in CR in 8%, PR in 35%, SD in 48% and PD in 9% according to mRECIST. Objective response rates improved over time in 20% and 26% according to RECIST 1.1. and mRECIST, respectively. Most common new grade 3-4 biochemical toxicity was lymphocytopenia (6.7%). No unexpected clinical toxicities occurred. Radioembolization-specific complications occurred in < 4%. In symptomatic patients, improvement and resolution of symptoms occurred in 44% and 34%, respectively. Median overall survival from first radioembolization was 3.7, 2.7 and 0.7 years for G1, G2 and G3, respectively. Objective response is independent of NEN grade or primary tumour origin. Significant prognostic factors for survival were NEN grade/Ki67 index, ≥ 75% intrahepatic tumour load, the presence of extrahepatic disease and disease control rate according to RECIST 1.1., Conclusion: Safety and efficacy of radioembolization in NEN patients was confirmed with a high disease control rate of 91% in progressive patients and alleviation of NEN-related symptoms in 79% of symptomatic patients., Level of Evidence: 4.

Background: Patients with heart failure (HF) have a high incidence of hospital readmissions. However risk models that explore predictors of a single readmission may be less useful at identifying the patients with frequent readmissions who contribute to a disproportionately large proportion of morbidity and health care costs., Methods: A total of 6252 patients enrolled in the Management of Cardiac Failure Program (MACARF) in Northern Sydney Area Hospitals between 1998 and 2015 were randomly divided into derivation and validation cohorts to create and test a risk model for predictors of ≥2 readmissions or death within 1year of initial hospitalisation for HF., Results: Multivariate predictors of frequent (≥2) readmissions or death were a history of ischaemic heart disease and chronic kidney disease, being unmarried, having anaemia, low serum albumin, elevated creatinine, prolonged hospital stay (>7 days), and not receiving beta blockers on discharge. Event rates increased with a higher risk score (p<0.001) and the prediction was similar in the validation and derivation cohorts (p=0.588). The C-statistic was 0.65., Conclusions: Our risk score may assist in focussing health care resources and interventions by identifying the subset of HF patients at increased risk for a disproportionately high burden of disease., (Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: The World Health Organization (WHO) reported that colorectal cancer (CRC) was the third most common cancer in men and the second in women, worldwide. Our previous meta-analysis found Sophora flavescens increased tumour response rate in randomised controlled trials of CRC. We hypothesised that its principal constituent matrine had exerted anti-tumour effects., Purpose: To elucidate its mechanisms of action we investigated the dose-related anti-tumour effects of matrine on four human CRC cell-lines: LS174T, Caco-2, SW1116 and RKO. In a LS174T xenografted tumour model in nude mice we assessed the effects of matrine and oxaliplatin on tumour volume, weight and morphology. Computer simulated dockings for target proteins were also conducted., Methods and Design: Cell viability, cell cycle and apoptosis were measured by Cell Counting Kit-8 and flow cytometry, and Annexin V-FITC/PI double staining assay respectively. Western blot was performed to examine the expression of Bax, Bcl-2 and caspase-3 in the cells. The xenograft model and immunohistochemistry were used to investigate the effect of matrine in vivo. Oxaliplatin was set as positive control. Molecular docking was performed to predict the binding modes of matrine and oxaliplatin with target proteins using CDOCKER algorithm., Results: Matrine inhibited proliferation of cancer cells in a dose- and time-dependent manner. Matrine induced cell-cycle arrest at G1/G0 phase, induced apoptosis and reduced expression of Bcl-2 and caspase-3 while up-regulating Bax and cleaved caspase-3 in the four CRC cells. In vivo, matrine significantly inhibited tumour growth without side effects on physical health compared to the negative (vehicle) control group. Mice in the oxaliplatin group lost vigour, became frail and lost weight. Expression of Bcl-2 in tumour tissue was lower and Bax expression was higher in the matrine-treated groups compared to the negative control. In computer-simulated docking, matrine successfully docked into active sites of Bcl-2 and caspase-3., Conclusion: Matrine inhibited growth of colorectal cancer cells in vitro and in vivo. A molecular mechanism was apoptosis induction via effects on Bcl-2, Bax and caspase-3. Moreover, matrine showed minimum side effects and may provide a candidate for the development of new therapies for colorectal cancer., (Copyright © 2018. Published by Elsevier GmbH.)

