Helge Kleinhans

Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience.

Objective:To evaluate surgical strategies for neuroendocrine pancreatic tumors (NEPT) in the light of the new WHO classification from 2004 and to draw conclusions for future surgical concepts. Background:The extent of surgical resection in primary and recurrent NEPT is unclear. Methods:Between 1987 and 2004, 62 patients with sporadic NEPT were treated at our institution and sections from biopsy and resection specimen were histopathologically reclassified. Clinical presentation, surgery, metastases, and pattern of recurrence were related to survival. Results:Fifteen well-differentiated tumors (WDT, 24%), 39 low-grade carcinomas (LGC, 63%), and 8 high-grade carcinomas (HGC, 13%) were identified. Median observation time was 30.5 months; 48 of 62 patients (78%) were surgically resected, and in 45 patients R0/R1 status was achieved. Overall 2- and 5-year survival in the latter group was 80% and 64%, respectively. Retrospective WHO classification revealed that organ-preserving segmental resections had been performed in 10 LGC and 1 HGC. These patients showed equal outcome as radically resected counterparts (n = 19). Liver and other organ metastases were present in 19 of 62 patients (31%), and resection was accomplished in 7 of 19 patients, which conferred better overall survival (P = 0.026, log-rank test); 21 of 45 R0/R1-resected patients (47%) suffered from recurrence, and reoperation was accomplished in 9 patients, which resulted in better overall survival (P = 0.066). Conclusion:Organ-preserving resections offer sufficient local control in LGC; therefore, radical resections do not seem to be justified. On the other hand, radical resection is indicated even in metastasized patients or in case of loco-regional recurrence. The silent and slow course of the disease facilitates long-term surgical control.

Systemic Intravenous Infusion of Bovine Hemoglobin Significantly Reduces Microcirculatory Dysfunction in Experimentally Induced Pancreatitis in the Rat

Objective: To evaluate the effectiveness of bovine hemoglobin on pancreatic microcirculation and outcome in experimental acute rodent pancreatitis. Summary Background Data: Stasis of the pancreatic microcirculation initiates and aggravates acute pancreatitis. Hydroxyethyl-starch (HES) has been shown to improve pancreatic microcirculation. Similarly, bovine hemoglobin might improve rheology due to its colloid effect, but additionally supplies oxygen to oxygen depleted pancreatic tissue. Methods: In Wistar rats, severe acute pancreatitis was induced by administration of glucodeoxycholic acid i.d. and cerulein i.v. Pancreatic microcirculation was continuously monitored by fluorescence microscopy. Fifteen minutes after the initiation of acute pancreatitis, animals received either 0.8 mL bovine hemoglobin (Oxyglobin), HES, or 2.4 mL 0.9% NaCl i.v. at random. After 6 hours, animals were killed and histopathological damage of the pancreas was assessed using a validated histology score (0–16). Results: In comparison to controls, pancreatic microcirculation improved significantly in the HBOC group (mean difference of capillary density 31.4%; standard error 5.6%; P < 0.001; 95% confidence interval for difference 17.5–45.3). HES was not as effective as HBOC substitution. The histology score revealed less tissue damage in the HBOC group [6.25 vs. 9.25 (3–8.5 vs. 8–10.75, P < 0.001)] in comparison to controls and also in comparison to the HES group [6.25 vs. 8 (3–8.5 vs. 6.5–10.25, P < 0.006)]. Conclusions: In severe acute pancreatitis, single i.v. injection of bovine hemoglobin improves pancreatic microcirculation and reduces tissue damage.

