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Zusammenfassung Ziel: Der Ausschluss von Neovaskulaten via S100-Protein ist ungenau. Geklärt werden sollte, ob NGF (nerve growth factor) valider ist, zumal eine angiogenetische Potenz besteht. Methode: Nervenfaserfärbung gesunder (n = 16), variköser (n = 110) und von Rezidivvenen der Krosse (n = 24) mit S100- und NGF-Antikörpern (AK). Semiquantitative Evaluation der jeweiligen Nervenfaserdichte, Quotientenbildung zur Darstellung der Unterschiede. Zusätzlich Evaluation des prozentualen Anteils gefärbter Präparate. Ergebnisse: In allen Gruppen Nachweisbarkeit adventitieller Nervenfasern mit beiden AK. In Kontroll- und Varikosisgruppe war die NGF-Faserdichte kleiner als bei S100. Bei Rezidiven erreichte die NGF-Faserdichte Werte wie bei S100. Gegensätzlich zur NGF-Faserdichte sind S100-Werte bei Rezidiven kleiner, als bei S100-Kontrollen. Geringste Faserdichte für beide Proteine in der Varikosisgruppe. S100-Rezidive hatten den geringsten Anteil anfärbbarer Fasern. Schlussfolgerung: NGF könnte die venoneuronale Regeneration triggern und als Marker spezifischer als S100 sein. Die Varikogenese könnte durch eine reduzierte Venenwandinnervation (venoneuronale Degeneration) induziert werden.

Zusammenfassung Ziel: In zahlreichen Geweben gilt VEGF (vascular endothelial growth factor) als stärkster Stimulator der Angiogenese, die er u.a. mittels seines Rezeptors initiieren kann. Valide Untersuchungen zur mediatorgetriggerten Ätiopathogenese des varikösen Formenkreises existieren nahezu nicht. Vorliegende Untersuchung sollte die Funktion von VEGF und dessen Rezeptor für die Varikogenese und Neoangiogenese nach Krossektomie klären helfen. Patienten, Methode: Konsekutive Zuteilung von Patienten in Kontrollgruppe (n = 16), in Gruppe mit Primärvarikosis (n = 110) und in Gruppe mit Neovaskulatbildung (n = 24). Entnahme der Proben direkt an der Junktion zum tiefen Venensystem und sofortiges Abpräparieren von periadventitiellem Gewebe. Für die Rezidivgruppe wurden nur Präparate berücksichtigt, die den makroskopischen Kriterien von Neovaskulaten (Dünnwandigkeit, gewundener Verlauf, in Narbengewebe eingebettet) entsprachen. Immunhistochemische Färbung mit primären Antikörpern gegen VEGF und VEGF-Rezeptor. Anschließend semiquantitative Auswertung durch zwei geblindete Untersucher. Ergebnisse: Von der Kontrollgruppe über die Gruppe mit Primärvarikosis bis zu der mit Neovaskulatbildung kommt es zur statistisch signifikanten Zunahme der durchschnittlichen intimalen Färbeintensität und des prozentualen Anteils gefärbter Präparate. Schlussfolgerung: VEGF und VEGF-Rezeptor scheinen eine wesentliche Rolle in der Ätiopathogenese der Neovaskulatbildung nach Krossektomie zu spielen. Auch an der Varikogenese scheinen sie beteiligt zu sein. Für die Varikogenese kann nicht ausgeschlossen werden, dass diese Mediatoren erst nach Initiierung der Varikogenese verstärkt exprimiert werden.

This report evaluates the ring-ring option for eRHIC as a lower risk alternative to the linac-ring option. The reduced risk goes along with a reduced initial luminosity performance. However, a luminosity upgrade path is kept open. This upgrade path consists of two branches, with the ultimate upgrade being either a ring-ring or a linac-ring scheme. The linac-ring upgrade could be almost identical to the proposed linac-ring scheme, which is based on an ERL in the RHIC tunnel. This linac-ring version has been studied in great detail over the past ten years, and its significant risks are known. On the other hand, no detailed work on an ultimate performance ring-ring scenario has been performed yet, other than the development of a consistent parameter set. Pursuing the ring-ring upgrade path introduces high risks and requires significant design work that is beyond the scope of this report.

Successful preoperative localisation of parathyroid glands is essential for minimal-invasive surgery of hyperparathyroidism. The knowledge of the sonomorphology of the parathyroid glands, therefore, is an important prerequisite. This article shows that the sonomorphology of normal and pathologically transformed parathyroid glands is subject to a wide variety. The often simplified standard description of parathyroid glands as hypoechogenic and oval may lead to false negative cervical ultrasound examinations.