Background: Recent quality control of complex mixtures, including herbal medicines, is not limited to chemical chromatographic definition of one or two selected compounds; multivariate linear regression methods with dimension reduction or regularisation have been used to predict the bioactivity capacity from the chromatographic fingerprints of the herbal extracts. The challenge of this type of analysis requires a multi-dimensional approach at two levels: firstly each herb comprises complex mixtures of active and non-active chemical components; and secondly there are many factors relating to the growth, production, and processing of the herbal products. All these factors result in the significantly diverse concentrations of bioactive compounds in the herbal products. Therefore, it is imminent to have a predictive model with better generalisation that can accurately predict the bioactivity capacity of samples when only the chemical fingerprints data are available., Results: In this study, the algorithm of Stacking Multivariate Linear Regression (SMLR) and a few other commonly used chemometric approaches were evaluated. They were to predict the Cluster of Differentiation 80 (CD80) expression bioactivity of a commonly used herb, Astragali Radix (AR), from the corresponding chemical chromatographic fingerprints. SMLR provides a superior prediction accuracy in comparison with the other multivariate linear regression methods of PCR, PLSR, OPLS and EN in terms of MSEtest and the goodness of prediction of test samples., Conclusions: SMLR is a better platform than some multivariate linear regression methods. The first advantage of SMLR is that it has better generalisation to predict the bioactivity capacity of herbal medicines from their chromatographic fingerprints. Future studies should aim to further improve the SMLR algorithm. The second advantage of SMLR is that single chemical compounds can be effectively identified as highly bioactive components which demands further CD80 bioactivity confirmation..

Vena cava superior syndrome is a serious complication after heart transplantation, leading to low cardiac output, cerebral edema, and multi-organ dysfunction. We report three adult patients who underwent heart and heart-lung transplantation and required immediate postoperative balloon angioplasty and stent placement by interventional radiology. The observed obstructions were located at sites of intraoperatively removed pacemaker or defibrillator wires. Percutaneous stent placement immediately improved the hemodynamic condition of the patients. Early recognition of the complication and availability of immediate intervention are essential to prevent further deterioration., (© 2014 Wiley Periodicals, Inc.)

Reprogramming of NK cells with a chimeric antigen receptor (CAR) proved an effective strategy to increase NK cell reactivity and recognition specificity toward tumor cells. To enhance the cytotoxicity of NK cells against CD138-positive multiple myeloma (MM) cells, we generated genetically modified NK-92MI cells carrying a CAR that consists of an anti-CD138 single-chain variable fragment (scFv) fused to the CD3ζ chain as a signaling moiety. The genetic modification through a lentiviral vector did not affect the intrinsic cytolytic activity of NK-92MI toward human erythroleukemic cell line K562 cells or CD138-negative targets. However, these retargeted NK-92MI (NK-92MI-scFv) displayed markedly enhanced cytotoxicity against CD138-positive human MM cell lines (RPMI8226, U266 and NCI-H929) and primary MM cells at various effector-to-target ratios (E:T) as compared to the empty vector-transfected NK-92MI (NK-92MI-mock). In line with the enhanced cytotoxicity of NK-92MI-scFv, significant elevations in the secretion of granzyme B, interferon-γ and proportion of CD107a expression were also found in NK-92MI-scFv in response to CD138-positive targets compared with NK-92MI-mock. Most importantly, the enhancement in the cytotoxicity of NK-92MI-scFv did not attenuate with 10Gy-irradiation that sufficiently blocked cell proliferation. Moreover, the irradiated NK-92MI-scFv exerted definitely intensified anti-tumor activity toward CD138-positive MM cells than NK-92MI-mock in the xenograft NOD-SCID mouse model. This study provides the rationale and feasibility for adoptive immunotherapy with CD138-specific CAR-modified NK cells in CD138-positive plasmacytic malignancies, which potentially further improves remission quality and prolongs the remission duration of patients with MM after upfront chemotherapy., (Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

The aim of this article is to examine processes occurring within problem-based learning (PBL) courses (inside the black box) by contrasting these processes with outcome-based studies (from outside the black box). We review meta-analyses of input-output studies of PBL in comparison with traditional approaches and provide a summary of qualitative, phenomenographic and factor analytic analyses of student experiences when studying health sciences (dentistry and medicine) using PBL curricula. Results from meta-analyses showed PBL courses were preferred for the long-term retention of course content, short-term retention involving elaboration of new information and the application of clinical skills and reasoning. Traditional approaches were favoured for short-term retention of course content that did not require any elaboration. The qualitative studies reveal a diversity of student views about the concept of PBL pedagogy and approaches to learning in PBL curricula. They show that the ways in which students approach their studies in PBL in health sciences are closely related to how they conceive of PBL and that these dimensions are closely related to how the goals and standards of PBL courses are perceived.

Favorable outcomes after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) are well described for patients who fall within defined tumor criteria. The effectiveness of tumor therapies to maintain tumor characteristics within these criteria or to downstage more advanced tumors to fall within these criteria is not well understood. The aim of this study was to examine the response to transcatheter arterial chemoinfusion (TACI) in HCC patients awaiting LT and its efficacy for downstaging or bridging to transplantation. We performed a retrospective study of 248 consecutive TACI cases in 122 HCC patients at a single U.S. medical center. Patients were divided into two groups: those who met the Milan criteria on initial HCC diagnosis (n = 95) and those with more advanced disease (n = 27). With TACI treatment, 87% of the Milan criteria group remained within the Milan criteria and 63% of patients with more advanced disease were successfully downstaged to fall within the Milan criteria. In conclusion, TACI appears to be an effective treatment as a bridge to LT for nearly 90% patients presenting within the Milan criteria and an effective downstaging modality for over half of those whose tumor burden was initially beyond the Milan criteria.

