Intraindividual comparison of human radial and internal thoracic arteries in vitro and the effect of preoperative calcium blocker therapy

The patency rate of radial artery (RA) conduits is considerably lower than that of internal thoracic artery (ITA) grafts and the evidence suggests that this is due to a clinically suspected higher incidence of vasospasm. The aim of this study was, therefore, to compare intraindividually the pharmacological reactivity of RA with that of ITA. Both RA and ITA were taken from the same patients and investigated in parallel. Changes in tone were monitored isometrically on ring preparations from both arteries in organ baths with modified Krebs-Henseleit solution containing 1.25 mm calcium chloride at 1 g passive preload. In intraindividual comparisons maximal receptor-mediated contractile responses to noradrenaline and endothelin-1 and endothelium-dependent acetylcholine-induced relaxant responses revealed no differences between both arteries. By contrast, depolarization-induced contractions to potassium chloride (KCl) appeared to be significantly higher in RA than in ITA. Further analysis, however, revealed that this difference was due to preoperative calcium entry blocker (Ca(2+)eB) therapy. Compared with control tissues, maximal responses to KCl were significantly attenuated in the ITA but unchanged in RA when arteries were obtained from patients with preoperative Ca(2+)eB therapy. The present results suggested that functional responses to pharmacological stimuli of both RA and ITA were quite similar. Preoperative Ca(2+)eB therapy, however, attenuated markedly responses to KCl of the ITA leaving those of RA unchanged. These results, demonstrating a lower sensitivity to Ca(2+)eB of RA, therefore suggested that in addition to Ca(2+)eB other classes of drug may be more effective at reducing the propensity of RA conduits to vasospasm.

Cone beam computed tomography in implant dentistry: a systematic review focusing on guidelines, indications, and radiation dose risks.

PURPOSE The aim of the paper is to identify, review, analyze, and summarize available evidence in three areas on the use of cross-sectional imaging, specifically maxillofacial cone beam computed tomography (CBCT) in pre- and postoperative dental implant therapy: (1) Available clinical use guidelines, (2) indications and contraindications for use, and (3) assessment of associated radiation dose risk. MATERIALS AND METHODS Three focused questions were developed to address the aims. A systematic literature review was performed using a PICO-based search strategy based on MeSH key words specific to each focused question of English-language publications indexed in the MEDLINE database retrospectively from October 31, 2012. These results were supplemented by a hand search and gray literature search. RESULTS Twelve publications were identified providing guidelines for the use of cross-sectional radiography, particularly CBCT imaging, for the pre- and/or postoperative assessment of potential dental implant sites. The publications discovered by the PICO strategy (43 articles), hand (12), and gray literature searches (1) for the second focus question regarding indications and contraindications for CBCT use in implant dentistry were either cohort or case-controlled studies. For the third question on the assessment of associated radiation dose risk, a total of 22 articles were included. Publication characteristics and themes were summarized in tabular format. CONCLUSIONS The reported indications for CBCT use in implant dentistry vary from preoperative analysis regarding specific anatomic considerations, site development using grafts, and computer-assisted treatment planning to postoperative evaluation focusing on complications due to damage of neurovascular structures. Effective doses for different CBCT devices exhibit a wide range with the lowest dose being almost 100 times less than the highest dose. Significant dose reduction can be achieved by adjusting operating parameters, including exposure factors and reducing the field of view (FOV) to the actual region of interest.

Targeted alpha-radionuclide therapy of functionally critically located gliomas with 213Bi-DOTA-[Thi8,Met(O2)11]-substance P: a pilot trial

Functionally critically located gliomas represent a challenging subgroup of intrinsic brain neoplasms. Standard therapeutic recommendations often cannot be applied, because radical treatment and preservation of neurological function are contrary goals. The successful targeting of gliomas with locally injected beta radiation-emitting (90)Y-DOTAGA-substance P has been shown previously. However, in critically located tumours, the mean tissue range of 5 mm of (90)Y may seriously damage adjacent brain areas. In contrast, the alpha radiation-emitting radionuclide (213)Bi with a mean tissue range of 81 microm may have a more favourable toxicity profile. Therefore, we evaluated locally injected (213)Bi-DOTA-substance P in patients with critically located gliomas as the primary therapeutic modality.