This case report will give an example for the necessity of performing an ultrasound examination of the neck before resection of the parathyroid glands. In end-stage renal failure a 38-year-old man developed secondary hyperparathyroidism (HPT). Four glands were removed. Two years later the patient revealed persisting HPT. At this point an ultrasound examination was performed and demonstrated a fifth parathyroid gland located inside the thyroid gland. The case illustrates the benefit of cervical ultrasound, even in cases of secondary hyperparathyroidism, prior to any cervical exploration.

Komplexe supraaortale Gefasbefunde bedurfen eines individuellen Therapiemanagements. Wir berichten uber einen 74-jahrigen Patienten, bei dem 1980 bei einem supraaortalen komplexen Verschlussprozess ein Subklavia-Subklavia-Bypass implantiert worden war und der sich jetzt mit einem Aneurysma in Bypassmitte, einer Abgangsstenose der linken A. subclavia, einem Verschluss des Truncus brachiocephalicus und der linken A. carotis communis vorstellte. Wahrend des stationaren Aufenthalts kam es zum spontanen Bypassverschluss mit kompensierter Ischamie. Primar wurde die linke A. subclavia mittels PTA und Stent versorgt, dann erfolgte die Neuanlage des Subklavia-Subklavia-Bypasses. Neurologie und Bildgebung waren postoperativ regelgerecht. Komplexe supraaortale Gefasbefunde konnen in Kombination interventioneller und offener Verfahren erfolgreich behandelt werden.

The Efremov Institute and DESY have designed in collaboration high performance normal conducting quadrupole magnets for the HERA luminosity upgrade. One of the most ambitious is the type GA. It has a length of 3.85 m, a pole radius of 35 mm and must provide a maximum gradient of 26 T/m. The required field nonlinearity is /spl Delta/B/B/spl les/3/spl times/10/sup -4/ at a reference radius of 25 mm. A special feature is a clearance between the coil and the iron yoke that holds the separate electron beam pipe. This contribution deals with the production of the magnets and the results of the mechanical as well as magnetic measurements in comparison with the design values.

The Efremov Institute and DESY have designed in collaboration high performance normal conducting septum half-quadrupole magnets for the HERA luminosity upgrade. These magnets of the type GM have a length of 3.4 m. The 85 mm thick vertical mirror plate is cut out near the origin to provide a septum of 5 mm thickness. By this way a virtually field free space allows the passage of the separate e-beam very close to the high gradient field region.

For the HERA luminosity upgrade two types of compact multifunction superconducting magnets, denoted GO and GG, are needed for installation inside the existing ZEUS and H1 experimental detectors in the year 2000. These magnets contain multiple concentric coil layers organized into independently powered quadrupole, dipole, skew quadrupole and skew dipole coil windings. Production of the first of three GO magnets using a newly constructed coil winding machine is currently in progress at BNL. The GG design is being completed and parallel production at BNL of three GG units will start soon. In this paper we highlight HERA upgrade magnet design challenges, present our production solutions and relate experience and results gained from warm and cold testing of short model magnets.

HISTORY AND CLINICAL FINDINGS A 62-year-old woman was admitted because of sudden onset of increasingly severe pain in the left lower leg and foot. She also reported having had diarrhoea for the past few days. INVESTIGATIONS Physical examination revealed a cold and pale left leg below the knee joint. Peripheral sensory and motor functions were normal. While femoral and popliteal arterial pulses were normally palpable, foot pulses were not felt. Magnetic resonance angiography of the pelvic and leg arteries showed an embolic occlusion of the left popliteal artery extending to the arteries of the lower leg. DIAGNOSIS, TREATMENT AND COURSE Because of the acute embolic occlusion of the deep femoral and popliteal arteries an embolectomy of the deep and superficial femoral arteries was performed. The source of the emboli had been a free-floating thrombus in the descending aorta. Subsequently a persistent fever and leukocytosis occurred which had been cause by a septic splenic infarction. A conventional splenectomy was done. The postoperative was protracted, because of the development of a pancreatic fistula, which responded to treatment. Anticoagulation treatment started. The patient was finally discharged after more than five weeks. CONCLUSION After urgent surgical treatment of an acute peripheral arterial occlusion its cause needs to be identified. Transthoracic echocardiography, computed tomography and magnetic resonance angiography are the methods of choice. If there is a floating aortic thrombus further embolizations, including septic splenic emboli may occur.

