Interobserver agreement on definition of the target volume in stereotactic radiotherapy for pancreatic adenocarcinoma using different imaging modalities.

PURPOSE: The aim of this study was to evaluate interobserver agreement (IOA) on target volume definition for pancreatic cancer (PACA) within the Radiosurgery and Stereotactic Radiotherapy Working Group of the German Society of Radiation Oncology (DEGRO) and to identify the influence of imaging modalities on the definition of the target volumes. METHODS: Two cases of locally advanced PACA and one local recurrence were selected from a large SBRT database. Delineation was based on either a planning 4D CT with or without (w/wo) IV contrast, w/wo PET/CT, and w/wo diagnostic MRI. Novel compared to other studies, a combination of four metrics was used to integrate several aspects of target volume segmentation: the Dice coefficient (DSC), the Hausdorff distance (HD), the probabilistic distance (PBD), and the volumetric similarity (VS). RESULTS: For all three GTVs, the median DSC was 0.75 (range 0.17-0.95), the median HD 15 (range 3.22-67.11) mm, the median PBD 0.33 (range 0.06-4.86), and the median VS was 0.88 (range 0.31-1). For ITVs and PTVs the results were similar. When comparing the imaging modalities for delineation, the best agreement for the GTV was achieved using PET/CT, and for the ITV and PTV using 4D PET/CT, in treatment position with abdominal compression. CONCLUSION: Overall, there was good GTV agreement (DSC). Combined metrics appeared to allow a more valid detection of interobserver variation. For SBRT, either 4D PET/CT or 3D PET/CT in treatment position with abdominal compression leads to better agreement and should be considered as a very useful imaging modality for the definition of treatment volumes in pancreatic SBRT. Contouring does not appear to be the weakest link in the treatment planning chain of SBRT for PACA.

Association between omentin-1, adiponectin and bone health under consideration of osteoprotegerin as possible mediator.

PURPOSE: Several studies implicated a crosstalk between bone and fat in the pathogenesis of osteoporosis. Few studies indicated an association between adiponectin and omentin-1 on the bone remodeling process and bone mineral density, and suggested osteoprotegerin (OPG) as a mediator of this relationship. However, only limited evidence on this relationship is available in humans. Therefore, this study aimed to investigate the association between omentin-1, adiponectin and broadband ultrasound attenuation (BUA) in peri-/premenopausal and postmenopausal women, and to assess the role of OPG as a possible mediator. METHODS: Data from the German population-based EPIC-Potsdam cohort comprising 637 women were analyzed. Multivariable-adjusted ANCOVA including age, BMI, waist circumference, smoking status, education, physical activity, adiponectin or omentin-1 and hormone use was used to investigate potential relationships between the adipokines and BUA levels. A mediation analysis assessed the mediating effect of OPG on the association of BUA and omentin-1 levels. RESULTS: Peri-/premenopausal women had higher BUA levels (112.5 ± 10.1 dB/MHz), compared to postmenopausal women (106.3 ± 10.0 dB/MHz). In peri-/premenopausal women neither adiponectin nor omentin-1 was significantly associated with BUA. In postmenopausal women, adiponectin was not associated with BUA, but 10 % increase in the omentin-1 concentration was significantly associated with 0.44 dB/MHz lower BUA levels (p = 0.01). Omentin-1 was positively associated with OPG (p = 0.02); however, OPG was not significantly related to BUA (p = 0.62). CONCLUSION: Our study provides evidence for an inverse association between circulating omentin-1 and BUA levels in postmenopausal women. However, the present findings do not support a mediating effect of OPG in the adipose tissue-bone pathway.

Examining Radiation-Induced In Vivo and In Vitro Gene Expression Changes of the Peripheral Blood in Different Laboratories for Biodosimetry Purposes: First RENEB Gene Expression Study.