Echinococcus multilocularis: the impact of ionizing radiation on metacestodes

Alveolar echinococcosis is caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis. Current chemotherapeutical options for the treatment of echinococcosis are not satisfactory, and novel drugs and/or other potential means of therapy are needed. E. multilocularis metacestodes are characterized by almost potentially unlimited growth, and also display other features of cancerous tumours. In this study, we exposed metacestodes that were generated in vitro to 50-100 Gy ionizing irradiation, and subsequently investigated the short-term (10-12 days post-treatment) and long-term (14 weeks post-treatment) effects. We found, that in the short-term, no release of alkaline phosphatase (EmAP) activity as a measure for potentially induced damage and loss of viability could be detected, and that the protein expression pattern and protease activities in vesicle fluids and medium supernatants did not alter dramatically following irradiation. However, irradiation was associated with distinct morphological and ultrastructural alterations in the tissue of metacestodes, affecting most notably cell-cell contacts, mitochondrial shape, glycogen-storage cells and lipid droplet formation. These could be detected already at 10 days following treatment and remained as such also in the long-term. In addition, as determined after 14 weeks of culture, irradiation affected the proliferation and the growth of E. multilocularis metacestodes. Thus, we demonstrate that radiotherapy does not have a clear-cut parasitocidal effect, but can lead to metabolic impairment of E. multilocularis metacestodes, as reflected by the distinct morphological and structural alterations induced by irradiation treatment.

Therapy response with diffusion MRI: an update

The efficiency of an oncological treatment regimen is often assessed by morphological criteria such as tumour size evaluated by cross-sectional imaging, or by laboratory measurements of plasma biomarkers. Because these types of measures typically allow for assessment of treatment response several weeks or even months after the start of therapy, earlier response assessment that provides insight into tumour function is needed. This is particularly urgent for the evaluation of newer targeted therapies and for fractionated therapies that are delivered over a period of weeks to allow for a change of treatment in non-responding patients. Diffusion-weighted MRI (DW-MRI) is a non-invasive imaging tool that does not involve radiation or contrast media, and is sensitive to tissue microstructure and function on a cellular level. DW-MRI parameters have shown sensitivity to treatment response in a growing number of tumour types and organ sites, with additional potential as predictive parameters for treatment outcome. A brief overview of DW-MRI principles is provided here, followed by a review of recent literature in which DW-MRI has been used to monitor and predict tumour response to various therapeutic regimens.

[Ultrasound in anesthesiology--ultrasound in interventional pain therapy]

Ultrasound is an emerging new imaging and guiding technique for diagnostic or therapeutic interventional pain procedures. Advantages are the real time monitoring of the targeted structures, the placement of the instruments and the visualization of local anaesthetic spread without exposing patients and personal to radiation. Pain specialists need a large anatomical knowledge and training to use the new method safely and distinctively. The increasing published data available and the personal experience of the authors suggest a potential usefulness in interventional pain therapy, but also limitations.

Up-regulation of somatostatin receptor density on rat CA20948 tumors escaped from low dose [(177)Lu-DOTA(0),Tyr(3)]octreotate therapy

AIM: Peptide receptor radionuclide therapy using the somatostatin analogue [(177)Lu-DOTA(0),Tyr(3)]octreotate is a convincing treatment modality for metastasized neuroendocrine tumors. Therapeutic doses are administered in 4 cycles with 6-10 week intervals. A high somatostatin receptor density on tumor cells is a prerequisite at every administration to enable effective therapy. In this study, the density of the somatostatin receptor subtype 2 (sst2) was investigated in the rat CA20948 pancreatic tumor model after low dose [(177)Lu-DOTA(0), Tyr(3)]octreotate administration resulting in approximately 20 Gy tumor radiation absorbed dose, whereas 60 Gy is needed to induce complete tumor regression in these and the majority of tumors. METHODS: Sixteen days after inoculation of the CA20948 tumor, male Lewis rats were injected with 185 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate to initiate a decline in tumor size. Approximately 40 days after injection, tumors re-grew progressively after initial response. Quantification of sst2 expression was performed using in vitro autoradiography on frozen sections of three groups: control (not-treated) tumors, tumors in regression and tumors in re-growth. Histology and proliferation were determined using HE- and anti-Ki-67-staining. RESULTS: The sst2 expression on CA20948 tumor cells decreased significantly after therapy to 5% of control level. However, tumors escaping from therapy showed an up-regulated sst2 level of 2-5 times higher sst2 density compared to control tumors. CONCLUSION: After a suboptimal therapeutic dose of [(177)Lu-DOTA(0),Tyr(3)]octreotate, escape of tumors is likely to occur. Since these cells show an up-regulated sst2 receptor density, a next therapeutic administration of radiolabelled sst2 analogue can be expected to be highly effective.