Anastomotic leakage remains a key factor for morbidity after colonic surgery. The aim of the study was to analyse the outcome of different therapeutical approaches.Of 1731 consecutive patients undergoing colonic resection between 1998 and 2005 at our institution, 67 patients with anastomotic leakage were identified from a prospective database. A logistic regression model was used to determine factors which influenced the therapeutic approach and outcome.The overall anastomotic leakage rate was 3.5%. All patients were re-operated. The anastomosis was resected without restoration of continuity in 31 but preserved in 36 patients. An ileostomy was constructed in 27 of 36 patients with anastomotic leakage after repair or revision of the anastomosis, the remaining nine cases were treated without ileostomy. Five of these latter nine vs three of the 27 patients with ileostomy experienced re-leakage (P = 0.05). The overall mortality was 25%. The Mannheim Peritonitis Index was 17.44 for survivors vs 25.64 for nonsurvivors (P0.001). Restoration of intestinal continuity was performed in 95% of the patients with ileostomy and in 88% after Hartmann's procedure. Multivariate analysis identified multi organ failure as the only factor predictive of a fatal outcome (P0.001). An ASA-score of more than 2 (P = 0.02) and peritonitis (P = 0.002) were reasons for not preserving the anastomosis.Repair or redo of the anastomosis without a protective ileostomy frequently results in failure of the procedure. After Hartmann's operation or split stoma creation a majority of patients undergo restoration of intestinal continuity.

A 62-year-old woman was admitted because of sudden onset of increasingly severe pain in the left lower leg and foot. She also reported having had diarrhoea for the past few days.Physical examination revealed a cold and pale left leg below the knee joint. Peripheral sensory and motor functions were normal. While femoral and popliteal arterial pulses were normally palpable, foot pulses were not felt. Magnetic resonance angiography of the pelvic and leg arteries showed an embolic occlusion of the left popliteal artery extending to the arteries of the lower leg.Because of the acute embolic occlusion of the deep femoral and popliteal arteries an embolectomy of the deep and superficial femoral arteries was performed. The source of the emboli had been a free-floating thrombus in the descending aorta. Subsequently a persistent fever and leukocytosis occurred which had been cause by a septic splenic infarction. A conventional splenectomy was done. The postoperative was protracted, because of the development of a pancreatic fistula, which responded to treatment. Anticoagulation treatment started. The patient was finally discharged after more than five weeks.After urgent surgical treatment of an acute peripheral arterial occlusion its cause needs to be identified. Transthoracic echocardiography, computed tomography and magnetic resonance angiography are the methods of choice. If there is a floating aortic thrombus further embolizations, including septic splenic emboli may occur.

Neoadjuvant radiation or chemoradiation followed by oncological resection is the current treatment of choice for locally advanced rectal cancer. Profound diagnostics are mandatory to stratify patients for neoadjuvant treatment or primary surgery. Here, magnetic resonance tomography most probably will become the standard modality due to its ability to predict involvement of the circumferential resection margin during surgery. While the initiation of chemoradiation in T4 rectal cancer and patients with distal tumours potentially undergoing sphincter-preserving surgery is unequivocal, the treatment of choice for the remaining patients is undecided. Here, short-term radiotherapy (5 x 5 Gy) competes with chemoradiation of different intensity. In surgical oncology, minimally invasive surgery of the rectum needs further evidence before it can be accepted as an equivalent. Finally, the increase in multimodality treatment will ultimately increase the incidence of late functional sequelae which, up to now, are underrepresented in most reports due to the priority of oncological results. Since responders to neoadjuvant treatment are the ones who benefit most from these therapies, research related to prediction of treatment response has a fundamental role.

The physics, and a design, of a Large Hadron Electron Collider (LHeC) are sketched. With high luminosity, 10^{33}cm^{-2}s^{-1}, and high energy, \sqrt{s}=1.4 TeV, such a collider can be built in which a 70 GeV electron (positron) beam in the LHC tunnel is in collision with one of the LHC hadron beams and which operates simultaneously with the LHC. The LHeC makes possible deep-inelastic lepton-hadron (ep, eD and eA) scattering for momentum transfers Q^2 beyond 10^6 GeV^2 and for Bjorken x down to the 10^{-6}. New sensitivity to the existence of new states of matter, primarily in the lepton-quark sector and in dense partonic systems, is achieved. The precision possible with an electron-hadron experiment brings in addition crucial accuracy in the determination of hadron structure, as described in Quantum Chromodynamics, and of parton dynamics at the TeV energy scale. The LHeC thus complements the proton-proton and ion programmes, adds substantial new discovery potential to them, and is important for a full understanding of physics in the LHC energy range., Version published as 2006_JINST_1_P10001. Originally contributed to the Open Symposium on European Strategy for Particle Physics Research, LAL Orsay, France, February 2006

Die erhohte Expression von VEGF-R korrespondiert zu Voruntersuchungen (VEGF) in Neovaskulaten/ Rezidivarizen und legt eine grundsatzliche Bedeutung fur die Angioneogenese bei dieser Erkrankung nahe. Der Nachweis von NGF in Neovaskulaten kann als ein weiterer Hinweis gewertet werden, dass Nervenfaserwachstum kein absolutes Ausschlusskriterium einer echten Neovaskularisation ist.

