Stereotactic radiosurgery and radiotherapy for resected brain metastases: current pattern of care in the Radiosurgery and Stereotactic Radiotherapy Working Group of the German Association for Radiation Oncology (DEGRO).

PURPOSE: Preoperative stereotactic radiosurgery (SRS) of brain metastases may achieve similar local control and better leptomeningeal control rates than postoperative fractionated stereotactic radiotherapy (FSRT) in patients treated with elective metastasectomy. To plan a multicentre trial of preoperative SRS compared with postoperative FSRT, a survey of experts was conducted to determine current practice. METHODS: A survey with 15 questions was distributed to the DEGRO Radiosurgery and Stereotactic Radiotherapy Working Group. Participants were asked under what circumstances they offered SRS, FSRT, partial and/or whole brain radiotherapy before or after resection of a brain metastasis, as well as the feasibility of preoperative stereotactic radiosurgery and neurosurgical resection within 6 days. RESULTS: Of 25 participants from 24 centres, 22 completed 100% of the questions. 24 respondents were radiation oncologists and 1 was a neurosurgeon. All 24 centres have one or more dedicated radiosurgery platform and all offer postoperative FSRT. Preoperative SRS is offered by 4/24 (16.7%) centres, and 9/24 (37.5%) sometimes recommend single-fraction postoperative SRS. Partial brain irradiation is offered by 8/24 (33.3%) centres and 12/24 (50%) occasionally recommend whole-brain irradiation. Two centres are participating in clinical trials of preoperative SRS. SRS techniques and fractionation varied between centres. CONCLUSION: All responding centres currently offer postoperative FSRT after brain metastasectomy. Approximately one third offer single-fraction postoperative SRS and four already perform preoperative SRS. With regard to potential co-investigators, 18 were identified for the PREOP­2 multicentre trial, which will randomise between preoperative SRS and postoperative FSRT.

Adjuvant radiochemotherapy in patients with locally advanced high-risk cervical cancer.

BACKGROUND AND PURPOSE: The aim of this retrospective study was to analyze the outcome of patients with locally advanced cervical carcinoma treated by adjuvant radiochemotherapy and to determine risk factors for local and distant relapse. Furthermore, acute and late effects of treatment were recorded. PATIENTS AND METHODS: A total of 72 patients with FIGO stages I-III cervical carcinoma were treated by radical hysterectomy, pelvic lymphadenectomy, and postoperative radiochemotherapy. Only patients with positive pelvic lymph nodes, parametrial involvement, positive margins, or tumor bulk were eligible. Patients were irradiated with a standard pelvic field (50.4 Gy in 28 fractions). The majority of patients received platinum-based chemotherapy. RESULTS: After a median follow-up of 37 months, estimated 1-, 2-, and 4-year disease-free survival (DFS) and overall survival (OS) rates were 89%, 80%, 68% and 95%, 88%, 76%, respectively. Nine of the 72 patients had pelvic recurrences including only 1 isolated local failure; 23 of the 72 patients presented with distant relapse. The majority of relapses occurred within the first 3 years after adjuvant treatment. The number of positive pelvic lymph nodes (> 1) was the strongest prognostic factor for DFS. Treatment was well tolerated with transient acute hematologic (~30%) and gastrointestinal (~30%) grade 3 toxicity. Small bowel obstruction (~6%) was the only important late sequelae. CONCLUSION: Adjuvant radiochemotherapy in patients with advanced cervical cancer and several risk factors is highly effective to prevent local relapse. Future efforts to improve outcome should be placed on improvement of systemic control especially in subgroups with high-risk features for distant relapse. Combined treatment was well tolerated with moderate acute and late toxicity.

Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer.

BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is clinically defined by familial clustering of colorectal cancer and other associated tumours. METHODS: By thorough molecular and clinical evaluation of 41 families, two different groups were characterised: group 1, 25 families with truncating mutations in MLH1 or MSH2 (12 novel mutations); and group 2, 16 Amsterdam positive families without mutations in these genes and without microsatellite instability in their corresponding tumours. RESULTS: Significant clinical differences between these two groups were found. Firstly, earlier age of onset for all colorectal cancers (median 41 v 55 years; p < 0.001) and all tumours (median 43 v 56 years; p = 0.022) was observed, comparing groups 1 and 2. Secondly, 68% of the index colorectal cancers were localised proximally of the splenic flexure in group 1 compared with 14% in group 2 (p < 0.010). Thirdly, more synchronous and metachronous colorectal (p = 0.017) and extracolorectal tumours (p < 0.001) were found in group 1. Fourthly, a higher colorectal adenoma/carcinoma ratio (p = 0.030) and a tendency towards more synchronous or metachronous adenomas in group 2 (p = 0.084) was observed, indicating a slower progression of adenomas to carcinomas. As three mutation negative tumours revealed chromosomal instability after comparative genomic hybridisation, these tumours may be caused by one or more highly penetrant disease alleles from the chromosomal instability pathway. CONCLUSION: These data show that HNPCC includes at least two entities with clinical and molecular differences. This will have implications for surveillance programmes and for cancer research.

Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid inducible kinase SGK1.

The stimulation of cell proliferation by insulin like growth factor IGF-1 has previously been shown to depend on activation of voltage gated K(+) channels. The signaling involved in activation of voltage gated K(+) channel Kv1.3 includes the phosphatidylinositol-3 (PI3) protein kinase, 3-phosphoinositide dependent protein kinase PDK1 and the serum and glucocorticoid inducible kinase SGK1. However, nothing is known about mechanisms mediating the stimulation of Kv1.3 by SGK1. Most recently, SGK1 has been shown to phosphorylate and thus inactivate the ubiquitin ligase Nedd4-2. The present study has been performed to explore whether the regulation of Kv1.3 involves Nedd4-2. To this end Kv1.3 has been expressed in Xenopus oocytes with or without coexpression of Nedd4-2 and/or constitutively active (S422D)SGK1. In oocytes expressing Kv1.3 but not in water injected oocytes, depolarization from a holding potential of -80 mV to +20 mV triggers rapidly inactivating currents typical for Kv1.3. Coexpression of Nedd4-2 decreases, coexpression of (S422D)SGK1 enhances the currents significantly. The effects of either Nedd4-2 or of SGK1 are abrogated by destruction of the respective catalytic subunits ((C938S)Nedd4-2 or (K127N)SGK1). Further experiments revealed that wild type SGK1 and SGK3 and to a lesser extent SGK2 are similarly effective in stimulating Kv1.3 in both, presence and absence of Nedd4-2. It is concluded that Kv1.3 is downregulated by Nedd4-2 and stimulates by SGK1, SGK2, and SGK3. The data thus disclose a novel mechanism of Kv1.3 channel regulation.

K+ channel activation by all three isoforms of serum- and glucocorticoid-dependent protein kinase SGK.

The serum- and glucocorticoid-dependent kinase SGK1 was originally identified as a glucocorticoid-sensitive gene. Subsequently, the two homologous kinases SGK2 and SGK3 have been cloned, being products of distinct genes, which are differentially expressed and share 80% identity in amino acid sequence in their catalytic domains. While SGK1 has been shown to activate ion channels, including K(+) channels, the functions of SGK2 and SGK3 have not been examined. The present study was therefore performed to elucidate the effect of SGK1, SGK2, and SGK3 on electrical properties of renal epithelial cells. To this end human embryonic kidney (HEK293) cells were transfected with the kinases and ion-channel activity determined using the patch-clamp technique. In non-transfected cells and in cells transfected with the empty GFP construct a voltage-gated K(+) current was observed amounting to 303+/-19 pA ( n=13) and 299+/-29 pA ( n=23), respectively. Transfection with SGK1, SGK2 or SGK3 increased the voltage-gated K(+) current to 1056+/-152 pA ( n=17), 555+/-47 pA ( n=17), and 775+/-98 pA ( n=16), respectively. The K(+) current was fully blocked by 3 mM tetraethylammonium chloride and inhibited 45% by the Kv1 channel blocker margatoxin (10 nM). In dual electrode voltage-clamp experiments SGK isoforms up-regulated Kv1 voltage-gated K(+)channels expressed in Xenopus laevis oocytes. The present observations thus reveal a powerful stimulating effect of all three isoforms of SGK on K(+) channels. Those effects may participate in regulation of epithelial transport, cell proliferation, and neuromuscular excitability.

