P. M. Markus

Surgical cure for early rectal carcinoma and large adenoma: transanal endoscopic microsurgery (using ultrasound or electrosurgery) compared to conventional local and radical resection.

Abstract Background and aims. The minimally invasive technique of transanal endoscopic microsurgery (TEM) combines the benefits of local resections, a low complication rate and high patient comfort, with low recurrence rate and excellent survival rate after radical surgery (RS). The use of an ultrasonically activated scalpel rather than electrosurgery further improves the results of TEM. Patients and methods. A retrospective study was performed of 182 operations on 162 patients with early rectal carcinoma (pT1, G1/2) or adenoma to compare the outcome following four different kinds of surgical resection techniques: RS (anterior or abdominoperineal resection; n=27), conventional transanal resection using Parks retractor (TP; n=76), transanal endoscopic microsurgery (TEM) with electrosurgery (TEM-ES; n=45), and TEM with UltraCision (TEM-UC; n=34). One-third of the patients with RS (33%) received either a colostomy or a protective loop-ileostomy. Results. Operation time with TEM-UC was significantly shorter than with TEM-ES or RS. Hospitalization was significantly longer with RS than for TEM or TP. Complication rate with TEM was significantly lower than with RS. Recurrence rate with RS and TEM was significantly lower than with TP, with a trend to TEM-UC being better than TEM-ES. Mortality rate was 3.7% with RS and 0 with TP and TEM. The 2-year survival rate was 96.3% with RS and 100% each with TP and TEM. Conclusion. TEM using UC seems to be the technique of choice. TP leads to an unacceptable recurrence rate, and RS results in a higher incidence of complication and impairment of life quality.

Phase II Trial of Carcinoembryonic Antigen Radioimmunotherapy With 131I-Labetuzumab After Salvage Resection of Colorectal Metastases in the Liver: Five-Year Safety and Efficacy Results

PURPOSE Although complete resection (R0) of liver metastases (LM) remains the treatment of choice for colorectal cancer (CRC) patients amenable to curative therapy, only approximately one third survive for 5 years. The objective of this phase II study was to evaluate the safety and efficacy of radioimmunotherapy (RAIT) after salvage resection of LM. PATIENTS AND METHODS Twenty-three patients who underwent surgery for LM of CRC received a dose of 40 to 60 mCi/m2 of 131I-labetuzumab, which is a humanized monoclonal antibody against carcinoembryonic antigen. Safety (n = 23), disease-free survival (DFS; n = 19), and overall survival (OS; n = 19) were determined. RESULTS With a median follow-up of 64 months, the median OS time from the first liver resection for RAIT patients was 68.0 months (95% CI, 46.0 months to infinity), and the median DFS time was 18.0 months (95% CI, 11.0 to 31.0 months). The 5-year survival rate was 51.3%. RAIT benefited patients independently of bilobar involvement, size and number of LM, and resection margins. The major adverse effect was transient myelosuppression, resulting mostly in grade < or = 3 neutropenia and/or thrombocytopenia. CONCLUSION Because both the median OS and 5-year survival rates seem to be improved with adjuvant RAIT after complete LM resection in CRC, compared with historical and contemporaneous controls not receiving RAIT, these results justify further evaluation of this modality in a multicenter, randomized trial.

Pylorus Preservation Has No Impact on Delayed Gastric Emptying After Pancreatic Head Resection

Objectives Delayed gastric emptying (DGE) has been specifically attributed to pylorus-preserving pancreaticoduodenectomy (PPPD). As PPPD has been shown to be comparable with the classic Kausch-Whipple pancreaticoduodenectomy (KWPD) in terms of oncological radicality, DGE has advanced to be the leading argument for hemigastrectomy in PD. Methods A prospective, nonrandomized comparison of patients undergoing PPPD (n = 113), KWPD (n = 19), and duodenum-preserving, pancreatic head resection (DPPHR, n = 18) for various diseases was performed. First, groups were analyzed with regard to structural similarity; then, they were compared with special emphasis on DGE and other postoperative complications. Finally, further prognostic factors were sought that had an impact on DGE. Results The PPPD group was comparable with the KWPD group, but not to the DPPHR population. The in-clinic course after DPPHR compared favorably with PPPD as well as KWPD, and, here, no DGE occurred. The overall morbidity rates of PPPD and KWPD were comparable; 1 patient died in hospital (mortality rate, 0.7%). The gastric tube after PPPD and KWPD could be withdrawn at a median of 2 and 3 days, respectively, a liquid diet was started after 4 and 5 days, respectively, and a full diet was tolerated after 10 days each (n.s.). DGE was distributed evenly among PPPD (12%) and KWPD patients (21%, n.s.), and it was noted almost exclusively when other postoperative complications were present (P < 0.0001). No further prognostic factors influencing DGE could be identified. Conclusion Pylorus preservation does not increase the frequency of DGE. DGE almost exclusively occurs as a consequence of other postoperative complications. Therefore, DGE should not be used as an argument to advocate hemigastrectomy in PPPD.