This case report will give an example for the necessity of performing an ultrasound examination of the neck before resection of the parathyroid glands. In end-stage renal failure a 38-year-old man developed secondary hyperparathyroidism (HPT). Four glands were removed. Two years later the patient revealed persisting HPT. At this point an ultrasound examination was performed and demonstrated a fifth parathyroid gland located inside the thyroid gland. The case illustrates the benefit of cervical ultrasound, even in cases of secondary hyperparathyroidism, prior to any cervical exploration.

Despite R0-resection up to 30% of patients with colorectal cancer stage UICC I and II die of recurrent disease. This tumor progression could be caused by isolated disseminated tumor cells in lymph nodes which are not detected by current staging methods. The purpose of this study was to develop a system for detecting lymphogenic tumor cell dissemination in colorectal cancer. With the established CK 20-RT-PCR we detected tumor cells in 32 of 107 histopathologically negative lymph nodes from patients with colorectal cancer. We conclude that the CK 20-RT-PCR is more sensitive than immunohistochemical methods in detecting isolated disseminated tumor cells of colorectal cancer in lymph nodes. To evaluate the prognostic significance of lymphogenic disseminated tumor cells the examination and follow-up of more patients is necessary.

We report on first experience with colliding electron and proton beams in HERA. In 1992, the first year of operation, HERA has delivered some 60(nb)/sup -1/ of e-p luminosity to the experiments H1 and ZEUS. The beam energies amounted to 26 GeV and 820 GeV. A maximum luminosity of 2.2/spl times/10/sup 29/ cm/sup -2/ s/sup -1/ has been achieved by colliding a train of nine electron bunches against nine proton bunches. A complete collection of data is contained in a reference. The beams could be brought into and held in collision without problems. The lifetime of the proton beam in collision is as long as 50h. This requires both careful matching of the electron and proton beam cross sections and also that the two orbits coincide within /spl sime/0.2/spl sigma/ beam size at the interaction point. The proton beam suffered a beam-beam tune shift of up to /spl Delta/Q/sub xspl sime/0.0018. This is close to the limit which was assumed in the design of HERA. Nonetheless, there is only little degradation in the proton beam quality in collision. Under these conditions, the proton beam fills could be stored and be made available for collision for some 24 h in HERA. >

In ep colliding beam measurements, approximate equality of electron and quark energies is desirable for good detection efficiency. In the TeV CM energy regime, synchrotron radiation makes this requirement very expensive to meet using a storage ring for the electrons. A scheme is outlined that ameliorates this problem by using a superconducting linac for electron acceleration. Parameter lists show that such an approach may be practical for next-generation ep colliders beyond HERA (Hadron Electron Ring Accelerator). An example of a 300-GeV electron beam colliding with the HERA p ring is shown. Examples up to square root s=12 TeV are given. >

The field error of the HERA magnets are examined with reference to the stability of the proton beam. The dynamics of the proton beam under the influence of the strong persistent field errors and the correction and compensation scheme of HERA is presented and discussed. It is concluded that the field quality of the HERA superconducting magnets is remarkably good. Unavoidable strong systematic persistent current sextupolar, decapolar, and dodecapolar field errors have to be compensated for by compensation coils. Differences between the production lines do not cause problems due to ordered sequences of magnet installations. Simulations of single particle stability of a proton beam in HERA at injection energy promise sufficient aperture for stable synchrobetatron oscillations. First results from the commissioning of the HERA proton ring are presented. It has been demonstrated that a proton beam can be stored in HERA at 40 GeV with a reasonable lifetime. >

A high-luminosity asymmetric beauty factory in the PETRA tunnel is discussed. The facility consists of two storage rings of 2304 m circumference, each which share the tunnel with the PETRA machine. The high energy ring (HER) of the beauty factory will be operated with a beam energy of 9.33 GeV and the beam of the low energy ring (LER) has 3.0 GeV. The concept of a broadband feedback system has been developed to control multibunch instabilities. >