Cerebral localization and regulation of the cell volume-sensitive serum- and glucocorticoid-dependent kinase SGK1.

The serum- and glucocorticoid-dependent kinase SGK1 is regulated by alterations of cell volume, whereby cell shrinkage increases and cell swelling decreases the transcription, expression and activity of SGK1. The kinase is expressed in all human tissues studied including the brain. The present study was performed to localize the sites of SGK1 transcription in the brain, to elucidate the influence of the hydration status on SGK1 transcription and to explore the functional significance of altered SGK1 expression. Northern blot analysis of human brain showed SGK1 to be expressed in all cerebral structures examined: amygdala, caudate nucleus, corpus callosum, hippocampus, substantia nigra, subthalamic nucleus and thalamus. In situ hybridization and immunohistochemistry in the rat revealed increased expression of SGK1 in neurons of the hippocampal area CA3 after dehydration, compared with similar slices from brains of euvolaemic rats. Additionally, several oligodendrocytes, a few microglial cells, but no astrocytes, were positive for SGK1. The abundance of SGK1 mRNA in the temporal lobe, including hippocampus, was increased by dehydration and SGK1 transcription in neuroblastoma cells was stimulated by an increase of extracellular osmolarity. Co-expression studies in Xenopus laevis oocytes revealed that SGK1 markedly increased the activity of the neuronal K+ channel Kv1.3. As activation of K+ channels modifies excitation of neuronal cells, SGK1 may participate in the regulation of neuronal excitability.

[Management of hemorrhage and perforation following endoscopic sphincterotomy]. / Management von Blutungen und Perforationen nach endoskopischer Sphinkterotomie.

Bleeding and perforation are rare but dangerous complications of diagnostic and therapeutic ERCP and endoscopic sphincterotomy (EST). To evaluate the clinical outcome of patients treated for complicated EST in our surgical department, data were collected prospectively between 1/1995 and 3/2000. A total of 9 patients were admitted to our department, 7 women and 2 men, average age 60 (range 41-72) years. 5 patients were treated for severe hemorrhage, all of them underwent laparotomy following duodenotomy and oversewing of the sphincterotomy site. In average 10 hours (range 4-20) after endoscopy. One of these patients died due to multiple organ failure. In 4 additional patients a retroperitoneal perforation was discovered, 2 of these patients underwent laparotomy and drainage of the retroperitoneal cavity. The other two patients were sufficiently treated by percutaneous drainage. One of the patients, who underwent surgical drainage for retroperitoneal perforation died. In conclusion for severe hemorrhage duodenotomy and oversewing of the bleeding site is recommended in combination with common bile duct T-drain or other draining procedures. The treatment for perforation should depend on the clinical finding. A laparotomy seems not always to be necessary.

Deep prosthesis infection in incisional hernia repair: predictive factors and clinical outcome.

OBJECTIVE: To evaluate the incidence of prosthetic infection in incisional hernia repairs, to determine whether there are any factors associated with prosthetic infection and to describe the clinical outcome. DESIGN: Retrospective clinical study. SETTING: Teaching hospital, Germany. SUBJECTS: 121 consecutive patients who underwent incisional hernia repair in our department from December 1994 to December 1999. INTERVENTION: Hernia repair by implantation of an alloplastic prosthesis by the Stoppa-Rives technique. MAIN OUTCOME MEASURES: Postoperative deep prosthetic infection and associated factors. RESULTS: All 121 patients had the mesh implanted in the subfascial plane, 77 had a polypropylene mesh (Prolene) (64%), 7 had a polyester mesh (Mersilene) (6%), and 37 patients had a expanded polytetrafluoroethylene patch (ePTFE, Gore-Tex) (31%). Postoperatively the mesh became infected in 8 patients (7%), a mean of 4.5 months (range 0.5-16) after hernia repair. All three infected ePTFE patches had to be removed whereas drainage was sufficient treatment for the infected polypropylene and polyester meshes. CONCLUSION: Once a mesh infection is verified adequate drainage seems to be sufficient for polypropylene and polyester meshes but ePTFE patches should be removed.

[Experiences with reconstruction of large abdominal wall cicatricial hernias using Stoppa-Rives pre-peritoneal mesh-plasty]. / Erfahrungen mit der Rekonstruktion grosser Bauchwandnarbenhernien mittels präperitonealer Netzplastik nach Stoppa-Rives.