The risk of a large-scale event leading to acute radiation exposure necessitates the development of high-throughput methods for providing rapid individual dose estimates. Our work addresses three goals, which align with the directive of the European Union's Realizing the European Network of Biodosimetry project (EU-RENB): 1. To examine the suitability of different gene expression platforms for biodosimetry purposes; 2. To perform this examination using blood samples collected from prostate cancer patients (in vivo) and from healthy donors (in vitro); and 3. To compare radiation-induced gene expression changes of the in vivo with in vitro blood samples. For the in vitro part of this study, EDTA-treated whole blood was irradiated immediately after venipuncture using single X-ray doses (1 Gy/min(-1) dose rate, 100 keV). Blood samples used to generate calibration curves as well as 10 coded (blinded) samples (0-4 Gy dose range) were incubated for 24 h in vitro, lysed and shipped on wet ice. For the in vivo part of the study PAXgene tubes were used and peripheral blood (2.5 ml) was collected from prostate cancer patients before and 24 h after the first fractionated 2 Gy dose of localized radiotherapy to the pelvis [linear accelerator (LINAC), 580 MU/min, exposure 1-1.5 min]. Assays were run in each laboratory according to locally established protocols using either microarray platforms (2 laboratories) or qRT-PCR (2 laboratories). Report times on dose estimates were documented. The mean absolute difference of estimated doses relative to the true doses (Gy) were calculated. Doses were also merged into binary categories reflecting aspects of clinical/diagnostic relevance. For the in vitro part of the study, the earliest report time on dose estimates was 7 h for qRT-PCR and 35 h for microarrays. Methodological variance of gene expression measurements (CV ≤10% for technical replicates) and interindividual variance (≤twofold for all genes) were low. Dose estimates based on one gene, ferredoxin reductase (FDXR), using qRT-PCR were as precise as dose estimates based on multiple genes using microarrays, but the precision decreased at doses ≥2 Gy. Binary dose categories comprising, for example, unexposed compared with exposed samples, could be completely discriminated with most of our methods. Exposed prostate cancer blood samples (n = 4) could be completely discriminated from unexposed blood samples (n = 4, P < 0.03, two-sided Fisher's exact test) without individual controls. This could be performed by introducing an in vitro-to-in vivo correction factor of FDXR, which varied among the laboratories. After that the in vitro-constructed calibration curves could be used for dose estimation of the in vivo exposed prostate cancer blood samples within an accuracy window of ±0.5 Gy in both contributing qRT-PCR laboratories. In conclusion, early and precise dose estimates can be performed, in particular at doses ≤2 Gy in vitro. Blood samples of prostate cancer patients exposed to 0.09-0.017 Gy could be completely discriminated from pre-exposure blood samples with the doses successfully estimated using adjusted in vitro-constructed calibration curves.

Benefit of Contrast-Enhanced Ultrasound (CEUS) in the Follow-Up Care of Patients with Colon Cancer: A Prospective Multicenter Study.

PURPOSE: According to the German guidelines on colorectal cancer, unenhanced ultrasound is recommended for follow-up. On the other hand, ultrasound and radiology societies specify the use of contrast-enhanced ultrasound for ruling out liver metastases. Studies focusing on the follow-up of cancer patients are lacking. The goal of this multicenter study initiated by the German Ultrasound Society (DEGUM) was to determine the potential benefit of contrast-enhanced ultrasound in the follow-up of patients with colon cancer. MATERIALS AND METHODS: Follow-up patients with colon cancer (UICC > IIa) were investigated. As scheduled according to the German guidelines, unenhanced ultrasound was performed followed by contrast-enhanced ultrasound. All liver lesions were recorded. In case of additional metastases detected on contrast-enhanced ultrasound, contrast-enhanced CT, MRI or biopsy was performed to confirm additional liver metastases. RESULTS: A total of 45 liver metastases were detected in 26/290 patients (= 9 %) using unenhanced ultrasound. A further 28 metastases were detected on contrast-enhanced ultrasound in these 26 patients. In 18 patients showing no liver metastases, 40 additional metastases were detected on unenhanced ultrasound. This means that 44 patients with a total of 113 liver metastases were detected on contrast-enhanced ultrasound (p = 0.0006). CONCLUSION: Contrast-enhanced ultrasound should be recommended in the follow-up of patients with colon cancer in addition to unenhanced ultrasound - the up-to-date standard.

Statement of the section internal medicine of the DEGUM - ultrasound obtains pole position for clinical imaging in acute diverticulitis.

