Johannes Scheele

A critical review of the major indicators of prognosis after resection of hepatic metastases from colorectal carcinoma

Hepatic resections for metastatic colorectal cancer have dramatically increased, and there is clear evidence of the effectiveness of this type of surgery. Controversy, however, persists regarding appropriate patient selection, extent and timing of liver resection, and adjuvant or alternative therapeutic options. This article reviews the authors experience with more than 600 hepatic resections and the relevant literature is discussed. The results underscore the importance of macroscopically and histologically complete tumor clearance, a so-called R0 resection.

Resektion colorectaler Lebermetastasen Welche Prognosefaktoren bestimmen die Patientenselektion

Abstract.Aim of the study: Based on a consecutive series of patients undergoing liver resection for colorectal metastases, indicators of prognosis and selection criteria were evaluated. Patients and methods: From 1960 to 1998, a total of 654 patients underwent resection of colorectal liver metastases. In 516 patients (78.9 %) this was an R0 resection for initial metastatic disease. These patients form the basis for the investigation. Results: 30-day mortality in this group was 5.8 %, while the total procedure-related mortality was 8.3 %. Significant morbidity was observed in 16 % of patients. Follow-up information until 1 January, 2000 was achieved in 99.5 % of patients. Including operative mortality, the actuarial 5-, 10-, and 20-year survival is 38 ± 5 %, 27 ± 6 % und 24 ± 24 %, rising to 41 ± 5 %, 29 ± 6 % and 26 ± 26 % after excluding operative deaths. Tumor-free survival is 35 ± 5 % at 5 years. In the multivariate analysis the following factors are associated with decreased crude survival: extrahepatic tumor (P < 0.0001), intraoperative hypotension (P = 0.0001), non-anatomical procedures (P = 0.0002), a metastasis diameter ≥ 5 cm (P = 0.0002), unfavourable grading of the primary tumor (P = 0.0003), satellite metastases (P = 0.0069), mesenteric lymph node involvement (P = 0.0260), use of FFP (P = 0.0307) and synchronous diagnosis of metastases (P = 0.1240). With respect to disease-free survival metastasis diameter is first, followed by extrahepatic disease (P < 0.0001 each). Satellite metastases are removed, while the primary tumor site becomes important with inferior results for rectal cancer (P = 0.0188). The other factors remain stable and in the same order. The number of independent tumor nodules as well as the width of resection margin fail to be significant in both univariate and multivariate analysis. Conclusion: These results underline the paramount importance of an R0 resection, but diminish the relevance of most commonly used “contraindications”. For the actual decision on liver resection, beside the possibility of achieving an R0 situation, safety aspects regarding comorbidity and acceptable extent of parenchyma loss represent the prime limitation.Zusammenfassung.Ziel der Untersuchung: Anhand einer konsekutiven Serie von Patienten mit Leberresektion wegen Metastasen eines colorectalen Carcinoms sollten Prognoseindikatoren und Selektionskriterien evaluiert werden. Patienten und Methoden: Von 1960 bis 1998 erfolgte bei 654 Patienten eine Resektion colorectaler Lebermetastasen. Bei 516 von ihnen (78,9 %) lag eine R0-Resektion bei erstmaliger Metastasenentfernung vor. Diese 516 Patienten bilden die Grundlage der Untersuchung. Ergebnis: Die 30-Tages-Letalität betrug 5,8 %, die Gesamtletalität lag bei 8,3 %. Nennenswerte nicht tödliche Komplikationen wurden bei 16 % der Patienten beobachtet. Zum 1. Januar 2000 konnte für 99,5 % der Patienten eine Nachbeobachtung erreicht werden. Unter Ein- und Ausschluß der Operationsletalität beträgt die kumulative Überlebensrate nach 5, 10 und 20 Jahren 38 ± 5 %, 27 ± 6 % und 24 ± 24 % bzw. 41 ± 5 %, 29 ± 6 % und 26 ± 26 %. Das tumorfreie Überleben nach 5 Jahren liegt bei 35 ± 5 %. In der multivariaten Analyse sind folgende Faktoren mit einem reduzierten Überleben verbunden: Extrahepatischer Tumor (p < 0,0001), intraoperative hypotensive Phasen (p = 0,0001), nichtanatomische Resektionsverfahren (p = 0,0002), ein Metastasendurchmesser ≥ 5 cm (p = 0,0002), ein ungünstiger Malignitätsgrad des Primärtumors (p = 0,0003), Satellitenmetastasen (p = 0,0069), mesenteriale Lymphknotenmetastasen (p = 0,0260), die Verabreichung von FFP (p = 0,0307) und eine synchrone Metastasendiagnose (p = 0,1240). In Hinsicht auf das tumorfreie Überleben rückt der Metastasendurchmesser vor den extrahepatischen Tumor (p jeweils < 0,0001), die Satellitenmetastasen werden sekundär wieder ausgeschlossen, während die Lokalisation des Primärtumors mit schlechteren Resultaten für das Rectumcarcinom (p = 0,0188) hinzukommt. Die übrigen Faktoren bleiben, auch in der Reihenfolge ihrer Bedeutung, weitgehend konstant. Ohne Einfluß sind sowohl multi- als auch univariat die Anzahl eigenständiger Tumorknoten und der Sicherheitsabstand. Schlußfolgerungen: Die Ergebnisse belegen die überragende Bedeutung einer R0-Resektion und relativieren die Relevanz der meisten überkommenen „Kontraindikationen“. Für aktuelle Resektionsentscheidungen sind neben der Chance auf das Erreichen einer R0-Situation zunehmend Sicherheitsaspekte limitierend, insbesondere Begleiterkrankungen und zumutbares Resektionsausmaß.