BACKGROUND: The observed recurrence-rate up to 20-50% of conventional incisional-hernia repair might be improved by alloplastic hernia repair in "sublay-technique" described by Stoppa and Rives. METHODS: From 12/94 to 12/97 122 pt. underwent surgery of incisional hernia of whom 50 had a very large abdominal wall defect so that hernia repair by alloplastic technique was necessary. All 50 pt. had mesh-implantation in subfascial plane, 28 pt. by ePTFE-patch (Gore-Tex) and 22 pt. by polypropylen-mesh (Prolene). RESULTS: The implantation-procedure required a mean time of 165 min. (range 55-345 min.). There were pulmonary complications in 2 patients (4%) of whom one had to be ventilated over 34 days, prosthesis-infection occurred in 3 pt. (6%). Follow-up on average 19 months (range 5-44 months) postoperatively revealed 5 hernia-recurrences (10.4%) in 48 patients. CONCLUSION: Mesh-implantation for hernia repair in sublay-technique requires intensive preparation of preperitoneal plane. Thus it took approximately 3 hours for mesh-implantation in this study. From our data Stoppa-Rives-procedure seems to be effective for 4-repair of large incisional hernias and allows immediate abdominal wall stress.

[Brief preoperative radiotherapy in surgical therapy of rectal carcinoma. Long-term results of a prospective randomized study]. / Präoperative Kurzzeitstrahlentherapie in der chirurgischen Therapie des Rectumcarcinoms. Langzeitergebnisse einer prospektiv-randomisierten Studie.

To ascertain whether preoperative short-term radiotherapy can improve local tumor control and the long-term survival of patients with operable rectal cancer, a prospective randomised trial was performed from 1988 to 1993. Ninety-three patients with rectal cancer were either directly treated with surgery (n = 46) or underwent preoperative radiotherapy with 5 x 3.3 Gy irradiation and operation within 48 h (n = 47). If indicated (T4, UICC stage III) patients also received postoperative irradiation. Comparison of the methods of operation (abdominoperineal amputation versus anterior resection) revealed no significant difference in 5-year survival rate (P = 0.393). Local control of R0-resected tumors was improved after preoperative irradiation (P = 0.08). The 5-year survival rate was significantly higher after preoperative short-term radiotherapy (P = 0.027). Preoperative radiotherapy is not an independent factor according to overall survival (P = 0.078) and local recurrence (P = 0.07). In agreement with the results of other authors the present study indicates improved local tumor control of rectal cancer after preoperative radiation therapy. The 5-year survival rate was significantly better after preoperative radiotherapy than after surgery alone.

Natural competence for DNA transformation in Helicobacter pylori: identification and genetic characterization of the comB locus.

The gram-negative bacterial pathogen Helicobacter pylori, an important aetiological agent of gastroduodenal disease in humans, belongs to a group of bacterial species displaying competence for genetic transformation. Here, we describe the comB gene locus of H. pylori involved in DNA transformation competence. It consists of a cluster of four tandemly arranged genes with partially overlapping open reading frames, orf2, comB1, comB2 and comB3, constituting a single transcriptional unit. Orf2 encodes a 37-amino-acid peptide carrying a signal sequence, whereas comB1, comB2 and comB3 produce 29 kDa, 38 kDa and 42 kDa proteins, respectively, as demonstrated by immunoblotting with specific antisera. For Orf2 and ComB1, no homologous proteins were identified in the database. For ComB3, the best homologies were found with TraS/TraB from the Pseudomonas aeruginosa conjugative plasmid RP1 and TrbI of plasmid RP4, VirB10 from the Ti plasmid of Agrobacterium tumefaciens and PtlG, a protein involved in secretion of pertussis toxin of Bordetella pertussis. Defined transposon knock-out mutants in individual comB genes resulted in transformation-defective phenotypes ranging from a 90% reduction to a complete loss of the natural transformation efficiency. The comB2 and comB3 genes show homology to HP0528 and HP0527, respectively, located on the cagII pathogenicity island of H. pylori strain 26695.