[Endovascular therapy of an abdominal aortic aneurysm in a renal transplant recipient]

INTRODUCTION: The indications for endovascular aortic aneurysm repair (EVAR) are mainly established in hostile abdomen, in patients with significant comorbidities which affect the general operability of the patient and, given the necessary infrastructure, also in ruptured aneurysm. Along to those, we present another possible indication in the presence of a kidney allograft in patients with aortic aneurysm. METHODS: Based on a case report of aorto-biiliac stent-graft repair of an infrarenal aortic aneurysm in a patient with renal allograft, a systematic review of the literature was performed of all similar cases concerning surgical therapy in this constellation. RESULTS: EVAR was performed using an aorto-biiliac system (Zenith) Trifab, COOK) in a 61-year-old male patient 11 years after heterotopic renal allotransplantation in the right iliac fossa. Preoperative renal function was normal. Because the donor renal artery was anastomosed to the recipient's external iliac artery the stent-graft was implanted from the left common femoral artery to minimize temporary allograft ischemia. The intra- and postoperative course was uneventful with a follow-up of presently 12 months. A primary type-II endoleak (retroleak from a lumbar artery) is being treated conservatively so far with embolization being a future option. At present there are 15 cases of EVAR in renal allograft patients that have been reported, all of them being successful. DISCUSSION: All data existing in the literature reported to date as well as our own experience justify the first choice of EVAR in morphologically suitable cases. One major advantage of EVAR in this constellation is the avoidance of aortic cross clamping which poses the graft at risk of ischemia. Long-term results will be most important for definite assessment of EVAR. However, contrast media application during the operation and for CT surveillance should be considered as a major disadvantage.

Progress on BIG 1-02/IBCSG 27-02/NSABP B-37, a prospective randomized trial evaluating chemotherapy after local therapy for isolated locoregional recurrences of breast cancer

BACKGROUND: The utility of chemotherapy for women who experience a locoregional recurrence after primary treatment of early breast cancer remains an open question. An international collaborative trial is being conducted by the Breast International Group (BIG), the International Breast Cancer Study Group (IBCSG), and the National Surgical Adjuvant Breast and Bowel Project (NSABP) to determine the effectiveness of cytotoxic therapy for these patients, either alone or in addition to selective use of hormonal therapy and trastuzumab. METHODS: The trial population includes women who have had a previous diagnosis of invasive breast cancer treated by mastectomy or breast-conserving surgery, but subsequently develop an isolated local and/or regional ipsilateral invasive recurrence. Excision of all macroscopic tumor without evidence of systemic disease is required for study entry. Patients are randomized to receive chemotherapy or no chemotherapy; type of chemotherapy is not protocol-specified. Radiation, hormonal therapy, and trastuzumab are given as appropriate. The primary endpoint is disease-free survival (DFS). Quality-of-life measurements are collected at baseline, and then at 9 and 12 months. The accrual goal is 977 patients. RESULTS: This report describes the characteristics of the first 99 patients. Sites of recurrence at study entry were: breast (56%), mastectomy scar/chest wall (35%), and regional lymph nodes (9%). Two-thirds of patients have estrogen-receptor-positive recurrences. CONCLUSION: This is the only trial actively investigating the question of "adjuvant" chemotherapy in locally recurrent breast cancer. The case mix of accrual to date indicates a broad representation of this patient population.