17th IEEE Particle Accelerator Conference, PAC 97, Vancouver, USA, 12 May 1997 - 16 May 1997; 65 pp. (1997)., The HERA electron-proton collider at Hamburg Germany, designed for collisions of 820 GeV protons with 30 GeV electrons is now in its 6th year of operation. It delivers luminosity for the colliding beam detectors H1 and ZEUS and longitudinally polarized positrons for the internal target experiment HERMES. HERA is operated close to the design luminosity with peak values of 1.2 $\times$ 10$^{31}$ cm$^{−2}$ sec$^{−1}$. While the beam currents still fall short of expectations, the luminosity was increased by focusing the beams very tightly at the interaction points at the expense of using up most of the margins on aperture, chromaticity and beam-beam tuneshift. In 1996, an integrated luminosity of $\int$ $\mathcal{Ldt}$ = 17.2$\mathcal{pb}^{−1}$ has been delivered. Despite the strong beam-beam interactions, the degree of longitudinal polarization of the positron beam is, with (50-60)%, larger than expected. Despite the good results of HERA, more luminosity is needed for the physics program in the next decade. Preparations are underway to increase the luminosity by rebuilding the low-$\beta$ insertions. With unconventional new types of magnets, it seems to be possible to increase the luminosity substantially. The expected value is $\mathcal{L}_{peak}$ =7.5 $\times$ 10$^{31}$cm$^{−2}$sec$^{−1}$ which is five times larger than the design value.

Dynamic aperture experiments at the Fermilab Main Ring, the Tevatron, the SPS and HERA are reviewed and compared with simulations. The agreement between experiments with additional strong nonlinearities and corresponding simulations is fairly good, if the relevant parameters are sufficiently well known and included in the model. Direct comparison is more problematic if machines under normal operating conditions with relatively weak non-linear fields are considered. Nevertheless, the agreement is reasonable and discrepancies can be accounted for by known imperfections of the model.

The combined effect of non-linear fields and a tune modulation with fast and slow frequency components results in an enhanced emittance growth and increased loss rate in hadron storage rings. In the proton storage ring of HERA, a fast harmonic tune modulation is caused by ripples in the power supplies and a slow tune modulation by the ground motion in the HERA tunnel. The recognition of the damaging effect of fast tune modulation frequencies on the particle dynamics initiated attempts to compensate for the fast frequency components in HERA. The fast tune modulation frequencies in the proton beam can be measured with a phase-locked-loop and the compensation can be established by generating an additional external tune modulation with the same frequency but with a 180/spl deg/ phase difference. The following work summarizes the results of recent experiments in the proton storage ring of HERA where the generation of an additional tune modulation led to a significant reduction of the proton loss rate during luminosity operation.

The emittance growth in HERA at luminosity is about 1 /spl pi/mm-mrad/hr. Intra-beam scattering and the beam-beam interaction coupled with tune modulation account for only part of the growth. Here we discuss the contribution of random tune fluctuations in the presence of nonlinear fields to the emittance growth of protons. At injection energy, a recent experiment with noise deliberately injected into a chain of correction quadrupoles showed no significant effect on the emittance growth and loss rates except at high noise voltages. The results of this experiment are compared with a tracking study. We also present the results of a study done of the emittance growth due to the beam-beam interaction in the presence of tune noise. A future experiment to determine the effects of tune noise on the proton emittance growth rate with colliding beams is planned.

The Search for Therapeutic Gain in Radiation Oncology Novel strategies in radiation oncology aim at increasing the therapeutic gain, i.e., to decrease side effects while maintaining cure rates, or to increase cure rates at the same level of complications. Over the years, physical and biological strategies have been developed to achieve this goal. The physical development led to the possibility of precise, computer-controlled beam application by using modern imaging techniques and three-dimensional treatment planning. Improved patient immobilization methods allow minimal safety distances, resulting in steep dose gradients when used together with isocentric multi-field techniques. These predominantly stereotactic irradiation techniques yield therapeutic gain towards the tumor surrounding normal tissue. A critical issue that determines the tolerance of radiation therapy are structures at risk within the target volume. Fractionation is a reliable method to exploit the differential potential for recovery of radiation-induced DNA damage in normal tissues. Radiogenetic strategies aim at the sensibilization of tumor cells by targeting specific characteristics like mutations of p53. The reverse idea, gene-therapeutic radioprotection of normal tissue, is under investigation.