This paper reviews and interprets the role of ultrasonography in view of the recently published Guideline on diverticular disease of the Consensus conference of the German Societies of Gastroenterology (DGVS) and Visceral Surgery (DGAV) implying a new classification of diverticular disease (CDD). Qualified US is not only equipotent to qualified CT and frequently effectual for diagnosis but considers relevant legislation for radiation exposure protection. Unsurpassed resolution allows detailed resolution thereby allowing to differentiate and stratify the relevant types of diverticular disease. Subsequently, US is considered the first choice of imaging in diverticular disease. Vice versa, CT has definite indications in unclear / discrepant situations ­ or insufficient US-performance.

[Autoimmune pancreatitis]. / Autoimmunpankreatitis.

Autoimmune pancreatitis is a relatively rare form of chronic pancreatitis which is characterized by a lymphoplasmatic infiltrate with a storiform fibrosis and often goes along with painless jaundice and discrete discomfort of the upper abdomen. Clinically we distinguish between two subtypes, which differ in terms of their histology, clinical picture and prognosis. Type 1 autoimmune pancreatitis is the pancreatic manifestation of the IgG4-associated syndrome which also involves other organs. About one third of the patients can only be diagnosed after either histological prove or a successful steroid trail. Type 2 is IgG4-negative with the histological picture of an idiopathic duct centric pancreatitis and is to higher degree associated with inflammatory bowel disease. A definitive diagnosis can only be made using biopsy. Usually both forms show response to steroid treatment, but in type 1 up to 50 % of the patients might develop a relapse. The biggest challenge and most important differential diagnosis remains the discrimination of AIP from pancreatic cancer, because also AIP can cause mass of the pancreatic head, lymphadenopathy and ductal obstruction. This article summarizes recent advances on epidemiology, clinical presentation, diagnostic strategy, therapy and differential diagnosis in this relatively unknown disease.

Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations.

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) (MIM 270 400) is an autosomal recessive multiple congenital anomalies/mental retardation syndrome caused by mutations in the Delta7-sterol reductase (DHCR7, E.C.1.3.1.21) gene. The prevalence of SLOS has been estimated to range between 1:15000 and 1:60000 in populations of European origin. METHODS AND RESULTS: We have analysed the frequency, origin, and age of DHCR7 mutations in European populations. In 263 SLOS patients 10 common alleles (c.964-1G>C, p.Trp151X, p.Thr93Met, p.Val326Leu, p.Arg352Trp, p.Arg404Cys, p.Phe302Leu, p.Leu157Pro, p.Gly410Ser, p.Arg445Gln) were found to constitute approximately 80% of disease-causing mutations. As reported before, the mutational spectra differed significantly between populations, and frequency peaks of common mutations were observed in North-West (c.964-1G>C), North-East (p.Trp151X, p.Val326Leu) and Southern Europe (p.Thr93Met). SLOS was virtually absent from Finland. The analysis of nearly 8000 alleles from 10 different European populations confirmed a geographical distribution of DHCR7 mutations as reported in previous studies. The common Null mutations in Northern Europe (combined ca. 1:70) occurred at a much higher frequency than expected from the reported prevalence of SLOS. In contrast the most common mutation in Mediterranean SLOS patients (p.Thr93Met) had a low population frequency. Haplotypes were constructed for SLOS chromosomes, and for wild-type chromosomes of African and European origins using eight cSNPs in the DHCR7 gene. The DHCR7 orthologue was sequenced in eight chimpanzees (Pan troglodytes) and three microsatellites were analysed in 50 of the SLOS families in order to estimate the age of the three major SLOS-causing mutations. CONCLUSIONS: The results indicate a time of first appearance of c.964-1G>C and p.Trp151X some 3000 years ago in North-West and North-East Europe, respectively. The p.Thr93Met mutations on the J haplotype has probably first arisen approximately 6000 years ago in the Eastern Mediterranean. Together, it appears that a combination of founder effects, recurrent mutations, and drift have shaped the present frequency distribution of DHCR7 mutations in Europe.

Excimer laser pumped by an intense, high-energy heavy-ion beam.