Objective: This study assessed midterm results of emergency endovascular stent-grafting for patients with life-threatening complications of acute type B aortic dissection., Methods: Between November 1996 and June 2004, 16 patients with complicated acute type B aortic dissections (mean age 57 years, range 16-88 years) underwent endovascular stent-grafting within 48 hours of presentation. Complications included contained rupture, hemothorax, refractory chest pain, and severe visceral or lower limb ischemia. Stent-graft types included custom-made first-generation endografts and second-generation commercial stent-grafts (Gore Excluder or TAG; W. L. Gore & Associates, Inc, Flagstaff, Ariz.). Follow-up was 100% complete, averaged 36 +/- 36 months, and included postprocedural surveillance computed tomographic scans., Results: Early mortality was 25% +/- 11% (70% confidence limit), with no late deaths. No new neurologic complications occurred. According to the latest scan, 4 patients (25%) had complete thrombosis of the false lumen; the lumen was partially thrombosed in 6 patients (38%). Distal aortic diameter was increased in only 1 patient. Actuarial survival at 1 and 5 years was 73% +/- 11%; freedom from treatment failure (including aortic rupture, device fault, reintervention, aortic death, or sudden, unexplained late death) was 67% +/- 14% at 5 years., Conclusion: With follow-up to 9 years, endovascular stent-grafting for patients with complicated acute type B aortic dissection conferred benefit. Consideration of emergency stent-grafting may improve the dismal outlook for these patients; future refinements in stent-graft design and technology and earlier diagnosis and intervention should be associated with improved results.

Oral anticancer drug treatment represents a significant change to current oncology practice. Support for oral anticancer treatment is driven by issues of pharmacoeconomics, accommodating the need for protracted drug administration for many emerging cytostatic therapies, response to patient preference and in improving patient quality of life. Much focus has concentrated on defining the cellular mechanisms underlying the pharmacokinetic limitations associated with the oral route of administration. However, the potential effects of oral anticancer drugs on gut associated host mediated immunity have been overlooked. Given that the immune system is central for tumour rejection, an assessment of the potential effects oral anticancer drugs may have at this level, and the impact of this on the treatment of gastrointestinal malignancy is of significant clinical importance. P-glycoprotein is a multidrug transporter that contributes to the reduced bioavailability of many orally administered medications. P-glycoprotein achieves this by virtue of its drug efflux capacity at the level of the gut epithelia. P-glycoprotein is also notorious for contributing to the multidrug resistance phenotype observed in many drug refractory human cancers. Likewise, this drug transporter serves a role in the cells of the immune system; particularly in dendritic cell maturation and function. This multifaceted involvement in drug disposition, cancer drug resistance and regulation of the immune response makes P-glycoprotein an attractive target for the optimization of oral anticancer drug treatment strategies. This review introduces and discusses for the first time the potential impact that oral anticancer drugs may have on P-glycoprotein expression and function and the potential consequences of this on dendritic cell function in relation to human cancer. This review also aims to foster a better understanding of the host mediated immunological mechanisms which may be potentially manipulated in cancer patients undergoing oral chemotherapy.

Current cancer chemotherapeutic drugs have limited efficacy due to the fact that tumour cells are a rapidly changing target characterised by genomic instability. Unlike tumour cells, activated endothelial cells (ECs) required for angiogenesis, a process indisputably crucial to tumour growth and metastasis, were originally considered to be ideal therapeutic targets free of drug resistance. Additionally, unlike preclinical studies in mice using inhibitors targeting the powerful EC mitogen--vascular endothelial growth factor (VEGF)--overall survival benefit with anti-VEGF therapy used as monotherapy has yet to be demonstrated in phase III clinical trials. In contrast, VEGF-specific antibodies combined with current chemotherapy have resulted in improved outcomes in certain previously untreated cancers. This has led some researchers to hypothesize that combined treatments targeting other angiogenic molecules besides VEGF, and/or targeting not only ECs but other angiogenic non-EC types, may offer alternative but effective therapeutic options for eradicating malignant tumours. A rational approach to effective anti-angiogenic combination therapy will, however, require further understanding of the molecular and cellular mechanisms which undergird tumour vascularisation. Recent studies involving judicious use of powerful new genetic approaches have provided unprecedented insights into how different molecular and cellular mechanisms cooperate to build, branch and mature the growing vessel network so pivotal to tumour growth and survival. This review covers our current understanding of how the various key players--the tumour cells, stromal cells, endothelial cells and pericytes, and bone-marrow-derived haematopoietic and putative endothelial progenitors interact via their cell-derived pro- or anti-angiogenic factors to regulate tumour angiogenesis.