[Identification of hashish samples with inductively coupled high-frequency plasma emission spectrometry and neutron activation analysis and data handling with neuronal networks. 1. Methods for the quantitative determination of characteristic trace elements]. / Identitätsprüfung von Haschischproben mittels induktiv gekoppelter Hochfrequenzplasma-Emissions-Spektrometrie und Neutronenaktivierungs-Analyse und Datenverarbeitung mit neuronalen Netzen. 1. Mitt: Verfahren zur quantitativen Bestimmung charakteristischer Spurenelemente.

Neutron activation analysis (NAA) and inductively coupled plasma emission spectrometry (ICP-AES) were used to quantify the relative contents of Fe, Sc, Ce, Pa, Cr, Co, respectively the absolute contents of Cr, Zn, Mn, Fe, Mg, Al, Cu, Ti, Ca, Sr in hashish samples, seized in different countries. The samples were processed after dry ashing by means of instrumental NAA and after wet mineralization by means of ICP-AES. For determination of the sampling and measurement errors, one of the samples was analyzed repeatedly with both methods. Classifying hashish samples with regard to concentration of certain elements could be done by artificial neural networks with a modified backpropagation algorithm. By this way, identity and non identity of one unknown sample with one of many different samples as data pool can be ascertained, on principle.

[Increase of phlegmonous forms of infection following angina]. / Uber eine Häufung phlegmonöser Formen von Sepsis nach Angina.

A sudden mini-epidemic of severe septic cervical soft tissue phlegmons following pharyngitis with thrombophlebitis of the jugular veins, mediastinitis and meningeal irritation posed problems of diagnosis and therapy because the typical symptoms were masked by the preceding treatment with antibiotics. The disease could only be partially controlled by intensive care. Three illustrative cases are reported.

[Tonsillectomy in factor XII deficiency]. / Tonsillektomie bei Faktor-XII-Mangel.

A case of tonsillectomy in a 22-year-old female patient suffering from isolated deficiency of factor XII is presented. The importance of close cooperation of surgeon and haemostaseologist is pointed out. Preoperative, intraoperative and postoperative precautions are discussed.

The epidemiology of sarcoidosis in Rochester, Minnesota: a population-based study of incidence and survival.

Using the unique data resources of the Rochester Epidemiology Project, a community-based study of clinically diagnosed sarcoidosis was conducted. In this population-based study, the 75 Rochester, Minnesota, residents with sarcoidosis initially diagnosed between 1946 and 1975 (incidence cohort) were followed through their comprehensive medical records in the community to January 1, 1982. The age- and sex-adjusted incidence of sarcoidosis was 6.1 per 100,000 person-years. The age-adjusted incidence of sarcoidosis was similar in males (5.9) and females (6.3), with a peak incidence in males 30 to 39 years old (18.7) and in females 40 to 49 years old (15.6). A secular increase in sarcoidosis incidence was noted in the period 1946-1975 for females, with a marked increase in the number and percentage of biopsy-documented cases. Seasonal variation in sarcoidosis incidence was minimal, with a seasonal peak of 31% of the Rochester cases being diagnosed during the spring (March-May). Survival, compared with that of the North Central United States, was unimpaired in this sarcoidosis incidence cohort.

[On the precision of copper determination in liver punctates by neutron activation analysis]. / Zur Genauigkeit aktivierungsanalytischer Kupferbestimmungen in Leberpunktaten.

Variation in the copper contents of liver biopsy specimens was determined by destructive activation analysis of 39 punctates of one liver. The error of method was evaluated by repeated analysis of both the NBS standard Bovine Liver material and homogenized liver. The inhomogeneity of the biopsy specimens with regard to their copper concentrations was shown by comparison of the coefficients of variation. Because of the relatively small variability of the copper concentrations, however, the analysis of single liver punctates provides adequate information for the diagnosis and course of Morbus Wilson.

Detection of repeated arsenical poisoning by neutron activation analysis of foot nail segments.

In one case of repeated ingestions of arsenic over a period of one year, the value of sectional toe nail analysis was investigated. The arsenic determinations were performed by instrumental neutron activation analysis. After subdividing the nail transversely into segments of 0.5 mm length, several maxima and minima of arsenic concentrations were found. Taking the nail growth into consideration, these characteristics of curve correspond to the known dates of treatments and of dismissals from the hospital. The results exclude an external arsenic contamination of the nail.