Human adenoma cells are highly susceptible to the genotoxic action of 4-hydroxy-2-nonenal

Oxidative stress and resulting lipid peroxidation are important risk factors for dietary-associated colon cancer. To get a better understanding of the underlying molecular mechanisms, we need to characterise the risk potential of the key compounds, which cause DNA damage in cancer-relevant genes and especially in human target cells. Here, we investigated the genotoxic effects of 4-hydroxy-2-nonenal (HNE) and hydrogen peroxide (H(2)O(2)) in human colon cells (LT97). LT97 is a recently established cell line from a differentiated microadenoma and represents cells from frequent preneoplastic lesions of the colon. The genomic characterisation of LT97 was performed with 24-colour FISH. Genotoxicity was determined with single cell microgelelectrophoresis (Comet assay). Comet FISH was used to study the sensitivity of TP53-a crucial target gene for the transition of adenoma to carcinoma-towards HNE. Expression of glutathione S-transferases (GST), which deactivates HNE, was determined as GST activity and GSTP1 protein levels. LT97 cells were compared to primary human colon cells and to a differentiated clone of HT29. Karyotyping revealed that the LT97 cell line had a stable karyotype with only two clones, each containing a translocation t(7;17) and one aberrant chromosome 1. The Comet assay experiments showed that both HNE and H(2)O(2) were clearly genotoxic in the different human colon cells. HNE was more genotoxic in LT97 than in HT29clone19A and primary human colon cells. After HNE incubation, TP53 migrated more efficiently into the comet tail than the global DNA, which suggests a higher susceptibility of the TP53 gene to HNE. GST expression was significantly lower in LT97 than in HT29clone19A cells, which could explain the higher genotoxicity of HNE in the colon adenoma cells. In conclusion, the LT97 is a relevant model for studying genotoxicity of colon cancer risk factors since colon adenoma are common preneoplastic lesions occurring in advanced age.