Improvement of Impaired Microcirculation and Tissue Oxygenation by Hemodilution with Hydroxyethyl Starch plus Cell-Free Hemoglobin in Acute Porcine Pancreatitis

Aims: To avoid the progression from mild edematous acute pancreatitis (AP) to the severe necrotizing form, one therapeutic option is to improve pancreatic microcirculation and tissue oxygenation. The aim of the study was to evaluate the influence of improved rheology (isovolemic hemodilution) plus enhanced oxygen supply (bovine hemoglobin HBOC-301) on pancreatic microcirculation, tissue oxygenation and survival in severe acute experimental pancreatitis. Methods: Severe AP was induced in 39 pigs (25–30 kg BW) by stimulation with intravenous administration of cerulein plus a pressure- and volume-controlled 10-min intraductal infusion of glycodeoxycholic acid. Seventy-five minutes after induction of AP, animals were randomized and hemodiluted isovolemically (PAOP constant) with either 10% hydroxyethyl starch (HES) 200,000/0.5 plus HBOC-301 (+0.6 g/dl plasmatic hemoglobin; Oxyglobin®, Biopure, Cambridge, Mass., USA), or 10% HES 200,000/0.5, or Ringer’s solution to a hematocrit of 15%. Hemodynamics, oxygen transport parameters, pancreatic microcirculation and tissue oxygen tension were evaluated over 6 h. Then the abdomen was closed, animals were extubated and observed for 6 days. After that, the surviving animals were sacrificed and specimens were taken from the pancreas. The histopathologic findings were scored by two blinded pathologists who quantified acinar necrosis, fat necrosis, inflammation and edema. Results: Isovolemic hemodilution with HES plus HBOC-301 reduced mortality and preserved pancreatic microcirculation compared with Ringer’s solution, but was not significantly different from hemodilution with HES alone. Only treatment with HES plus HBOC-301 normalized pancreatic tissue oxygen tension compared with IHD with HES or Ringer’s solution alone. Conclusions: IHD with HES plus HBOC-301 as a combination of rheologic and O2-delivering therapy may represent a novel therapeutic option for treatment of AP.

Microsatellite DNA alterations of gastrointestinal stromal tumors are predictive for outcome

Purpose: In gastrointestinal stromal tumors (GIST), loss of heterozygosity (LOH) on chromosome 22 and its presumptive biological function has been described. The prognostic value of these and other DNA regions for patient survival remains unclear. Experimental Design: Sixty patients who underwent surgery at our institution between 1992 and 2003 for GIST were histopathologically reclassified by immunohistochemistry and the GIST consensus group criteria 2001. Twenty-one microsatellite loci on chromosomes 3, 9, 13, 17, 18, and 22 were screened for alterations in tumor and healthy DNA. Survival was calculated by Kaplan-Meier plots. Results: Eleven (18.3%) of 60 patients showed metastases at presentation. Thirteen (21.7%) of 60 were high-risk GISTs. LOH was found in all tumors. Twenty-eight (46.7%) of 60 showed more than two LOH in 21 microsatellite marker sites. The frequency of single marker LOH varied from 1.7% to 28.3% among tumors. Frequent LOH was found on chromosomes 22 and 17. The correlation of LOH positivity and the consensus scoring was significant (P = 0.005, χ2 test). After a median observation time of 33.3 months (95% confidence interval, 23.9-42.6), overall survival was best for patients with tumors of very low, low, and intermediate risks with only 6 of 36 death events, whereas 14 of 24 high-risk and metastasized patients had died (P < 0.001, log-rank test). Likewise, LOH significantly predicted survival (P = 0.013) and the effect was particularly detrimental for LOH on chromosome 17 (P < 0.001). Conclusions: LOH is a useful phenomenon for the prognosis of GIST. Rather than chromosome 22 markers, chromosome 17 markers independently predict survival.