Radioimmunotherapy of small-volume disease of metastatic colorectal cancer.

Whereas radioimmunotherapy (RIT) has shown disappointing results in bulky, solid tumors, preclinical results in small‐volume disease and in an adjuvant setting are promising. In a previous Phase I study, the authors had encouraging results with the iodine‐131 (131I)–labeled humanized anti–carcinoembryonic antigen (anti‐CEA) antibody (MAb) hMN‐14 in small‐volume disease of colorectal cancer. The aim of this study was to evaluate, in a subsequent Phase II trial, the therapeutic efficacy of this 131I‐labeled humanized anti‐CEA antibody in colorectal cancer patients with small‐volume disease or in an adjuvant setting.

Predicting postoperative morbidity by clinical assessment.

The aim of this study was to determine the accuracy of prediction of the surgeons ‘gut‐feeling’ in estimating postoperative outcome.

Hepatocyte-supported serum-free culture of rat liver sinusoidal endothelial cells∗

BACKGROUND/AIMS A major problem in rat liver endothelial cell culture is the rapid loss of cells after 48 h. This study aimed to develop a protocol that allowed easy maintenance and proliferation of sinusoidal endothelial cells in serum-free culture for 5-6 days. METHODS Cells isolated from adult rat liver by collagenase digestion were purified by centrifugal elutriation and cultured on glutaraldehyde-crosslinked collagen. RESULTS At high plating densities cells could be maintained serum-free for 6 days in the presence of hydrocortisone and basic fibroblast growth factor; at lower plating densities medium had to be supplemented with additional growth-promoting factors. Conditioned medium of adult rat hepatocytes proved to be the most effective growth stimulus; it increased thymidine incorporation, DNA content and cell number per dish with a half-maximal effect at 20% (v/v). Cell proliferation was also observed with either vascular endothelial growth factor, phorbol ester or conditioned media from FAO or HEPG2 liver cell lines provided the cultures were additionally supplemented with 1% newborn calf serum. Vascular endothelial growth factor was detected in all conditioned media. In the absence of hepatocyte-conditioned medium, 1% serum helped to maintain cultures; it itself exerted a low proliferative effect. Higher serum concentrations (>5%), however, led to cell loss after 48 h. The numerous sieve plates of 6-h-old cells progressively disappeared during culture and were replaced by randomly distributed pores, which later grouped together at cell-cell borders. More than 90% of the cells endocytosed acetylated low-density lipoprotein. CONCLUSIONS The study shows that cultured hepatocytes secrete growth-promoting substances that stimulate in vitro endothelial cell proliferation in the absence of serum; this effect could be mimicked by the combined addition of vascular endothelial growth factor and 1% serum. The new media formulations should facilitate future research on liver endothelial cells in mono- or coculture.

Präoperative Diagnostik beim lokal fortgeschrittenen Rektumkarzinom (≥T3 oder N+)