Background: Transcatheter arterial chemoembolization (TACE) has become one of the most common treatments for unresectable hepatocellular carcinoma. Published studies of TACE report a 5-16% risk of serious complications. Compared with TACE, transcatheter arterial chemoinfusion (TACI) may have similar efficacy and fewer side effects., Aim: To examine the clinical outcomes of TACI., Methods: We performed a retrospective cohort study of 345 consecutive TACI cases in 165 patients performed at a single United States medical center between 1998 and 2002. Primary outcomes were tumour response and survival rates., Results: Only seven patients were hospitalized for more than 24 h after the procedure, and only three patients had worsening of liver function within 30 days of TACI. Survival was significantly poorer for patients with tumour-node-metastasis (TNM) IV compared to those with TNM I-III and also for patients with Child's class B/C vs. A. Following adjustment for age, gender, ethnicity and aetiology of liver diseases, independent predictors of poor survival were Child's class B/C [Hazard Ratio (HR) = 1.69, P = 0.024] and TNM IV staging (HR = 1.63, P = 0.014)., Conclusions: TACI appears to be safe and effective for unresectable hepatocellular carcinoma with TNM stage I-III; randomized controlled trials are needed to compare TACI to TACE.

We administered an adenoviral vector, Onyx-015, into the hepatic artery of patients with metastatic colorectal cancer involving the liver. Thirty-five patients enrolled in this multi-institutional phase I/II trial received up to eight arterial infusions of up to 2 x 10(12) viral particles. Hepatic toxicity was the primary dose-limiting toxicity observed in preclinical models. However, nearly 200 infusions of this adenoviral vector were administered directly into the hepatic artery without significant toxicity. Therefore, we undertook this analysis to determine the impact of repeated adenoviral exposure on hepatic function. Seventeen patients were treated at our institution, providing a detailed data set on the changes in hepatic function following repeated exposure to adenovirus. No changes in hepatic function occurred with the first treatment of Onyx-015 among these patients. Transient increases in transaminase levels occurred in one patient starting with the second infusion and transient increases in bilirubin was observed in two patients starting with the fifth treatment. These changes occurred too early to be explained by viral-mediated lysis of hepatocytes. In addition, viremia was observed starting 3-5 days after the viral infusion in half of the patient, but was not associated with hepatic toxicity. To further understand the basis for the minimal hepatic toxicity of adenoviral vectors, we evaluated the replication of adenovirus in primary hepatocytes and tumor cells in culture and the expression of the coxsackie-adenoviral receptor (CAR) in normal liver and colon cancer metastatic to the liver. We found that adenovirus replicates poorly in primary hepatocytes but replicates efficiently in tumors including tumors derived from hepatocytes. In addition, we found that CAR is localized at junctions between hepatocytes and is inaccessible to hepatic blood flow. CAR is not expressed on tumor vasculature but is expressed on tumor cells. Spatial restriction of CAR to the intercellular space in normal liver and diminished replication of adenovirus in hepatocytes may explain the minimal toxicity observed following repeated hepatic artery infusions with Onyx-015.

Effective learning in higher education is associated with students' perceptions of clear goals and standards of an educational program. In programs using problem-based learning (PBL), students' conceptions of what PBL is about could determine how well they perceive the clarity of goals and standards of their program. In this study the authors aim to investigate the relationship between the nature of first-year students' conceptions of PBL and their perceptions of the clarity of goals and standards of a graduate-entry, problem-based medical program. Results are that most students conceive of PBL as mainly working collaboratively to solve and understand a problem, and place less emphasis on PBL as learning independently. There is no relationship between students' conceptions and perceived clarity of course goals and standards. It is suggested that teachers not only need to help students develop their understanding of what PBL is about but also need to help students learn how to self-regulate their learning in PBL programs.

The objectives of this study included the following: obtaining qualitative information on tobacco use among Cambodian Americans, identifying cultural factors that influence tobacco use and acquiring information for the development of effective smoking prevention and cessation strategies. Data were collected by using demographic and behavioral questionnaires and focus group interviews. A total of 14 focus group interviews that covered cultural practices associated with smoking were administered. Statistical analyses included univariate frequency distributions and cross-tabulations. The subjects (n = 119) were Cambodian American volunteers who participated in social services programs offered by a community service organization. All subjects were 18 years of age or older and resided in the city of Long Beach. The principal outcomes measured were cigarette smoking and tobacco use. Other variables included reasons for smoking, traditional uses of tobacco, stress factors related to smoking and the perceived health effects of smoking. Predisposing, reinforcing and enabling factors associated with tobacco-use behaviors included peer group influences, smoking adopted as a coping method, tobacco used for medicinal purposes and smoking practiced within cultural traditions. The frequency of smoking was four times higher among males than among females. Smokers (n = 29) in comparison with non-smokers (n = 90) tended to be men (79% versus 33%), not married (68% versus 49%) and unemployed (79% versus 54%), and had attained somewhat lower levels of education. The role of cultural factors needs to be considered when designing appropriate smoking cessation strategies for Cambodian Americans.

High-flow priapism results from disruption of the intercavernosal artery resulting in an arteriocavernosal fistula and is rarely encountered in the pediatric and adolescent population. Clinically it manifests as a painless, prolonged erection after perineal trauma. Treatment has ranged from expectant management to open surgical exploration with vessel ligation. Internal pudendal arteriogram and superselective embolization with autologous blood clot has emerged as a safe and effective treatment modality in the young male population. Here the authors present 3 patients with high-flow priapism and discuss management of this rare clinical entity.