Soft tissue sarcomas (STS) are frequently resected incompletely or without an adequate margin. In such clinical situations an oncological re-resection (wide or compartmental resection or amputation) is recommended. Here, we evaluate the results of oncological re-resection for STS.Prospectively gathered data on 67 patients who underwent oncological re-resection after inadequate (intracapsular or marginal) surgery for primary soft tissue sarcomas were analyzed.STS were located in the extremities (85%) and trunk (15%). Advanced UICC stages (1992, 4th edn., 2nd Rev.), IIB-IIIB predominated (66%). Twenty-five patients received intraoperative radiotherapy. Morbidity of re-resection was 28.4%. Residual tumor was detected in 64% of the specimens and clear margins were obtained in 60 patients (90%). With a median follow-up of 57 months the overall local control in patients with tumor-free resection margins was 88% (UICC IA-IIA 100%, IIB-IIIB 82%). Patients treated by adjuvant intraoperative radiotherapy for UICC stages IIB-IIIB with clear margins achieved 90% local control. The 5-year overall survival rate was 87% in patients with tumor-free resection margins.These findings support the strategy of oncological re-resection after previously non-oncological surgery of STS and imply that re-resection is the prerequisite for any effective adjuvant therapy modality.

A study on future large accelerators [1] has considered a facility, which is designed, built and operated by a worldwide collaboration of equal partner institutions, and which is remote from most of these institutions. The full range of operation was considered including commi-ssioning, machine development, maintenance, trouble shooting and repair. Experience from existing accele-rators confirms that most of these activities are already performed 'remotely'. The large high-energy physics ex-periments and astronomy projects, already involve inter-national collaborations of distant institutions. Based on this experience, the prospects for a machine operated remotely from far sites are encouraging. Experts from each laboratory would remain at their home institution but continue to participate in the operation of the machine after construction. Experts are required to be on site only during initial commissioning and for par-ticularly difficult problems. Repairs require an on-site non-expert maintenance crew. Most of the interventions can be made without an expert and many of the rest resolved with remote assistance. There appears to be no technical obstacle to controlling an accelerator from a distance. The major challenge is to solve the complex management and communication problems., Comment: ICALEPCS 2001 abstract ID No. FRBI001 invited talk submitting author F. Willeke 5 pages, 1 figure

A study on future large accelerators [1] has considered a facility, which is designed, built and operated by a worldwide collaboration of equal partner institutions, and which is remote from most of these institutions. The full range of operation was considered including commissioning, machine development, maintenance, troubleshooting and repair. Experience from existing accelerators confirms that most of these activities are already performed 'remotely'. The large high-energy physics experiments and astronomy projects, already involve international collaborations of distant institutions. Based on this experience, the prospects for a machine operated remotely from far sites are encouraging. Experts from each laboratory would remain at their home institution but continue to participate in the operation of the machine after construction. Experts are required to be on site only during initial commissioning and for particularly difficult problems. Repairs require an on-site non-expert maintenance crew. Most of the interventions can be made without an expert and many of the rest resolved with remote assistance. There appears to be no technical obstacle to controlling an accelerator from a distance. The major challenge is to solve the complex management and communication problems., Comment: 5 pages, Invited talk at PAC2001, Chicago, IL

Soft tissue sarcoma has a high risk of local recurrence. Therefore, extensive surgical resection has been combined with radiotherapy to improve long-term results. Because external beam radiation doses may be limited by adjacent radiosensitive tissue, intraoperative boost radiation has been devised to achieve a higher total radiation dose in combination with external beam radiotherapy. We report our experience with this multimodal approach for primary and recurrent soft tissue sarcoma.Clinical and pathological data were extracted from a prospective data base including all patients with a diagnosis of soft tissue sarcoma treated at the Department of Surgery, University of Heidelberg between 1988 and 1999. Intraoperative radiotherapy dosages were 12-15 Gy for the extremities and 15-18 Gy for the trunk and the retroperitoneum. Additional external beam radiotherapy was given at 40 Gy, whenever possible.Between 1988 and 1999, a total of 251 patients with primary or recurrent soft tissue sarcoma of the extremities, the trunk or the retroperitoneum were treated. The mean (+/- SD) age of 136 men and 115 women was 53+/-16 years. Five of 251 patients died post-operatively, giving a mortality rate of 2.0%. Intraoperative radiotherapy (IORT) was used in 92 patients (37%). Surgical complications were more frequent in IORT patients (30 of 92; 33%) compared to non-IORT patients (36 of 159; 23% P=0.1). Infectious complications were significantly more frequent in patients receiving IORT (P=0.03). Two hundred and four patients were macroscopically tumour-free (R0, R1 resection). For these patients multivariate analysis identified grading (relative risk (RR) 3.1-6.6; P0.001), age (over 55 years; (RR) 1.8: P0.008) and tumour location in the retroperitoneum (RR 2.2; P0.004) as independently associated with recurrence-free survival. The use of IORT (P0.02) reduced the relative risk of death or recurrence by 40% (RR 0.6; P0.02). Sex, primary vs. recurrent tumour, T classification and R-status (R0 vs. R1) were not significantly related to recurrence-free survival.In this prospective, non-randomized study of soft tissue sarcoma IORT was associated with a higher rate of infectious complications, but the the risk of death or recurrence was reduced by 40%.

