Thomas Meyer

The disappointing results of surgical therapy alone of ductal pancreatic cancer can only be improved using multimodal approaches. In contrast to adjuvant therapy, neoadjuvant chemoradiation is able to facilitate resectability with free margins and to lower lymphatic spread. Another advantage is better tolerability which consecutively allows applying multimodal treatment in a higher number of patients. Furthermore, the synopsis of the overall survival results of neoadjuvant trials suggests a higher rate compared to adjuvant trials. As there are no prospectively randomised studies for neoadjuvant therapy, the Interdisciplinary Study Group of Gastrointestinal Tumours of the German Cancer Aid has started such a trial. The study investigates the effect of neoadjuvant chemoradiation in locally resectable or probably resectable cancer of the pancreatic head without distant metastasis on median overall survival time compared to primary surgery. Adjuvant chemotherapy is integrated into both arms. The protocol of the study is presented in condensed form after an introducing survey on adjuvant and neoadjuvant therapy in pancreatic cancer.

Background: In selected patients with peritoneal carcinomatosis from colorectal cancer prognosis can be improved by hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery. The aim of this study was to evaluate the tumor response of peritoneal carcinomatosis in tumor-bearing rats treated with HIPEC. Methods: CC531 colon carcinoma (2,5 × 10⁶ cells), implanted intraperitoneally in Wag/Rija rats, was treated by hyperthermic intraperitoneal chemotherapy. After 10 days of tumor growth the animals were randomized into five groups of six animals each: group I: control (n = 6), group II: sham operated animals (n = 6), group III: hyperthermic intraperitoneal perfusion (HIP) without cytostatic drugs, group IV: HIPEC with mitomycin C in a concentration of 15 mg/m² (n = 6), group V: mitomycin C i.p. alone in a concentration of 10 mg/m² (n = 6). After 10 days the extent of tumor spread and histological outcome were analysed by autopsy. Results: All control animals developed extensive intraperitoneal tumor growth. Histological tumor load was significantly reduced in group III and group V and was lowest in group IV. In group II tumor load was significantly higher than in group I. Implanted metastases were significantly decreased in group IV compared with group I and group II. Conclusion: These findings indicate that HIPEC is an effective treatment for peritoneal carcinomatosis in this animal model. HIPEC reduced macroscopic and microscopic intraperitoneal tumor spread.

Background: Cytoreduction followed by hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival in patients with peritoneal carcinomatosis of colorectal origin. Animal models are important in the evaluation of new treatment modalities. The purpose of this study was to devise an experimental setting which can be routinely used for the investigation of HIPEC in peritoneal carcinomatosis. Methods: A new peritoneal perfusion system in tumor bearing rats were tested. For this purpose CC531 colon carcinoma cells were implanted intraperitoneally in Wag/Rija rats. After 10 days of tumor growth the animals were randomized into three groups of six animals each: group 1: control (n = 6), group 2: HIPEC with mitomycin C in a concentration of 15 mg/m² (n = 6), group III: mitomycin C i.p. as monotherapy in a concentration of 10 mg/m² (n = 6). After 10 days, total tumor weight and the extent of tumor spread, as classified by the modified Peritoneal Cancer Index (PCI), were assessed by autopsy of the animals. Results: No postoperative deaths were observed. Conjunctivitis, lethargy and loss of appetite were the main side effects in the HIPEC group. No severe locoregional or systemic toxity was observed. All control animals developed massive tumor growth. Tumor load was significantly reduced in the treatment group and was lowest in group II. Conclusion: The combination of hyperthermia with MMC resulted in an increased tumoricidal effect in the rat model. The presented model provides an opportunity to study the mechanism and effect of hyperthermic intraperitoneal chemotherapy and new drugs for this treatment modality.

Background: The aim of this experimental study was to determine the effect of mild hyperthermia on tumor response and angioneogenesis in an isolated limb perfusion model with a human melanoma xenograft. Methods: A human melanoma xenograft was implanted into the hindlimbs of 30 athymic nude rats. The animals were randomized into five groups: group I: control, group II: sham group, group III: external hyperthermia with a tissue temperature of 41.5°C for 30 minutes without ILP, group IV: normothermic ILP (tissue temperature 37°C for 30 minutes, group V: hyperthermic ILP (tissue temperature 41.5°C for 30 minutes). Tumor response was evaluated by tumor size determination and immunohistochemical analysis 6 weeks postoperatively. Tissue sections were investigated for expression of CD34 and basic fibroblast growth factor (bFGF). Results: Average tumor volumes of the controls (I) increased from 105 mm³ to 1388 mm³. In the sham operated group (II) tumor volumes were significantly larger than in group I. Tumor volumes in group IV were significantly smaller than in group I and lowest in group V. There were no significant differences in size between group I and group III after six weeks. In group III and IV each, 5 animals showed tumor progression and one had a partial tumor response. In group V only 2 animals showed tumor progression. Immunhistochemical analysis of the tissue sections demonstrated that angioneogenesis was more pronounced in group II than in group I and less pronounced in group IV and V compared with group I. Conclusions: Our results suggest that even a surgical manipulation such as a skin incision promotes tumor growth, probably by induction of growth factors like bFGF. External hyperthermia of 41.5°C tissue temperature for 30 minutes only has no impact on tumor growth and angioneogenesis in vivo.