AbstractIntroduction. Neoadjuvant radiochemotherapy (neoRT/CT) in locally advanced rectal cancer requires an exact initial determination of the depth of the cancerous infiltration (T-status) and of locoregional lymph node metastasis (N-status).For staging and restaging, contrastenhanced computed tomography (CT) is usually used. In specialised centers, the endorectal ultrasound (rES) may be preferred. Methods. Between January 1998 and May 2001, the T- and N-status of 102 patients with adenocarcinoma of the rectum (≥T3 or N+) was determined prospectively by rES and CT (group I: n=61 without neo-RT/CT, examined once; group II: n=41 examined before and after neoRT/CT). All diagnostic findings were compared using the (y)pTNMclassification. Results. In the patients from group I, the depth of infiltration (uT) was predicted correctly by rES in 75% and by CT in 48% of cases; the carcinomas were understaged in 10% and 41% of cases and overstaged in 15% and 11%, respectively.According to the histopathological findings, the N-status was determined correctly by rES and CT in 75% and 57% of cases, understaging occurred in 8% and 30% and overstaging in 17% and 13%, respectively. In cases in which both methods resulted in identical T- (uT+ctT) or N-staging (uN+ctN), the accuracy increased to 82% and 80%, respectively. In patients from group II, after neoRT/CT rES and CT allowed the exact prediction of the yuT-stage in 66% and 51%, respectively.Only 2% were understaged by rES (understaging by CT: 22%).Overstaging occurred in 32% and 27% by rES and CT, respectively.The N-status determined by rES and CT was in accordance with the histopathological findings in 68% and 76%of cases, respectively. Understaging occurred in 20% and 17%,overstaging in 12% and 7%, respectively.Again identical staging results in both rES and CT increased the accuracy of the T- (yuT+yctT) or N- (yuN+yctN) classification to 90% and 83%, respectively. In group II, downsizing of the tumor by more than one T-stage was correctly assessed by rES results in 15/20cases (75%). A complete remission of initial uT3-carcinoma was diagnosed correctly in only two of eight ypT0-cases. In contrast, CT demonstrated a remission of disease in all cases but was unable to predict the extent of tumour reduction. A remission of lymph node metastasis was accurately shown by rES in 17/19 cases (90%) and by CT in 10/12 cases (83%). Conclusion. The staging of pretherapeutic, locoregional T- and N-status by rES is superior to that by CT (T-status: P=0.0164, N-status: P=0.0035).At restaging, rES offers higher accuracy in the detection of residual tumour infiltration (but not significantly to CT, yT-status: P=0.0833, yN-status: P=0.7962) and assessment of local remission. Therefore rES should be the method of choice in staging to avoid overtreatment in neoadjuvant settings.After neoRT/CT, the predictive efficacy of the rES for the downsizing/-staging of rectal cancer must be evaluated on greater numbers of patients receiving standardised diagnostic procedures and therapy.ZusammenfassungEinleitung. Die neoadjuvante Radio-/Chemotherapie (neoRT/CT) des lokal fortgeschrittenen Rektumkarzinoms erfordert eine genaue prätherapeutische Einschätzung der Tumorinfiltrationstiefe (T-Status) und der lokoregionalen Lymphknotenmetastasierung (N-Status): Zum Staging und Restaging wird allgemein die Kontrastmittelgestützte Computertomographie (CT) und in spezialisierten Zentren die rektale Endosonographie (rES) favorisiert. Methoden. Von 01/98–05/01 wurde bei 102 Patienten (Pat.) mit einem Adenokarzinom des Rektums prospektiv der T- und N-Status per CT und rES bestimmt [Gruppe I: n=61 Pat.ohne neoRT/CT;Gruppe II: n=41 Pat.vor und nach neoRT/CT] und mit dem histopathologischen (y)pTNM-Befund verglichen. Ergebnisse. In Gruppe I traf die rES-Vorhersage bzgl.der Tumorinfiltrationstiefe (uT) in 75% zu (CT: 48%); 10% (CT: 41%) der Malignome wurden falsch zu niedrig (“understaging”) und 15% (CT: 11%) falsch zu hoch (“overstaging”) eingeschätzt.Der N-Status wurde per rES in 75% richtig erhoben (CT: 57%), das “understaging” lag bei 8% (CT: 30%) und das “overstaging” bei 17% (CT: 13%). In Gruppe II entsprach die rES-Vorhersage einer nach neoRT/CT verbliebenen Tumorinfiltration (yuT) in 66% (27/41 Pat.) dem ypT-Befund (CT: 51%).Lediglich 2% der Pat.wurden im Restaging mittels rES falsch zu niedrig (CT: 22%) und 32% (CT: 27%) falsch zu hoch eingeschätzt.Der yuN-Status entsprach in 68% (28/41 Pat.) der Histologie (CT: 76%), wobei ein “understaging” in 20% (CT: 17%) und ein “overstaging” in 12 % vorlag (CT: 7%). Eine komplette Remission (CR) initialer uT3-Rektumkarzinome wurde in 2 von 8 als ypT0 befundeten Fällen erfaßt.Demgegenüber sagte die CT bei allen 20 Pat. – allerdings ohne Festlegung auf das Remissionsausmaß – einen Tumorregress voraus. Eine CR initial vermuteter N-Infiltrationen konnte bei 17/19 Pat.(90%) per rES und bei 10/12 Pat. (83%) per CT korrekt vorausgesagt werden. Schlussfolgerung: Bei der prätherapeutischen T- und N-Beurteilung ist die rES der CT deutlich überlegen (T-Status: p=0.0164, N-Status: p=0.0035).Im Restaging ermöglicht die rES eine genauere, jedoch statistisch nicht signifikante Beurteilung der residuellen Tiefeninfiltration (yT-Status: p=0,0833; yN-Status: p=0,7962) und der lokalen Tumorremission.