Objective: Five years after reporting our initial stent-graft repair of descending thoracic aortic aneurysms experience, we determined the 5- to 10-year results of stent-graft treatment and identified risk factors for adverse late outcomes., Methods: Between 1992 and 1997, 103 patients (mean age 69 +/- 12 years) underwent repair using first-generation (custom-fabricated) stent grafts. Sixty-two patients (60%) were unsuitable candidates for conventional open surgical repair ("inoperable"). Follow-up was 100% complete (mean 4.5 +/- 2.5 years; maximum 10 years). Outcome variables included death and treatment failure (endoleak, aortic rupture, reintervention, and/or aortic-related or sudden death)., Results: Overall actuarial survival was 82% +/- 4%, 49% +/- 5%, and 27% +/- 6% at 1, 5, and 8 years. Survival in open surgical candidates was 93% +/- 4% and 78% +/- 6% and at 1 and 5 years compared with 74% +/- 6% and 31% +/- 6% in those deemed inoperable (P <.001). Independent risk factors for death were older age (hazard ratio = 1.1; P =.008), previous stroke (hazard ratio = 2.8; P =.003), and being designated an inoperable candidate (hazard ratio = 1.9; P =.04). Actuarial freedom from aortic reintervention and treatment failure at 8 years was 70% +/- 6% and 39% +/- 8%, respectively. Earlier operative year (hazard ratio = 1.2; P =.07), larger distal landing zone diameter (hazard ratio = 1.1; P =.001), and transposition of the left subclavian artery (hazard ratio = 3.3; P =.008) were determinants of treatment failure., Conclusions: Survival after aneurysm repair using crude, first-generation stent grafts was satisfactory in good operative candidates but bleak in the inoperable cohort, raising the question of whether asymptomatic patients should have even been treated. Late aortic complications were detected in many patients, reemphasizing the importance of serial imaging surveillance.

Murine T cells do not endogenously upregulate CD80 expression but rather acquire CD80 from antigen presenting cells (APC) during CD28 ligation. Murine CD80+ memory T cells undergo apoptosis in the presence of high levels of antigen while naive CD80+ T cells are capable of acting as APC and T cell:T cell ligation induces anergy and unresponsiveness to antigen rechallenge. Reversing T cell unresponsiveness may be a key factor in the development of immunotherapy strategies for patients with myeloma. We have determined that B7+ T cells (CD80+ or CD86+) are common in patients with myeloma (n = 45), can be either CD4 or CD8, tend to be associated with stable disease and are polyclonal memory T cells (CD45RO). CD80 mRNA expression was present in CD80+ monocytes but not in CD3+ cells with a similar level of CD80 antigen expression. CD80 and CD86 antigen expression was upregulated on B cells but not T cells during incubation with trimeric human CD40 ligand (huCD40LT) + IL-2. Although there was a gradual loss of expression during in vitro culture, CD80+ T cells could be purified for further study. We conclude that B7 expression is common on T cells of patients with myeloma but that this is acquired rather than endogenously produced. B7+ CD45RO+ T cells constitute a population of memory T cells chronically exposed to antigen and warrant further study.

Deep venous thrombosis (DVT) has potentially debilitating long-term sequelae if left untreated. Conventional treatment (systemic anticoagulation with heparin followed by coumadin or low molecular weight heparin) often does not adequately relieves clot burden or symptoms, and patients may be left with post-thrombotic syndrome. Although the advent of catheter-directed thrombolysis has markedly improved the treatment of DVT and long-term outcomes of patients treated for DVT, it remains only partially effective on subacute or chronic clot. Mechanical thrombolysis may work synergistically with catheter-directed thrombolysis to decrease clot burden, treatment time, and complication rates, thereby improving outcomes., (Copyright 2003 Elsevier Inc. All rights reserved.)

Replication-selective oncolytic adenoviruses are being developed for the treatment of cancer, but the safety and feasibility of repeated adenovirus delivery to tumors via the bloodstream was unknown, particularly in light of a patient death after hepatic artery infusion of a replication-defective adenovirus vector. We performed a Phase II trial of an oncolytic replication-selective adenovirus (dl1520, also known as Onyx-015) administered by hepatic artery infusion in patients with gastrointestinal carcinoma metastatic to the liver (n = 27). dl1520 was infused into the hepatic artery (2 x 10(12) particles) on days 1 and 8 as a single agent, and thereafter starting on day 22 in combination with i.v. 5-fluorouracil and leucovorin every 28 days. Repeated viral infusions were feasible, and no deaths occurred on study; reversible grade 3/4 hyperbilirubinemia occurred in 2 patients. Systemic inflammatory cytokine responses varied greatly between patients and even between cycles within a given patient. Proinflammatory cytokines [e.g., tumor necrosis factor, IFN-gamma, and interleukin (IL) 6] typically rose within 3 h and were followed at 18 h by a rise in IL-10. However, in the single patient who suffered a severe but reversible systemic inflammatory response, a unique cytokine profile was detected: marked acute increases of IL-6 (20-fold higher than average for all of the patients) and inhibition of IL-10 production. Delayed secondary peaks of viremia were reproducibly detected 3-6 days after treatment, even in the presence of high level neutralizing antibody titers and antiviral cytokines. Mathematical modeling was used to calculate the number of virus particles produced and shed into the blood with each replication cycle. The combination of virotherapy and chemotherapy had antitumoral activity in some chemotherapy-resistant colorectal tumors. The intra-arterial infusion of oncolytic adenoviruses warrants additional study.