Expression of the thrombin receptor PAR-1 correlates with tumour cell differentiation of pancreatic adenocarcinoma in vitro

Patients with pancreatic cancer frequently suffer from thrombosis due to excess thrombin generation. Yet, the effects of thrombin on pancreatic cancer are still poorly understood. The thrombin receptor PAR-1 is responsible for cellular effects of thrombin. PAR-1 plays an important role in the progression of different solid tumours inxa0vitro. In breast cancer the level of PAR-1 expression correlates with invasiveness. Our aim was to correlate PAR-1 mRNA and protein expression level with the grade of differentiation of pancreatic tissue and cancer cell lines. PAR-1 protein was not detectable in the epithelium of healthy pancreas. Analysis of PAR-1 protein expression by immunofluorescence staining of pancreatic cancer cell lines revealed a correlation to the grade of differentiation. Quantitative analysis of PAR-1 protein expression by Western Blot analysis confirmed these observations. Analysis of PAR-1 mRNA expression showed low levels in healthy pancreas compared to pancreatic cancer tissue and the pancreatic cancer cell line MIA PaCa-2. The level of PAR-1 mRNA differed up to 25 fold between the respective pancreatic cancer cell lines. The eminent differences in PAR-1 expression, both protein and mRNA, between healthy pancreatic tissue and pancreatic cancer inxa0vivo and inxa0vitro emphasise the putative role of PAR-1 in pancreatic cancer progression.

Characterization of functional thrombin receptors in human pancreatic tumor cells (MIA PACA-2)

In this article, the “tethered ligand” thrombin receptor was identified on human pancreatic tumor cells, MIA PaCa-2, using immunofluorescence studies with a monoclonal anti-thrombin receptor antibody. Pharmacological characterization, using 3H-labeled thrombin receptor activating peptide-6 (TRAP-6) as radioligand, demonstrated a single class of high-affinity binding sites (KD = 9.1 ± 1.8 × 10−7 M) and a binding capacity of 13.9 ± 0.7 fmol/mg protein. These binding sites represent functional thrombin receptors, as shown by α-thrombin- and TRAP-6-induced mobilization of free intracellular calcium, protein kinase C translocation from cytosol to the cell membrane, and stimulation of DNA synthesis in MIA PaCa-2 cells. These results provide the first identification of tethered ligand thrombin receptor in human pancreatic cancer cells and suggest thrombin receptor involvement in mechanisms of human pancreatic tumor progression.

Pulmonary resection for metastatic colon and upper rectum cancer

The predictive value of the route of venous drainage on prognosis was investigated in a consecutive series of 44 patients who underwent curative resection of pulmonary metastases from colorectal carcinoma. The primary tumor was located in the colon in 14 patients and in the upper third of the rectum in 11 patients, thus indicating blood drainage directed toward the portal vein (Group I). In 10 and 9 cases, respectively, the initial growth was in the middle and lower thirds of the rectum with the venous outflow at least partially directed into the vena cava (Group II). There was no obvious difference between the two groups regarding the initial site of cancer relapse. The liver was involved in 4 of 15 patients failing in Group I as opposed to 4 of 13 patients with hematogenous relapse in Group II. Median survival and tumor-free survival times were significantly longer in patients in Group I (58.4 and 50.2 months) than in patients in Group II (30.9 and 16.8 months), and, even more pronounced, in colon cancer patients (75.4 and 60.2 months) when compared with rectal cancer patients (31.0 and 17.9 months). In contrast, survival curves did not differ significantly if either the two groups with different routes of drainage (5-year survival 53 percentvs. 38 percent, 5-year tumor-free survival 43 percentvs.37 percent), or tumors of the colon and rectum (5-year survival 67 percentvs.38 percent, 5-year tumor-free survival 60 percentvs.32 percent) were compared using the log-rank test. Similar trends were obtained for the subgroup of 34 patients without previous or simultaneous extrapulmonary recurrent disease at the time of lung resection. The primary tumor site does therefore not become a major criterion in selecting patients for surgical resection.