Bei asymptomatischen pHPT wird die Indikation zur Operation kontrovers diskutiert. Das Ziel unserer Untersuchung war es, eine Operationsrisikoanalyse fur Patienten mit Ersteingriff vs. Reeingriff durchzufuhren. In einer prospektiven Studie wurden alle Patienten als oligo-/asymptomatisch eingestuft, die keine Organmanifestation des pHPT aufwiesen. Im Zeitraum zwischen 01.01.88 und 31.12.99 fuhrten wir bei 137 asymptomatischen Patienten mit einem pHPT einen operativen Eingriff durch. Bei 76,7% erfolgte ein kollarer Ersteingriff, 17,5% waren strumareseziert und bei 5,8% lag ein persistierender pHPT vor. 95,6% der Patienten zeigten eine Normalisierung des Serumkalziumspiegels. Die Risikofaktoren-analyse wies nur fur den zervikalen Reeingriff ein erhohtes Operationsrisiko fur eine Recurrensparese, Nachblutung oder Persistenz auf. Hier sollte die Operationsindikation nur unter besonderen Kautelen erfolgen (N. Recurrens-Monitoring). Patienten mit einem asymptomatischen pHPT konnen mit einem geringen Operationsrisiko prophylaktisch therapiert werden.

Tumor progression after curative resection of colorectal cancer is caused by tumor cell dissemination, currently undetected by standard clinical staging techniques. The detection of disseminated tumor cells could help to identify a patient subgroup at risk for disease relapse who could benefit from adjuvant therapy. In addition, the significance of lymphogenic compared with hematogenic colorectal cancer cell dissemination is unknown. However, this knowledge would strongly influence the development of future therapeutic regimes. The purpose of this study was to determine the extent of colorectal cancer cell dissemination in lymph nodes compared with blood and bone marrow. Using a CK 20-reverse transcription (RT)-PCR assay, we examined 279 lymph nodes, blood, and bone marrow samples from 20 patients with colorectal cancer. Of 16 patients (11 patients stage I, 5 patients stage II) with histopathologically tumor-free lymph nodes: 14 patients (10 patients stage I, 4 patients stage II) were found to have tumor cells in paracolonic lymph nodes; 12 patients (8 patients stage I, 4 patients stage II) were found to have tumor cells in the lymph nodes along the mesentery vessels; and, remarkably, 6 patients (4 patients stage I, 2 patients stage II) were found to have tumor cells in the apical lymph nodes. In contrast, tumor cells were detected in only two blood and three bone marrow samples of these patients. Thus, lymphogenic tumor cell dissemination is a very common and early event in colorectal cancer, preceding hematogenic tumor cell dissemination. In addition, our data strongly suggest that the detection of tumor cells in the apical lymph node by CK 20-RT-PCR has prognostic relevance. Our results underline the therapeutic importance of meticulous lymph node dissection and demonstrate that the detection of lymphogenic or hematogenic tumor cell dissemination by CK 20-RT-PCR will significantly improve current tumor staging protocols.

Various mesenchymal malignancies with a spindle cell morphology may mimic monophasic synovial sarcomas. We analysed, whether detection of SYT-SSX1/2 fusion transcripts, present as a consequence of a specific translocation [t(X;18)(p11.2;q11.2)] found in synovial sarcomas, are useful to confirm the diagnosis of synovial sarcoma. A nested RT-PCR protocol was established for the detection of SYT-SSX1/2 fusion transcripts. After RNA extraction of snap frozen tissue reverse transcription was carried out. In a nested PCR, the resulting cDNA samples were amplified and visualized on agarose gels. DNA sequencing of PCR products enabled the assignment of fusion transcripts to either the SYT-SSX1 or the SYT-SSX2 variant. We detected SYT-SSX1/2 fusion transcripts in seven monophasic and three biphasic synovial sarcomas. 20 out of 21 control tumour including leiomyosarcomas, malignant peripheral nerve sheath tumours, gastrointestinal stromal sarcomas and fibrosarcomas were negative in RT-PCR analysis. One case of recurrent spindle cell sarcoma originally classified as a fibrosarcoma revealed a SYT-SSX2 fusion transcript. These data provide further evidence that the RT-PCR amplification of SYT-SSX1/2 fusion transcripts permits the specific identification of synovial sarcomas. This diagnostic approach may be especially useful in cases with equivocal histomorphology.