High-energy heavy ions are an ideal tool to generate homogeneously excited, extended volumes of nonthermal plasmas. Here, the high-energy loss (dE/dx) and absolute power deposition of heavy ions interacting with matter has been used to pump an ultraviolet laser. A pulsed 70 MeV/u 238U beam with up to 2.5 x 10(9) particles in approximately 100 ns beam bunches was stopped in a 1.2 m long laser cell filled with a 1.6 bar Ar-Kr-F2 mixture (typically 50%:49.9%:0.1%). Laser effect on the 248 nm KrF* excimer transition is clearly demonstrated.

Endosonographic and histopathological staging of extrahepatic bile duct cancer: time to leave the present TNM-classification?

OBJECTIVES: The discrepancy between high rates of sensitivity, specificity, and accuracy for intraductal ultrasonography (IDUS) in extrahepatic bile duct carcinoma and the failure to depict different wall layers as defined by the TNM classification have not yet been elucidated sufficiently. METHODS: In a prospective study, endosonographic images were correlated with histomorphology including immunohistochemistry. Using IDUS, we examined fresh resection specimens of patients who had undergone pancreato-duodenectomy. For histological analysis, the formalin-fixed and paraffin-embedded specimens were stained by hematoxylin-eosin, elastica-van-Gieson, and immunohistochemically by smooth muscle-actin. To confirm our hypothesis, further cases from the archives were analyzed histopathologically and immunohistochemically. RESULTS: The various wall layers of the extrahepatic bile duct as described by the International Union Against Cancer are neither histomorphologically nor immunohistochemically consistently demonstrable. Especially, a clear differentiation between tumor invasion beyond the wall of the bile duct (T2) and invasion of the pancreas (T3) by histopathological means is often not possible. Endosonographic images using high-resolution miniprobes similarly confirm the difficulty in imaging various layers in the bile duct wall. CONCLUSIONS: Most adaptations made by the sixth edition of the TNM classification accommodate to the endosonographic and most of the histopathological findings as demonstrated in our study. In contrast to the new edition, however, our findings suggest to combine T2- and T3-staged tumors into one single class leading to clarification, and improved reproducibility of histopathological staging.

[Requirements and recommendations for performing endosonographies]. / Voraussetzungen und Empfehlungen zur Durchführung von Endosonographien - Eine Stellungnahme der Arbeitsgemeinschaft für endoskopischen Ultraschall in Nordrhein-Westfalen (AGEUS).

For improvement of quality the working group of the Society of Gastroenterology in Nordrhein-Westfalen (Germany) was engaged with the questions, which apparative, personal and training conditions for endoscopic ultrasound are useful. The following proposals were preliminarily presented at the annual Congress of the DGVS (German Society of Digestive and Metabolic Diseases) 2001. They are thought to be subject of discussion for guidelines to be elaborated by this national society.

[Endoscopic ultrasound in the long-term follow-up of primary lymphomas of the stomach under conservative therapy]. / Endosonographie im Langzeitverlauf primärer Magenlymphome unter konservativem Therapieansatz.

BACKGROUND AND AIMS: The stomach is the main site of primary extranodular manifestation of non-Hodgkin's lymphomas. Besides clinical staging additional to histological diagnoses, the endoscopic ultrasound (EUS) also becomes more important during follow-up courses of conservative therapy regimens (e. g. H.p. eradication; radiochemotherapy). The aim of the present study was to assess the impact of EUS during long-term observation of primary gastric lymphomas and to outline possible changes of the gastric wall. PATIENTS AND METHODS: Within the scope of 2 prospective multicenter study on primary gastrointestinal non-Hodgkin's lymphomas (GIT-NHL), which were performed at Muenster University Hospital, 26 patients undergoing conservative treatment were examined with endoscopic ultrasound at a three-month interval between 01/1992 and 11/1998. The mean survey period was 28 months (range 7-62). RESULTS: In 22 patients over a period of 21 months (range 4-51) a histological proven complete remission (CR) was found. In 2 patients only a partial remission (PR) was achieved within a time period of seven respectively eight months of survey. Two other patients developed early relapse of non-Hodgkin's lymphoma. In patients with CR the endoscopic ultrasound showed a highly significant decrease of gastric wall thickness 7 and 12 months after therapy was started. On average after 4.6 months enlarged lymph nodes were no more detectable, after 5.5 months thickness of the gastric wall and finally after 6.6 month the previous abolished layering of the gastric wall returned to normal. CONCLUSION: In patients with gastric non-Hodgkin's lymphomas endoscopic ultrasound seems to be the only valid method which demonstrates early changes of the gastric wall and its layering in an appropriate way and might therefore in addition be capable to differentiate between CR, recurrent or refractory non-Hodgkin's lymphoma.