Stellenwert der Rektumexstirpation im Therapiekonzept des tief sitzenden Rektumkarzinoms

AbstractIntroduction. The main objective of surgery of rectal carcinomas is to avoid a permanent colostomy by sphincter-sparing surgical procedures. A variety of different abdominoperineal resection rates is described in the literature.nMaterial/method. The study was performed in 2000 within the framework of a multicentric study including 282 hospitals.The purpose of the study was to document the quality of diagnosis and therapy for colorectal carcinomas.A total of 9477 patients were included in this study: 3402 suffering from a rectal carcinoma and 6075 suffering from a colon carcinoma.nResults. A total of 866 abdominoperineal resections was performed. This corresponds to an abdominoperineal resection rate of 27.4%. In 30.4% of all men and in 23.0% of all women an abdominoperineal resection was performed.Of all tumor patients who underwent abdominoperineal resection, 8.3% had a pT4 carcinoma and 57.5% a pT3 carcinoma.Adapted to the localization of the tumor in the rectum, i.e., the distance of the aboral tumor margin to the anal verge, the following abdominoperineal resection rates were found: <4 cm from the anal verge 84.6%, 4–7.9 cm 43.9%, 8–11.9 cm 5.8%, and 12–16 cm 0.5%.Intraoperative complications occurred in 11.8%, specific postoperative complications in 33.1%, and general postoperative complications in 27.4% of the patients.The postoperative lethality was 2.8%. The mean postoperative hospital stay was 21.7 days.Logistic regression identified the body mass index, gender, the distance of the carcinoma from the anal verge, and the T category as independent factors influencing the abdominoperineal resection rate.nDiscussion. Despite an overall decrease in use, abdominoperineal resection will continue to play an important role for the surgical treatment of low rectal cancers in routine clinical practice in Germany.It will remain an individual decision for each patient whether the tumor and the patient allow sphincter preservation or whether abdominoperineal resection seems to be necessary.According to the results of the present study,a general definition of an abdominoperineal resection rate in an unselected group of patients should be viewed critically.ZusammenfassungEinleitung. Die Vermeidung einer permanenten Kolostomie durch sphinktererhaltende Operationsverfahren ist ein Hauptziel der Rektumkarzinomchirurgie. In der Literatur werden sehr unterschiedliche Rektumexstirpationsraten angegeben.nMaterial/Methode. Die Untersuchung wurde innerhalb einer prospektiven Multicenterstudie zur Erfassung der Qualität der Diagnostik und Therapie des kolorektalen Karzinoms an 282 Kliniken innerhalb des Jahres 2000 durchgeführt. In dieser Untersuchung wurden 9.477 Patienten erfasst, 3.402 mit einem Rektumkarzinom und 6.075 mit einem Kolonkarzinom.nErgebnisse. Es wurden 866 Rektumexstirpationen durchgeführt.Dies entspricht einer Rektumexstirpationsrate von 27,4%; 30,4% aller Männer mit einem Rektumkarzinom und 23,0% aller Frauen wurden einer Rektumexstirpation unterzogen; 8,3% aller Tumore, die einer Rektumexstirpation zugeführt wurden,hatten eine pT4-Kategorie und 57,5% eine pT3-Kategorie.Die Rektumexstirpationsraten, adaptiert an die Höhenlokalisation des Tumors,d.h.Abstand des aboralen Tumorrandes von der Anokutanlinie, betrugen: <4 cm ab ACL – 84,6%, 4–7,9 cm – 43,9%,8–11,9 cm – 5,8% und 12–16 – – 0,5%.Intraoperative Komplikationen traten in 11,8%, spezifische postoperative Komplikationen in 33,1% und allgemeine postoperative Komplikationen in 27,4% auf.Die postoperative Letalität betrug 2,8%.Die postoperative Verweildauer lag bei 21,7 Tagen.Die logistische Regression zeigte den BMI,das Geschlecht, die Höhe des Karzinoms und die T-Kategorie als unabhängige Einflussfaktoren auf die Rektumexstirpationsrate.nDiskussion. Trotz insgesamt rückläufiger Häufigkeit spielt die abdominoperineale Rektumexstirpation in Deutschland auch weiterhin eine bedeutende Rolle bei der operativen Therapie tief sitzender Rektumkarzinome im klinischen Alltag. Es bleibt eine individuelle Entscheidung bei jedem einzelnen Patienten, ob eine Sphinktererhaltung von Seiten des Tumors und des Patienten machbar ist oder ob eine Exstirpation erforderlich erscheint. Die generelle Vorgabe einer Rektumexstirpationsrate bei einem unselektionierten Krankengut sollte nach den Ergebnissen der vorliegenden Untersuchung sehr kritisch gesehen werden.