Clinical Value of Loss of Heterozygosity in Serum Microsatellite DNA of Patients With Gastrointestinal Stromal Tumors

Goals To study the role of loss of heterozygosity (LOH) in serum microsatellite DNA of patients with gastrointestinal stromal tumors (GIST). Background In GIST, tumor markers from peripheral blood are missing. Study Seventy-eight patients (59 GIST, 13 leiomyomas, 2 leiomyosarcomas, and 4 schwannomas) underwent resection at our institute between 1985 and 2006. Thirty-three preoperative sera (26 GIST and 7 non-GIST) and 62 postoperative sera (47 GIST and 15 non-GIST) were available and tested for alterations in 12 representative microsatellite loci on chromosomes 22, 17, 13, 9, and 3, using fluorescence-based automated capillary electrophoresis by ABI Prism. Survival was calculated with Kaplan-Meier plots. Results Seventeen out of 26 GIST patients had a positive preoperative serum LOH score (≥2 LOH, sensitivity 65.4%), and 6 out of 7 non-GIST patients had a negative score (≤1 LOH, specificity 85.7%, P=0.030, Fisher exact test). Serum LOH in GIST were strongly correlated with Fletcher risk groups (P=0.016, χ2 test). All metastasized GIST (7/7) showed ≥2 LOH preoperatively. Postoperative sensitivity and specificity of LOH analysis for prediction of relapse in 47 GIST was 75.0% and 64.1%, respectively. After a median observation time of 51.3 months (95% confidence interval, 39.4-61.4), LOH in serum significantly predicted overall survival (P=0.007, log-rank test). Conclusions LOH serum analysis in GIST may play a role as a noninvasive, differential diagnostic, prognostic, and monitoring marker in the clinical routine.

Intrathoracic lesions in association with germ cell tumor of the testis

ZusammenfassungPulmonal und mediastinal vergrößerte Lymphknoten bei bekannten malignen Grunderkrankungen sind immer hochverdächtig auf eine lymphogene Metastasierung. Dies gilt insbesondere dann, wenn schon in regionären Lymphknotenstationen Tumorresiduen isoliert werden konnten. Dass trotz modernster präoperativer Diagnostik überraschende Befunde zutage kommen, zeigt der vorliegende Fall eines jungen Mannes mit einem nichtseminomatösen Hodenkarzinom, bei dem sich eine bihiläre Lymphknotenschwellung nicht als Rezidiv, sondern als ein simultane Sarkoidose herausstellte.AbstractIntrathoracic enlarged lymph nodes in patients with malignant diseases always arouse suspicion of lymphatic metastases. Despite modern diagnostic investigation, surprising findings sometimes emerge. The present case of a young man with intrathoracic lesions in association with a germ-cell tumor of the testis turned out to have sarcoidosis mimicking testicular cancer relapse.Intrathoracic enlarged lymph nodes in patients with malignant diseases always arouse suspicion of lymphatic metastases. Despite modern diagnostic investigation, surprising findings sometimes emerge. The present case of a young man with intrathoracic lesions in association with a germ-cell tumor of the testis turned out to have sarcoidosis mimicking testicular cancer relapse.

Bihiläre Lymphome bei nichtseminomatösem Keimzelltumor

ZusammenfassungPulmonal und mediastinal vergrößerte Lymphknoten bei bekannten malignen Grunderkrankungen sind immer hochverdächtig auf eine lymphogene Metastasierung. Dies gilt insbesondere dann, wenn schon in regionären Lymphknotenstationen Tumorresiduen isoliert werden konnten. Dass trotz modernster präoperativer Diagnostik überraschende Befunde zutage kommen, zeigt der vorliegende Fall eines jungen Mannes mit einem nichtseminomatösen Hodenkarzinom, bei dem sich eine bihiläre Lymphknotenschwellung nicht als Rezidiv, sondern als ein simultane Sarkoidose herausstellte.AbstractIntrathoracic enlarged lymph nodes in patients with malignant diseases always arouse suspicion of lymphatic metastases. Despite modern diagnostic investigation, surprising findings sometimes emerge. The present case of a young man with intrathoracic lesions in association with a germ-cell tumor of the testis turned out to have sarcoidosis mimicking testicular cancer relapse.Intrathoracic enlarged lymph nodes in patients with malignant diseases always arouse suspicion of lymphatic metastases. Despite modern diagnostic investigation, surprising findings sometimes emerge. The present case of a young man with intrathoracic lesions in association with a germ-cell tumor of the testis turned out to have sarcoidosis mimicking testicular cancer relapse.