Pancreatic intraductal ultrasonography (IDUS) allows early diagnosis of pancreatic carcinoma in situ: a case report.

A 66-year-old woman was admitted with diarrhea, weight loss, slight recurrent abdominal pain, and raised serum amylase and lipase. Lactose intolerance was diagnosed, and treatment was begun. The symptoms diminished. However, slight back pain and elevated serum amylase and lipase levels persisted. A pancreatic tumor was then suspected. Ultrasound, spiral computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance cholangiopancreatography (MRCP) examinations were inconclusive. Endoscopic retrograde cholangiopancreatography (ERCP) showed a slight narrowing of the pancreatic duct within the pancreatic body, and endoscopic ultrasound (EUS) revealed a 10 mm intrapancreatic lesion. Finally, intraductal ultrasonography (IDUS) reliably identified a small pancreatic tumor. The tumor was resected, and histology confirmed a well-differentiated adenocarcinoma in situ (UICC stage 0, TisN0M0). This case shows that using high-resolution imaging techniques such as EUS plus IDUS, small malignant pancreatic lesions can be detected at an early stage, when curative action is possible.

Papillary mesothelioma of the peritoneum in the absence of asbestos exposure.

BACKGROUND: Malignant mesothelioma of the peritoneum is a very rare neoplasm, commonly associated with asbestos exposure and often rapidly fatal. Well Differentiated Papillary Mesothelioma of the Peritoneum (WDPMP) is regarded as a less aggressive variety of the tumor. Progressive ascites is often the only clinical manifestation of the disease and differentiation of WDPMP from benign mesothelial hyperplasia or adenocarcinoma is difficult. PATIENTS AND METHODS: Here we report the case of a 45-year-old patient who presented with ascites but without evidence of portal hypertension, liver disease or abdominal malignancy. On diagnostic laparoscopy small tumor nodules were found to cover the parietal peritoneum and the greater omentum and histopathologically corresponded to papillary mesothelial hyperplasia with minimal nuclear atypia. Histochemically biopsies were positive for Calretinin, Cytokeratins and Epithelial Membrane Antigen (EMA). Based on these findings the diagnosis of WDPMP was made and the patient was closely followed without primary cytostatic therapy. CONCLUSIONS: Progressive ascites was the only clinical symptom in this patient, while liver disease, portal hypertension and gastrointestinal malignancies were ruled out by clinical, laboratory and imaging techniques. Laparoscopic biopsy revealed WDPMP to be the underlying disease. Immunocytochemistry is required to establish the diagnosis of this rare malignant disorder which is even more uncommon in the absence of a history of asbestos exposure. Due to the indolent course of WDPMP therapy should only be initiated when signs of rapid tumor progression become apparent.

High-dose interferon alpha-2a with ribavirin and amantadine in naïve chronic hepatitis C patients--results of a randomized, prospective, pilot study.