PAR1-type thrombin receptor stimulates migration and matrix adhesion of human colon carcinoma cells by a PKCepsilon-dependent mechanism.

The proteinase-activated receptor1 (PAR1) was characterized as a functional receptor for thrombin in cells from different tumor entities. In colon carcinoma, its function has to be defined. In this study we demonstrate that the PAR1-selective agonist peptide TFLLRN induced activation of protein kinase C isoenzymes alpha and epsilon in human HT-29 colon carcinoma cells expressing PAR1 endogeneously. On the cellular level, TFLLRN and thrombin prompted HT-29 cell migration and matrix adhesion by a PKCepsilon-dependent mechanism as concluded because of the inhibition of PAR1-mediated effects by the PKC inhibitor bisindolylmaleimide I and the PKCepsilon translocation inhibitory peptide EAVSLKPT but not by the PKC inhibitor Gö 6976. In addition, blockade of PAR1 by RWJ 56110, a selective PAR1 antagonist, fully abolished the effect of thrombin on HT-29 cell migration and adhesion. Therefore, PAR1 seems to be the responsible receptor for thrombin-induced migration and adhesion of human colon carcinoma cells including PKCepsilon as an essential signal transducer.

Importance of rectal extirpation for the therapy concept of low rectal cancers

AbstractIntroduction. The main objective of surgery of rectal carcinomas is to avoid a permanent colostomy by sphincter-sparing surgical procedures. A variety of different abdominoperineal resection rates is described in the literature.nMaterial/method. The study was performed in 2000 within the framework of a multicentric study including 282 hospitals.The purpose of the study was to document the quality of diagnosis and therapy for colorectal carcinomas.A total of 9477 patients were included in this study: 3402 suffering from a rectal carcinoma and 6075 suffering from a colon carcinoma.nResults. A total of 866 abdominoperineal resections was performed. This corresponds to an abdominoperineal resection rate of 27.4%. In 30.4% of all men and in 23.0% of all women an abdominoperineal resection was performed.Of all tumor patients who underwent abdominoperineal resection, 8.3% had a pT4 carcinoma and 57.5% a pT3 carcinoma.Adapted to the localization of the tumor in the rectum, i.e., the distance of the aboral tumor margin to the anal verge, the following abdominoperineal resection rates were found: <4 cm from the anal verge 84.6%, 4–7.9 cm 43.9%, 8–11.9 cm 5.8%, and 12–16 cm 0.5%.Intraoperative complications occurred in 11.8%, specific postoperative complications in 33.1%, and general postoperative complications in 27.4% of the patients.The postoperative lethality was 2.8%. The mean postoperative hospital stay was 21.7 days.Logistic regression identified the body mass index, gender, the distance of the carcinoma from the anal verge, and the T category as independent factors influencing the abdominoperineal resection rate.nDiscussion. Despite an overall decrease in use, abdominoperineal resection will continue to play an important role for the surgical treatment of low rectal cancers in routine clinical practice in Germany.It will remain an individual decision for each patient whether the tumor and the patient allow sphincter preservation or whether abdominoperineal resection seems to be necessary.According to the results of the present study,a general definition of an abdominoperineal resection rate in an unselected group of