Leiomyosarcoma (LMS) is a rare type of malignant soft tissue tumor occurring predominantly in adults. Up to now only few zytogenetic data resulting from chromosomal banding analyses were obtained from this tumor type. In general, highly complex karyotypes were observed, but no recurrent chromosomal aberrations could be identified. The aim of the present study was to analyze chromosomal imbalances in 14 cases of LMS using comparative genomic hybridization (CGH). Imbalances were detected in all cases analyzed, with chromosomal gains occurring more frequently than losses (9.9 gains/case vs. 6.9 losses/case, respectively). Chromosome arms predominantly overrepresented included Xp (9/14 cases), 5p and 8q (8/14 each), as well as 17p and 17q (6/14 each). Nineteen distinct high level amplifications, indicative for the location of relevant proto-oncogenes in LMS, were identified in nine different tumors. Interestingly, in three cases chromosomal arm 17p was involved. Interphase analysis with probes derived from the commonly amplified region 17p11-p12 revealed, that the tre oncogene is co-amplified and therefore could play a relevant role in LMS development. With regard to losses chromosome 13q was affected in 12/14, 10q in 8/14, and 2p as well as 2q in 7/14 tumors, respectively. The frequent deletions of chromosome 13 with a minimal affected region 13q14-q15 strongly support preliminary molecular evidence, that loss of the RB1 tumor suppressor gene is a critical step in LMS tumorigenesis.

This study evaluates limb-saving surgery (LSS) combined with intraoperative radiotherapy (IORT) and external beam radiotherapy (EBRT) for extremity sarcoma. Prospectively gathered data was analyzed for 50 patients. Advanced stages (UICC IIB-IIIB) predominated (80%) and 50% of the tumors were recurrent. Early local morbidity amounted to 32%, including wound infection (6), skin necrosis (3), hematoma (3) and others (4). Late morbidity of 10% consisted of a fracture, a fibrosis, two chronic lymphedemas and a neuropathy. One patient died (pulmonary embolism). Local control was obtained in 91% with an overall 3-year survival rate of 81% in cases treated with curative intent (follow-up 29 months). No survival benefit was found for patients with microscopically clear margins; however, local failure occurred less frequently (p = 0.02). Our results support the use of LSS with IORT and EBRT for extremity sarcoma and emphasize the importance of the surgical margin.

While clinical progress in the treatment of soft-tissue sarcoma is rather slow, some major contributions to the understanding of oncogenesis of these rare tumors have been achieved in the last decade. The central role of cell cycle regulation has been demonstrated in hereditary (p53, RB) and somatic mutations or variant expression of genes associated with cell cycle regulation (p53, BCL2, MDM2). For a subset of soft tissue sarcomas harboring chromosomal translocations, fusion genes resulting from these specific translocations were cloned and characterized. The clinical use of these fusion genes may not be restricted to diagnosis and prognosis, since these may serve as specific targets for molecular and immunologic therapy approaches.

Gastrointestinal stromal tumors (GIST) are rare. Their malignant variety represents only 3 percent of all malignant GI tumors. These tumors are most frequently found in the stomach and in the small bowel, while tumors of the large bowel are rare. Notably in the rectum slightly more tumors are found, easy access possibly enhancing diagnosis of asymptomatic lesions. Preoperatively and intraoperatively it is difficult to distinguish benign and malignant lesions. Treatment requires complete removal with a two centimeter margin. Systematic lymphadenectomy is not required. Tumor grading has been determined as prognostic factor for malignant GIST. Overall 5 year survival following potentially curative resection was 69 percent in our series of 46 patients.

It is planned to upgrade the HERA luminosity to 7.10/sup 31/ cm/sup -2/s/sup -1/, which is 4 times the original design luminosity. This is to be achieved by decreasing the proton beam size by moving quadrupoles closer to the interaction point and by increasing their strength. Similar measures decrease the electron beam size. However, to match the smaller proton beam size, the horizontal electron emittance additionally has to be decreased. The electron emittance can be decreased either by stronger focusing in the arcs, or by changing the damping partition numbers. In the HERA case, however, both methods have to be applied simultaneously, since changing the damping partition numbers increases the longitudinal emittance, which can only be tolerated with the current RF parameters if the bucket is increased by a stronger focusing in the arcs. These two methods of decreasing the emittance have competing effects on long term stability. Stronger focusing usually leads to a greater reduction of the dynamic aperture than of the emittance; whereas a change of the damping partition numbers tends to increase the dynamic aperture relative to the emittance. Playing the two competing effects against each other, it is possible to decrease the electron emittance while keeping the relative dynamic aperture as well as the requirements on the RF system tolerable.