BACKGROUND: Hepatitis C viral kinetic studies have demonstrated the increased anti-viral effect of higher than standard dosages of interferon and of daily treatment schedules. AIM: To compare, in a prospective, randomized, controlled trial, the efficacy and safety of high-dose interferon-alpha therapy vs. standard-dosage interferon-alpha therapy, in a triple therapy combination with ribavirin and amantadine. METHODS: Previously untreated patients with chronic hepatitis C were randomized to the standard interferon-alpha group (n = 15), receiving thrice weekly 6 MU interferon-alpha for 12 weeks, followed by 3 MU interferon-alpha for 36 weeks, or the high-dose interferon-alpha group (n = 15), receiving daily 9 MU interferon-alpha for 4 weeks, followed by 6 MU (weeks 5-8), 3 MU (weeks 9-12) and 1.5 MU (weeks 13-48) interferon-alpha. All patients were given ribavirin (1000-1200 mg) and amantadine (200 mg) daily for 48 weeks. RESULTS: At the end of treatment and after the 24-week follow-up period, serum hepatitis C virus RNA was undetectable in eight (53%) and six (40%) patients treated with standard-dosage interferon-alpha, respectively, compared with 11 (73%) and 10 (67%) treated with high-dose interferon-alpha, respectively (not significant). The safety profile of both treatment regimens was similar. Severe adverse events leading to withdrawal from the study occurred in one patient (7%) in each group, and in both groups one patient (7%) was lost during therapy for unknown reasons. CONCLUSIONS: The findings suggest that, although the difference between the response rates of standard and high-dose interferon-alpha regimens (within a triple anti-viral therapy combination) did not reach statistical significance, there was a clear trend towards a higher response with high-dose interferon-alpha therapy and an equal safety profile.

Endoscopic transpapillary biopsies and intraductal ultrasonography in the diagnostics of bile duct strictures: a prospective study.

BACKGROUND: In bile duct strictures, examination of wall layers by intraductal ultrasonography (IDUS) performed during endoscopic retrograde cholangiopancreatography (ERCP) may be diagnostically useful. METHODS: In the present study 60 patients with bile duct strictures of unknown aetiology were examined preoperatively by ERCP, including transpapillary biopsies and IDUS. Histopathological correlation was available for all patients undergoing these procedures. RESULTS: Postoperative diagnosis revealed 30 pancreatic carcinomas, 17 bile duct cancers, three gall bladder cancers, and 10 benign bile duct strictures. Using endoscopic transpapillary forceps biopsies (ETP), a correct preoperative diagnosis was achieved in 36 of 60 patients (60% of cases). Among the 50 malignant tumours, preoperative diagnosis by ETP revealed a sensitivity of 52% and a specificity of 100%. ERCP supplemented by IDUS allowed for correct preoperative diagnosis in 83% of cases (50 of 60 patients), which was significantly higher than the accuracy of ETP (p=0.008). By combining ETP with IDUS, a correct preoperative diagnosis was made in 59 of 60 patients resulting in an accuracy rate of 98%. CONCLUSIONS: Because of its low accuracy, exclusive use of ETP is not a reliable diagnostic tool for a definitive preoperative diagnosis of bile duct strictures. By combining IDUS and ETP with ERCP however, preoperative diagnostic accuracy can be improved substantially.

Generation of GW radiation pulses from a VUV free-electron laser operating in the femtosecond regime.

Experimental results are presented from vacuum-ultraviolet free-electron laser (FEL) operating in the self-amplified spontaneous emission (SASE) mode. The generation of ultrashort radiation pulses became possible due to specific tailoring of the bunch charge distribution. A complete characterization of the linear and nonlinear modes of the SASE FEL operation was performed. At saturation the FEL produces ultrashort pulses (30-100 fs FWHM) with a peak radiation power in the GW level and with full transverse coherence. The wavelength was tuned in the range of 95-105 nm.

[Decompressive craniectomy for severe intracranial hypertension due to cerebral infarction or meningoencephalitis]. / Kraniektomie bei Hirndrucksteigerung durch Hirninfarkte und Meningoenzephalitis.

We describe the clinical course and outcome following decompressive craniectomy in six patients. Five patients suffered from severe intracranial hypertension due to middle cerebral artery infarction. In one patient the cause was bacterial meningoencephalitis. Acute clinical and neuroradiological signs of intracranial hypertension were seen in all cases. Following ineffective conventional brain edema therapy, decompressive craniectomy was undertaken. In five cases intracranial pressure was sufficiently lowered. One patient developed transtentorial herniation with subsequent brain death. Four patients with middle artery infarction showed moderate neurological disorders and one patient with bacterial meningoencephalitis recovered completely after treatment. Craniectomy in malignant middle artery infarction should be taken into consideration if conventional brain edema therapy does not sufficiently reduce critically raised intracranial pressure. Craniectomy provides development of brain herniation. This treatment may reduce high lethality rate and high frequency of severe neurological disorders.