Rationale and Objectives: The purpose of this study was to provide in vivo demonstrations of the functionality of a truly hybrid interventional x-ray/magnetic resonance (MR) system., Materials and Methods: A digital flat-panel x-ray system (1,024(2) array of 200 microm pixels, 30 frames per second) was integrated into an interventional 0.5-T magnet. The hybrid system is capable of MR and x-ray imaging of the same field of view without patient movement. Two intravascular procedures were performed in a 22-kg porcine model: placement of a transjugular intrahepatic portosystemic shunt (TIPS) (x-ray-guided catheterization of the hepatic vein, MR fluoroscopy-guided portal puncture, and x-ray-guided stent placement) and mock chemoembolization (x-ray-guided subselective catheterization of a renal artery branch and MR evaluation of perfused volume)., Results: The resolution and frame rate of the x-ray fluoroscopy images were sufficient to visualize and place devices, including nitinol guidewires (0.016-0.035-inch diameter) and stents and a 2.3-F catheter. Fifth-order branches of the renal artery could be seen. The quality of both real-time (3.5 frames per second) and standard MR images was not affected by the x-ray system. During MR-guided TIPS placement, the trocar and the portal vein could be easily visualized, allowing successful puncture from hepatic to portal vein., Conclusion: Switching back and forth between x-ray and MR imaging modalities without requiring movement of the patient was demonstrated. The integrated nature of the system could be especially beneficial when x-ray and MR image guidance are used iteratively.

Objectives: We examined the impact of the increased sensitivity for hypervascular masses of multidetector CT hepatic arteriography on treatment decisions involving selective chemoembolization of hepatocellular carcinomas., Subjects and Methods: Thirty patients were referred for chemoembolization of unresectable hepatocellular carcinoma. Initial selective chemoembolization plans were formulated on the basis of diagnostic biphasic CT or MR imaging. Ultrafast CT hepatic arteriography was performed using a multidetector CT scanner and selective contrast material injection into the hepatic artery. The entire liver was scanned in a single breath-hold of approximately 20 sec with a slice thickness of 1 mm. Lesions and their arterial supplies were identified, and these data were immediately used to formulate a final plan for chemoembolization., Results: Hypervascular masses were detected in 29 patients. In 16 (53%) of the patients, preprocedural CT or MR imaging underestimated the number of lesions. In nine (30%) of these 16 patients, the additional lesions were detected only on CT hepatic arteriography, not on conventional angiography. CT hepatic arteriography findings had a major impact on planning the way in which chemoembolization treatment was performed. In three of the nine patients, the previously undetected lesions were treated with additional superselective chemoembolization. In the other six patients, chemoembolization was performed less selectively than originally planned., Conclusion: Primarily because of the high sensitivity of multidetector CT hepatic arteriography in revealing small and multifocal hepatomas, findings of this modality frequently alter treatment plans involving selective administration of chemoembolic material.

Percutaneous image-guided biopsies and fluid drainages are usually feasible with use of standard, mass-produced, straight needles. Occasionally, target lesions are completely surrounded by interposed structures, such as bone, bowel, colon, pancreas, bladder, or blood vessels, so percutaneous access appears impossible. Although the commercial availability of curved needles is very limited, custom bending of needles may allow unconventional access to these well-protected targets. This technique has been used to reach biopsy and drainage targets that would have otherwise required either high-risk transgression of interposed structures or more invasive surgical procedures.

Limited response to idiotype vaccination in patients with myeloma suggests that there is a need to develop better immunotherapy strategies. It has been determined that the number of high-potency CMRF44+CD14-CD19- dendritic cells (DCs) in the blood of patients with myeloma (range, 0.03%-0.8% of mononuclear cells [MNCs]; n = 26) was not significantly different from that in controls (range, 0.05%-0.8% of MNCs; n = 13). Expression of the costimulatory molecules CD80 and CD86 on DCs from these patients (mean, 29%+/-17% of MNCs and 85%+/-10% of MNCs, respectively) was also normal (mean, 29%+/-17% and 86%+/-16% of MNCs, respectively). Up-regulation of CD80 expression in response to stimulation by human huCD40LT + interleukin (IL)-2 was significantly reduced on the DCs of patients with myeloma during stable disease (n = 9) and was absent during progressive stages (n = 7) of disease. Similar effects were seen on B cells but not on monocytes of the same group of patients. CD86 expression on DCs was high before (86%) and after (89%) stimulation. Inhibition of CD80 up-regulation was neutralized by either anti-transforming growth factor (TGF)-beta1 or anti-IL-10. Up-regulation of CD80 on DCs of controls was inhibited by rTGF-beta1 in a dose-dependent manner. Serum TGF-beta1 and IL-10 levels were normal in most patients studied. Cytoplasmic TGF-beta1 was increased in plasma cells during progressive disease. Thus patients with myeloma have normal numbers of DCs, but CD80 expression may fail to be up-regulated in the presence of huCD40LT because of tumor-derived TGF-beta1 or IL-10. Autologous high-potency DCs may have to be tested for CD80 up-regulation and biologically modified ex vivo before idiotype priming for immunotherapy.