Bihiläre Lymphome bei nichtseminomatösem Keimzelltumor@@@Intrathoracic lesions in association with germ cell tumor of the testis

ZusammenfassungPulmonal und mediastinal vergrößerte Lymphknoten bei bekannten malignen Grunderkrankungen sind immer hochverdächtig auf eine lymphogene Metastasierung. Dies gilt insbesondere dann, wenn schon in regionären Lymphknotenstationen Tumorresiduen isoliert werden konnten. Dass trotz modernster präoperativer Diagnostik überraschende Befunde zutage kommen, zeigt der vorliegende Fall eines jungen Mannes mit einem nichtseminomatösen Hodenkarzinom, bei dem sich eine bihiläre Lymphknotenschwellung nicht als Rezidiv, sondern als ein simultane Sarkoidose herausstellte.AbstractIntrathoracic enlarged lymph nodes in patients with malignant diseases always arouse suspicion of lymphatic metastases. Despite modern diagnostic investigation, surprising findings sometimes emerge. The present case of a young man with intrathoracic lesions in association with a germ-cell tumor of the testis turned out to have sarcoidosis mimicking testicular cancer relapse.Intrathoracic enlarged lymph nodes in patients with malignant diseases always arouse suspicion of lymphatic metastases. Despite modern diagnostic investigation, surprising findings sometimes emerge. The present case of a young man with intrathoracic lesions in association with a germ-cell tumor of the testis turned out to have sarcoidosis mimicking testicular cancer relapse.

Effekt von bovinem Hämoglobin mit und ohne isovolämische Hämodilution auf die pankreatische Mikrozirkulation, den pankreatischen Gewebssauerstoffpartialdruck und das Überleben bei schwerer akuter Pankreatitis im Schweinemodell

To avoid the progression from mild edematous acute pancreatitis to the severe necrotising form, one therapeutic option is to improve pancreatic microcirculation. The aim of the study was to evaluate the influence of bovine haemoglobin with and without additional isovolemic hemodilution on pancreatic microcirculation, tissue oxygenation and survival in severe acute porcine pancreatitis. Methods: 39 pigs (25–30 kg BW) were anesthetised and catheters were placed. After midline laparotomy severe acute pancreatitis was induced (intraductal injection of glycodeoxycholic acid (0,4 ml /kg BW; 10 mmol/l) and cerulein i. v. (5 microg/kg BW/h)). After 75 minutes animals were randomised into three groups (each n = 13): 1: isovolemic hemodilution (IHD) with hydroxyethyl starch (HES) and additional bovine hemoglobin (HBOC-301, Biopure, MD); 2: application of HES and HBOC-301 without IHD and 3: IHD with Ringer’s solution. Then IHD was started until a hematocrit of 15% (50% of initial hematocrit) was reached. Pancreatic microcirculation was monitored using a laser-doppler scanner (Laser Perfusion Imager, Perimed, Sweden) and tissue oxygenation of the pancreas (tpO2) was measured using a Licox catheter (GMS, Kiel, FRG). After 6 hours, catheters were removed, the abdomen was closed and animals were extubated. After 6 days, surviving animals were sacrificed. Results: Induction of the acute pancreatitis led to an initial decrease of tpO2 in all groups irrespective of treatment. Isovolemic hemodilution (IHD) with hydroxyethyl starch and additional bovine hemoglobin as well as application of HES and HBOC-301 without IHD resulted in a significantely improved tissue oxygenation compared to control animals. Ten animals survived in group 1, while 9 animals in group 2 and only 2 animals in group 3 were alive at the end of the observational period (p = 0,001 Kruskal-Wallis Test). The extend of histologic tissue damage and the pancreatic microcirculation monitored using the laser-doppler scanner corresponded with these results. Conclusion: The applica-tion of HBOC-301 in combination with IHD as well as application of HES and HBOC-301 without IHD improved pancreatic tissue oxygenation and survival in severe acute porcine pancreatitis. Though, the additional treatment with IHD had no further effect on the monitored parameters.