Ziel: In einer Analyse über 22 Jahre wurde untersucht, welche Parameter sich in der operativen Behandlung von thorakalen Ösophaguskarzinomen im Lauf der Zeit verä nderten und inwiefern sie die Komplikationsrate beeinflussten. Patienten und Methodik: Bei 386 Patienten (männlich n=350, weiblich n=36) wurde zwischen 1978 und 1999 eine Resektion wegen eines thorakalen Ösophaguskarzinoms (Plattenepithelkarzinom n=300, Adenokarzinom n=86) vorgenommen. Zervikale Tumoren wurden von der Analyse ausgeschlossen. Die Zeiträume 1978-1988 (n=242) und 1989-1999 (n=144) wurden hinsichtlich Alter, Geschlecht, Histologie, Hauptlokalisation, neoadjuvante Therapie, operativer Zugang, Operationsmethode, zur Rekonstruktion verwendetes Organ, Position des Interponates, R- Klassifikation, pT/pN-Klassifikation, UICC-Stadium, Zahl dissezierter Lymphknoten, Komplikationsrate, postoperative Letalität und Überleben verglichen. Ergebnisse: Im Vergleich beider Zeiträume konnte eine signifikante Zunahme von Adenokarzinomen und Häufung der Tumorlokalisation im unteren Drittel beobachtet werden. Weiterhin ließen sich signifikante Veränderungen bei der Indikation zur neoadjuvanten Radiochemotherapie, der Wahl des operativen Zugangs, des zur Rekonstruktion verwendeten Organs, der R- Klassifikation und der Zahl dissezierter Lymphknoten feststellen. Ebenso verschob sich das Tumorstadium (pT/pN- Klassifikation und UICC-Stadium) signifikant hin zu früheren Stadien. Die Gesamtkomplikationsrate zeigte einen tendenziellen Rückgang von 68,5 auf 59,0 % (p=0,061). Die Klinikletalität reduzierte sich signifikant von 24 auf 12,5 %, während Anastomoseninsuffizienzen und Multiorganversagen etwa gleich häufig auftraten. Das mediane Überleben R0-resezierter Patienten stieg signifikant von 19 auf 34 Monate an. Schlussfolgerungen: Die Zunahme von Adenokarzinomen des Ösophagus, eine sorgfältigere Patientenselektion (Staging, Funktionsdiagnostik), eine ausgereiftere Operationstechnik sowie ein optimiertes intensivmedizinisches Management stellen die entscheidenden Veränderungen im operativen Management von Ösophaguskarzinomen dar und haben zu einer Prognoseverbesserung der kurativ resezierten Patienten geführt. Trotz zunehmender Radikalität des Eingriffes (Lymphknotendissektion) hat sich die Letalität der Operation bei tendenziell sinkender Gesamtkomplikationsrate nahezu halbiert. Aim: In an analysis over 22 years it was investigated which parameters have changed in the operative treatment of thoracic esophageal carcinoma over time and in how far they have influenced complication rate. Patients and Methods: Between 1978 and 1999 386 patients (350 men, 36 women) underwent resection for thoracic esophageal carcinoma (squamous cell carcinoma n=300, adenocarcinoma n=86). Cervical tumors were excluded from analysis. The time periods from 1978 to 1988 (n=242) and from 1989 to 1999 (n=144) were separately analyzed and compared with respect to age, sex, histological type, main tumor location, neoadjuvant therapy, method of operation, esophageal substitute and positioning of the substitute, R-status, pT/pN classification, UICC stage, number of dissected lymph nodes, complication rate, postoperative mortality and survival. Results: Comparison of the two time periods showed a signficant increase in adenocarcinomas and main tumor location in the lower thoracic third of the esophagus. Furthermore, significant changes concerning the indication of neoadjuvant chemoradiation, operative approach, esophageal substitute, R-status and number of dissected lymph nodes were observed. Tumor stage (pT/pN classification and UICC stage) significantly shifted towards earlier stages. Total complication rate dropped tendentially form 68.5 % to 59.0 % (p=0.061). Hospital mortality was significantly reduced from 24 % to 12.5 %, whereas anastomotic leakages and multiorgan failure remained on a constant level. Median survival of R0 resected patients was significantly prolonged from 19 months to 34 months. Conclusions: The increase of esophageal adenocarcinoma, a more strict patient selection (staging, functional status), standardization of operative technique as well as an optimized intensive care management are among the important changes in the operative management of thoracic esophageal carcinoma that have resulted in an improvement of prognosis of curatively resected patients. In spite of a more aggressive operative approach, i. e. lymph node dissection, operative mortality could be reduced by nearly 50 % in the face of a tendentially declining total complication rate.