patients should be viewed critically.ZusammenfassungEinleitung. Die Vermeidung einer permanenten Kolostomie durch sphinktererhaltende Operationsverfahren ist ein Hauptziel der Rektumkarzinomchirurgie. In der Literatur werden sehr unterschiedliche Rektumexstirpationsraten angegeben.nMaterial/Methode. Die Untersuchung wurde innerhalb einer prospektiven Multicenterstudie zur Erfassung der Qualität der Diagnostik und Therapie des kolorektalen Karzinoms an 282 Kliniken innerhalb des Jahres 2000 durchgeführt. In dieser Untersuchung wurden 9.477 Patienten erfasst, 3.402 mit einem Rektumkarzinom und 6.075 mit einem Kolonkarzinom.nErgebnisse. Es wurden 866 Rektumexstirpationen durchgeführt.Dies entspricht einer Rektumexstirpationsrate von 27,4%; 30,4% aller Männer mit einem Rektumkarzinom und 23,0% aller Frauen wurden einer Rektumexstirpation unterzogen; 8,3% aller Tumore, die einer Rektumexstirpation zugeführt wurden,hatten eine pT4-Kategorie und 57,5% eine pT3-Kategorie.Die Rektumexstirpationsraten, adaptiert an die Höhenlokalisation des Tumors,d.h.Abstand des aboralen Tumorrandes von der Anokutanlinie, betrugen: <4 cm ab ACL – 84,6%, 4–7,9 cm – 43,9%,8–11,9 cm – 5,8% und 12–16 – – 0,5%.Intraoperative Komplikationen traten in 11,8%, spezifische postoperative Komplikationen in 33,1% und allgemeine postoperative Komplikationen in 27,4% auf.Die postoperative Letalität betrug 2,8%.Die postoperative Verweildauer lag bei 21,7 Tagen.Die logistische Regression zeigte den BMI,das Geschlecht, die Höhe des Karzinoms und die T-Kategorie als unabhängige Einflussfaktoren auf die Rektumexstirpationsrate.nDiskussion. Trotz insgesamt rückläufiger Häufigkeit spielt die abdominoperineale Rektumexstirpation in Deutschland auch weiterhin eine bedeutende Rolle bei der operativen Therapie tief sitzender Rektumkarzinome im klinischen Alltag. Es bleibt eine individuelle Entscheidung bei jedem einzelnen Patienten, ob eine Sphinktererhaltung von Seiten des Tumors und des Patienten machbar ist oder ob eine Exstirpation erforderlich erscheint. Die generelle Vorgabe einer Rektumexstirpationsrate bei einem unselektionierten Krankengut sollte nach den Ergebnissen der vorliegenden Untersuchung sehr kritisch gesehen werden.

Resection of colorectal liver metastases revisited

Surgical resection has evolved into the treatment of choice for colorectal liver metastases. ~ Since 1980, single-institution series exceeding 100 patients have reported 5-year survival rates ranging from 22% to 48%, 2-13 and rates from collected series have ranged from 21% to 33% (Table I). 14-16 In our own experience of 376 patients who underwent potentially curative resections, the 5-year survival rate was 39% with 34% of patients free of disease (Fig. 1). 17 Optimized results in recent years may be the result of improved preoperative imaging techniques, increasing operative expertise, and optimal tailoring of the procedure to each patients individual needs. Certainly a great deal of selection bias is also involved. The development of indications for and contraindications to resection of metastatic colorectal cancer has, nevertheless, shown a continuous liberalization of proposed selection criteria. Therefore a current viewpoint should address general inclusion and exclusion guidelines, appropriate preoperative workup, timing of liver resection, therapeutic options in cases of tumor recurrence, and the balance between operative risks and prognostic benefits.