Tumor recovery by angiogenic switch from sprouting to intussusceptive angiogenesis after treatment with PTK787/ZK222584 or ionizing radiation

Inhibitors of angiogenesis and radiation induce compensatory changes in the tumor vasculature both during and after treatment cessation. To assess the responses to irradiation and vascular endothelial growth factor-receptor tyrosine kinase inhibition (by the vascular endothelial growth factor tyrosine kinase inhibitor PTK787/ZK222854), mammary carcinoma allografts were investigated by vascular casting; electron, light, and confocal microscopy; and immunoblotting. Irradiation and anti-angiogenic therapy had similar effects on the tumor vasculature. Both treatments reduced tumor vascularization, particularly in the tumor medulla. After cessation of therapy, the tumor vasculature expanded predominantly by intussusception with a plexus composed of enlarged sinusoidal-like vessels containing multiple transluminal tissue pillars. Tumor revascularization originated from preserved alpha-smooth muscle actin-positive vessels in the tumor cortex. Quantification revealed that recovery was characterized by an angiogenic switch from sprouting to intussusception. Up-regulated alpha-smooth muscle actin-expression during recovery reflected the recruitment of alpha-smooth muscle actin-positive cells for intussusception as part of the angio-adaptive mechanism. Tumor recovery was associated with a dramatic decrease (by 30% to 40%) in the intratumoral microvascular density, probably as a result of intussusceptive pruning and, surprisingly, with only a minimal reduction of the total microvascular (exchange) area. Therefore, the vascular supply to the tumor was not severely compromised, as demonstrated by hypoxia-inducible factor-1alpha expression. Both irradiation and anti-angiogenic therapy cause a switch from sprouting to intussusceptive angiogenesis, representing an escape mechanism and accounting for the development of resistance, as well as rapid recovery, after cessation of therapy.

Preoperative corticosteroids. A contraindication to lung transplantation?

Regular preoperative application of corticosteroids has been considered as a contraindication to lung transplantation for fear of an increased risk of postoperative morbidity and mortality. Recently, however, we have accepted patients for transplantation in whom treatment with steroid medication could not be terminated preoperatively. Up to February 1991, 27 unilateral and bilateral transplantations in 26 patients were analyzed. Corticosteroid therapy was discontinued at least three months prior to transplantation in 13 patients (group 1), whereas in 14 cases, the patients continued their daily corticosteroid therapy to the time of transplantation (prednisolone, 0.1 to 0.3 mg/kg/day; group 2). There were no significant differences between the groups with respect to sex, age, diagnosis, or type of transplantation. One limited bronchial dehiscence occurred; the incidence of postoperative bronchial stenosis was identical in both cohorts; one patient died in each group. In conclusion, no increased morbidity or mortality could be found following lung transplantation with regular preoperative administration of prednisolone up to 0.3 mg/kg/day. Thus, patients who cannot be weaned from their steroid medication but who otherwise are acceptable candidates should not be excluded from lung transplantation.

[Preoperative preparation of patients with cardiovascular disease for noncardiac surgery]

Preoperative preparation of patients with cardiovascular disease is best initiated by the general practitioner. Updated Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery have been published by the American Heart Association und American College of Cardiology (2007). Individual cardiac evaluation must take into account active cardiac conditions, functional capacity, additional clinical risk factors and surgical risk. Stable, asymptomatic patients with normal functional capacity can proceed to elective anesthesia and surgery without further cardiac evaluation. Active cardiac conditions require evaluation and treatment by a cardiology service prior to elective surgery. In stable patients with poor (<4 metabolic equivalents, MET) or unknown functional capacity and clinical risk factors, who are scheduled for intermediate- or high-risk surgery, further cardiac evaluation and preparation is to be considered. Established indicated beta blocker and statin medication is to be continued; timely institution of beta blocker medication (target heart rate, <65 bpm) may be required depending on the risk of surgery, the presence of coronary heart disease, and the number of clinical risk factors present. Following percutaneous coronary intervention, specific waiting periods are required prior to elective surgery. In patients on antiplatelet therapy, the risk of stopping it should be weighed against the benefit of reduction in bleeding complications from the planned surgery.