Ziel: Eine Dysfunktion der Epithelkörperchen gehört zu den typischen Komplikationen nach Schilddrüsenoperationen. Retrospektiv wurden Risikofaktoren für eine postoperative symptomatische Hypokalzämie analysiert. Methodik: 308 konsekutive Schilddrüsenresektionen (Frauen n = 236, Männer n = 72, Durchschnittsalter 53 Jahre) der Jahre 1996 und 1997 wurden ausgewertet. Überwiegend handelte es sich um euthyreote Knotenstrumen (n = 234, 74 %), bei 28 Patienten (9 %) lag ein Schilddrüsenkarzinom vor. Der häufigste Eingriff war die beidseitige funktionelle Schilddrüsenresektion (38 %, n = 116), der Anteil der Thyreoidektomien betrug 14 % (n = 44). Die Patienten mit postoperativer symptomatischer Hypokalzämie wurden über einen Zeitraum von median 32 Monaten nachbeobachtet. Ergebnisse: Postoperativ traten bei 18 Patienten (6 %) klinische Symptome einer Hypokalzämie auf, davon entwickelten drei Patienten einen transienten (n = 1) oder permanenten Hypoparathyreoidismus (n = 2). In der univariaten Analyse erwiesen sich die zugrunde liegende Schilddrüsenerkrankung, die Operationsmethode, die Entfernung sowie die Identifikation bzw. Reimplantation von Epithelkörperchen, in der multivariaten Analyse die Operationsmethode (Thyreoidektomie, relatives Risiko 6,9) und die Entfernung von Epithelkörperchen (relatives Risiko 23,9) als signifikante Risikofaktoren für die Entwicklung einer postoperativen symptomatischen Hypokalzämie (p < 0,05). Schlussfolgerungen: Patienten mit Thyreoidektomie, Operation wegen eines Schilddrüsenkarzinoms und intraoperativer Entfernung von Epithelkörperchen sollten postoperativ hinsichtlich einer Hypokalzämie besonders überwacht werden. Ein permanenter Hypoparathyreoidismus ist bei sorgfältiger Operationstechnik selten, insbesondere wenn intraoperativ mehrere Epithelkörperchen identifiziert und gegebenenfalls reimplantiert wurden. Purpose: Dysfunction of the parathyroid glands is a typical complication following thyroid surgery. Risk factors for the development of postoperative symptomatic hypocalcemia were retrospectively analyzed. Methods: 308 consecutive thyroid resections (women n = 236, men n = 72, mean age 53 years) performed in 1996 and 1997 were evaluated. Main diagnosis was non-toxic nodular goiter (n = 234, 76 %), 28 patients (9 %) had thyroid carcinoma. The most common operation performed was bilateral functional thyroid resection (n = 116, 38 %), the proportion of thyroidectomies was 14 % (n = 44). The patients with postoperative symptomatic hypocalcemia were followed for a median of 32 months. Results: Clinical symptoms of hypocalcemia were observed in 18 patients (6 %) postoperatively. Three patients developed transient (n = 1) or permanent hypothyroidism (n = 2). In univariate analysis, the underlying thyroid disease, the method of operative therapy, removal, identification and autotransplantation of parathyroid glands, in multivariate analysis, thyroidectomy (relative risk 6.9) and removal of parathyroid glands (relative risk 23.9) were proved to be significant risk factors for the development of postoperative symptomatic hypocalcemia (p < 0.05). Conclusions: Patients with thyroidectomy, operation for thyroid carcinoma and intraoperative removal of parathyroid glands should be closely followed for postoperative hypocalcemia. Exact surgical technique provided, permanent hypoparathyroidism is rare, particularly if several parathyroid glands were identified intraoperatively and autotransplanted, if necessary.