The occurrence of clonal T cells in multiple myeloma (MM), as defined by the presence of rearrangements in the T-cell receptor (TCR)-beta chains detected on Southern blotting, is associated with an improved prognosis. Recently, with the use of specific anti-TCR-variable-beta (anti-TCRV(beta)) antibodies, the presence in MM patients of expanded populations of T cells expressing particular V(beta) regions was reported. The majority of these T-cell expansions have the phenotype of cytotoxic T cells (CD8(+)CD57(+) and perforin positive). Since V(beta) expansions can result from either a true clonal population or a polyclonal response, the clonality of CD8(+)TCRV(beta)(+) T cells was tested by TCRV(beta) complementarity-determining region 3 length analysis and DNA sequencing of the variable region of the TCR. In this report, the CD57(+) and CD57(-) subpopulations within expanded TCRV(beta)(+)CD8(+) cell populations are compared, and it is demonstrated that the CD57(+) subpopulations are generally monoclonal or biclonal, whereas the corresponding CD57(-) cells are frequently polyclonal. The oligoclonality of CD57(+) expanded CD8(+) T cells but not their CD57(-) counterparts was also observed in age-matched controls, in which the T-cell expansions were mainly CD8(-). The CD8(+)CD57(+) clonal T cells had a low rate of turnover and expressed relatively lower levels of the apoptotic marker CD95 than their CD57(-) counterparts. Taken together, these findings demonstrate that MM is associated with CD57(+)CD8(+) T-cell clones, raising the possibility that the expansion and accumulation of activated clonal CD8(+) T cells in MM may be the result of persistent stimulation by tumor-associated antigens, combined with a reduced cellular death rate secondary to reduced expression of the apoptosis-related molecule CD95.

Both replication-incompetent and replication-selective adenoviruses are being developed for the treatment of cancer and other diseases. Concerns have been raised about the safety of intra-vascular adenovirus administration following a patient death on a clinical trial with a replication-defective adenovirus. In addition, the feasibility of vascular delivery to distant tumors has been questioned. dl1520 (ONYX-015) is a replication-selective adenovirus that has previously shown safety and antitumoral activity following intratumoral injection. This is the first report of intra-vascular administration with a genetically engineered, replication-selective virus. A phase I dose-escalation trial was performed in patients with liver-predominant gastrointestinal carcinoma (n = 11 total; primarily colorectal). dl1520 was infused into the hepatic artery at doses of 2 x 10(8)-2 x 10(1)2 particles for two cycles (days 1 and 8). Subsequent cycles of dl1520 were administered in combination with intravenous 5-fluorouracil (5-FU) and leucovorin. No dose-limiting toxicity, maximally tolerated dose or treatment-emergent clinical hepatotoxicity were identified following dl1520 infusion. Mild to moderate fever, rigors and fatigue were the most common adverse events. Antibody titers increased significantly in all patients. Viral replication was detectable in patients receiving the highest two doses. An objective response was demonstrated in combination with chemotherapy in a patient who was refractory to both 5-FU and dl1520 as single agents. Therefore, hepatic artery infusion of the attenuated adenovirus dl1520 was well-tolerated at doses resulting in infection, replication and chemotherapy-associated antitumoral activity.

Purpose: To evaluate delayed complications after esophageal expandable metallic stent placement., Materials and Methods: From April 1993 to December 1997, 90 expandable metallic stents were placed in 82 consecutive patients with inoperable malignant esophageal obstruction (n = 49) or malignant esophagorespiratory fistula (n = 33). Stents used included covered Gianturco-Rosch Z stents (n = 20), Wallstents (covered, n = 31; uncovered, n = 13), and Ultraflex stents (covered, n = 8; uncovered, n = 10). Patients were followed prospectively and monitored for delayed complications, defined as major (hemorrhage, tracheal compression, stent migration, perforation or fistula formation, granulomatous obstruction, tumor ingrowth and overgrowth, funnel phenomenon, and stent covering disruption) or minor (reflux, chest pain, and food impaction)., Results: Mean survival was 4.5 months after stent placement (range, 3 weeks to 26 months). The overall incidence of delayed complications was 64.6%, with 17 patients (20.7%) experiencing more than one complication. The rates of delayed complications in patients with Z stents, Wallstents, and Ultraflex stents were 75.0%, 68.1%, and 44.4%, respectively (P <.05). Most complications were life-threatening and occurred more frequently when stents were placed in the proximal third of the esophagus, compared with more distally (P <.05). Thirteen patients (15.9%) died from complications directly related to stent placement., Conclusion: Esophageal stent placement for malignant obstruction or fistula is associated with a substantial incidence of delayed complications.