Multicenter phase II trial of preoperative induction chemotherapy followed by chemoradiation with docetaxel and cisplatin for locally advanced esophageal carcinoma (SAKK 75/02)

BACKGROUND: This multicenter phase II study investigated the efficacy and feasibility of preoperative induction chemotherapy followed by chemoradiation and surgery in patients with esophageal carcinoma. PATIENTS AND METHODS: Patients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the esophagus received induction chemotherapy with cisplatin 75 mg/m(2) and docetaxel (Taxotere) 75 mg/m(2) on days 1 and 22, followed by radiotherapy of 45 Gy (25 x 1.8 Gy) and concurrent chemotherapy comprising cisplatin 25 mg/m(2) and docetaxel 20 mg/m(2) weekly for 5 weeks, followed by surgery. RESULTS: Sixty-six patients were enrolled at eleven centers and 57 underwent surgery. R0 resection was achieved in 52 patients. Fifteen patients showed complete, 16 patients nearly complete and 26 patients poor pathological remission. Median overall survival was 36.5 months and median event-free survival was 22.8 months. Squamous cell carcinoma and good pathologically documented response were associated with longer survival. Eighty-two percent of all included patients completed neoadjuvant therapy and survived for 30 days after surgery. Dysphagia and mucositis grade 3/4 were infrequent (<9%) during chemoradiation. Five patients (9%) died due to surgical complications. CONCLUSIONS: This neoadjuvant, taxane-containing regimen was efficacious and feasible in patients with locally advanced esophageal cancer in a multicenter, community-based setting and represents a suitable backbone for further investigation.

Limited predictive value of FDG-PET for response assessment in the preoperative treatment of esophageal cancer: results of a prospective multi-center trial (SAKK 75/02)

BACKGROUND: Only responding patients benefit from preoperative therapy for locally advanced esophageal carcinoma. Early detection of non-responders may avoid futile treatment and delayed surgery. PATIENTS AND METHODS: In a multi-center phase ll trial, patients with resectable, locally advanced esophageal carcinoma were treated with 2 cycles of induction chemotherapy followed by chemoradiotherapy (CRT) and surgery. Positron emission tomography with 2[fluorine-18]fluoro-2-deoxy-d-glucose (FDG-PET) was performed at baseline and after induction chemotherapy. The metabolic response was correlated with tumor regression grade (TRG). A decrease in FDG tumor uptake of less than 40% was prospectively hypothesized as a predictor for histopathological non-response (TRG > 2) after CRT. RESULTS: 45 patients were included. The median decrease in FDG tumor uptake after chemotherapy correlated well with TRG after completion of CRT (p = 0.021). For an individual patient, less than 40% decrease in FDG tumor uptake after induction chemotherapy predicted histopathological non-response after completion of CRT, with a sensitivity of 68% and a specificity of 52% (positive predictive value 58%, negative predictive value 63%). CONCLUSIONS: Metabolic response correlated with histopathology after preoperative therapy. However, FDG-PET did not predict non-response after induction chemotherapy with sufficient clinical accuracy to justify withdrawal of subsequent CRT and selection of patients to proceed directly to surgery.

Intratumoural budding (ITB) in preoperative biopsies predicts the presence of lymph node and distant metastases in colon and rectal cancer patients

Background:In colorectal cancer (CRC), tumour budding at the invasion front is associated with lymph node (LN) and distant metastasis. Interestingly, tumour budding can also be detected in biopsies (intratumoural budding; ITB) and may have similar clinical importance. Here we investigate whether ITB in preoperative CRC biopsies can be translated into daily diagnostic practice.Methods:Preoperative biopsies from 133 CRC patients (no neoadjuvant therapy) underwent immunohistochemistry for pan-cytokeratin marker AE1/AE3. Across all biopsies for each patient, the densest region of buds at × 40 (high-power field; HPF) was identified and buds were counted.Results:A greater number of tumour buds in the biopsy was associated with pT stage (P=0.0143), LN metastasis (P=0.0007), lymphatic (P=0.0065) and venous vessel invasion (P=0.0318) and distant metastasis (cM1) (P=0.0013). Using logistic regression, a 'scale' was developed to estimate the probability of LN and distant metastasis using the number of tumour buds (e.g. 10 buds per HPF: 64% chance of LN metastasis; 30 buds per HPF: 86% chance). Inter-observer agreement for ITB was excellent (intraclass correlation coefficient: 0.813).Conclusion:Tumour budding can be assessed in the preoperative biopsy of CRC patients. It is practical, reproducible and predictive of LN and distant metastasis. Intratumoural budding qualifies for further investigation in the prospective setting.