B cells recruited into splenic antibody responses grow exponentially, either in extrafollicular foci as plasmablasts, or in follicles where they form germinal centers. Both responses yield plasma cells. Although many splenic plasma cells survive <3 d, some live much longer. This study shows that early plasma cell death relates to a finite capacity of the spleen to sustain plasma cells rather than a life span endowed by the cell's origin or the quality of antibody it produces. Antibody responses were compared where the peak numbers of plasma cells in spleen sections varied between 100 and 5,000 cells/mm(2). In each response, plasmablast clones divided some five times, with the peak numbers of plasma cells produced relating directly to the number of B cells recruited into the response. The spleen seems to have the capacity to sustain between 20 and 100 plasma cells/mm(2). When this number is exceeded, there is a loss of excess cells. Immunoglobulin variable region gene sequencing, and 5-bromo-2'-deoxyuridine pulse-chase studies indicate that long-lived splenic plasma cells are a mixture of cells derived from the extrafollicular and germinal center responses and cells derived from virgin and memory B cells. Only a proportion has switched immunoglobulin class.

Purpose: To evaluate the feasibility of endovascular techniques in treating venous outflow obstruction resulting from compression of the iliac vein by the iliac artery of the left lower extremity (May-Thurner syndrome)., Materials and Methods: A retrospective analysis of 39 patients (29 women, 10 men; median age, 46 years) with iliac vein compression syndrome (IVCS) was performed. Nineteen patients presented with acute deep vein thrombosis (DVT) and 20 patients presented with chronic symptoms. All patients presented with leg edema or pain. In the acute group, patients were treated with catheter-directed thrombolysis (120,000-180,000 IU urokinase/h) and angioplasty followed by stent placement. In the chronic group, patients were treated with use of angioplasty and stent placement alone (n = 8), or in combination with thrombolysis (n = 12). Patients were then followed-up with duplex ultrasound and a quality-of-life assessment., Results: Initial technical success was achieved in 34 of 39 patients (87%). The overall patency rate at 1 year was 79%. Symptomatically, 85% of patients were completely or partially improved compared with findings before treatment. Thirty-five of 39 patients received stents. The 1-year patency rate for patients with acute symptoms who received stents was 91.6%; for patients with chronic symptoms who received stents, the 1-year patency rate was 93.9%. Five technical failures occurred. Major complications included acute iliac vein rethrombosis (< 24 hours) requiring reintervention (n = 2). Minor complications included perisheath hematomas (n = 4) and minor bleeding (n = 1). There were no deaths, pulmonary embolus, cerebral hemorrhage, or major bleeding complications., Conclusion: Endovascular reconstruction of occluded iliac veins secondary to IVCS (May-Thurner) appears to be safe and effective.

The presence of T-cell clones in peripheral blood has been previously shown to be associated with a survival advantage in patients with multiple myeloma and suggests that the expanded T-cell populations may be involved in an anti-tumour response. We studied the T-cell receptor (TCR) repertoire of 38 patients with myeloma to identify and characterize the expanded T-cell populations by flow cytometry. T-cell expansions were found in 79% of the patients. The expansions occurred randomly among the 21 variable regions of the TCR beta chain (Vbeta) studied, representing 62% of the V-beta repertoire, and were stable during an 18-month follow-up. The phenotype of the expanded V-beta populations was predominantly CD8+, CD57+, CD28- and perforin+, which differed significantly from the other non-expanded Vbeta populations. The expression of the apoptosis markers Fas (CD95) and bcl-2 were similar between the expanded and non-expanded Vbeta populations. In conclusion, expanded T-cell populations were frequent in patients with myeloma, they remained unchanged during follow-up and had phenotypic characteristics of cytotoxic T cells. These data add further support to the concept that the T-cell expansions may have an immunoregulatory role in myeloma.

Purpose: To evaluate the potential of covered stents to replace surgery in the treatment of subclavian artery aneurysms and traumatic injuries., Materials and Methods: Nine patients (five men, four women; age range, 20-83 years; mean, 54 years) with subclavian artery aneurysms (n = 5) or fistulas (n = 4) were treated with stent-grafts. All devices used were custom-made, consisting of polytetrafluoroethylene (PTFE)-covered Palmaz (n = 5), Wallstent (n = 2), Z stents (n = 8), or a polyester-covered Z stent (n = 1). One patient was lost to follow-up after 2 months. All others were followed up with clinical evaluation, computed tomography (CT), and/or ultrasound., Results: All devices were deployed successfully with exclusion of the aneurysms and fistulas. There were two procedure-related complications (22%), consisting of groin pseudoaneurysms requiring surgical repair 3 and 9 days after the procedure. One of those patients required additional oral antibiotic therapy for a postsurgical groin wound infection. One patient developed a stenosis at 12 months, which required angioplasty. The stent-graft thrombosed in one patient because of a kink 2 months after placement, which was successfully treated by thrombolysis and placement of a Wallstent. The primary and secondary patencies are 89% and 100%, respectively, after a mean follow-up of 29 months (2-66 mo)., Conclusion: Mid-term results of stent-graft therapy of subclavian artery aneurysms and fistulas are encouraging, with low morbidity and excellent clinical outcome.