Liver repopulation after hepatocellular transplantation: integration and interaction of transplanted hepatocytes in the host.

The mechanisms of donor hepatocyte integration into recipient liver are not fully understood. We investigated mechanisms of both the integration and interaction of transplanted hepatocytes with host liver cells as well as the repopulation of the host organ following intraportal transplantation. Mature hepatocytes were injected into the portal vein of dipeptidylpeptidase IV (DPPIV)-deficient rats pretreated with retrorsine and subjected to 30% partial hepatectomy to ensure selective donor growth. The degree of integration and proliferation was studied by colocalizing transplanted cells (DPPIV positive) with connexin 32, MMP-2, and OX-43 (multilayer immunofluorescence imaging). FACS analysis was established to assess the extent of repopulation quantitatively. Transplanted hepatocytes reached the distal portal spaces and sinusoids within 1 h after injection. A small proportion of cells succeeded in traversing the endothelial barrier through mechanical disruption in both locations. Transplanted hepatocytes lost their membrane-bound gap junctions (connexin 32) during this process. Successful integration of the donor cells required up to 5 days, heralded by gap junction reconstitution and the specific basolateral membrane expression of DPPIV. MMP-2 degraded the extracellular matrix in close proximity to donor cells, providing space for cell division. FACS analysis revealed that more than 37% of the liver was repopulated by cells derived from donors at 2 months after transplantation. Our data demonstrate a high degree of donor cell repopulation of the host organ and provide valuable insight into the specific mechanisms of donor cell integration. Connexin 32 expression in transplanted hepatocytes may serve as an indicator of their effective incorporation and communication within the recipient liver. FACS analysis reveals an accurate method to determine quantitatively the extent of liver repopulation.

[Preoperative diagnostic procedures in locally advanced rectal carcinoma (> or =T3 or N+). What does endoluminal ultrasound achieve at staging and restaging (after neoadjuvant radiochemotherapy) in contrast to computed tomography?].

AbstractIntroduction. Neoadjuvant radiochemotherapy (neoRT/CT) in locally advanced rectal cancer requires an exact initial determination of the depth of the cancerous infiltration (T-status) and of locoregional lymph node metastasis (N-status).For staging and restaging, contrastenhanced computed tomography (CT) is usually used. In specialised centers, the endorectal ultrasound (rES) may be preferred. Methods. Between January 1998 and May 2001, the T- and N-status of 102 patients with adenocarcinoma of the rectum (≥T3 or N+) was determined prospectively by rES and CT (group I: n=61 without neo-RT/CT, examined once; group II: n=41 examined before and after neoRT/CT). All diagnostic findings were compared using the (y)pTNMclassification. Results. In the patients from group I, the depth of infiltration (uT) was predicted correctly by rES in 75% and by CT in 48% of cases; the carcinomas were understaged in 10% and 41% of cases and overstaged in 15% and 11%, respectively.According to the histopathological findings, the N-status was determined correctly by rES and CT in 75% and 57% of cases, understaging occurred in 8% and 30% and overstaging in 17% and 13%, respectively. In cases in which both methods resulted in identical T- (uT+ctT) or N-staging (uN+ctN), the accuracy increased to 82% and 80%, respectively. In patients from group II, after neoRT/CT rES and CT allowed the exact prediction of the yuT-stage in 66% and 51%, respectively.Only 2% were understaged by rES (understaging by CT: 22%).Overstaging occurred in 32% and 27% by rES and CT, respectively.The N-status determined by rES and CT was in accordance with the histopathological findings in 68% and 76%of cases, respectively. Understaging occurred in 20% and 17%,overstaging in 12% and 7%, respectively.Again identical staging results in both rES and CT increased the accuracy of the T- (yuT+yctT) or N- (yuN+yctN) classification to 90% and 83%, respectively. In group II, downsizing of the tumor by more than one T-stage was correctly assessed by rES results in 15/20cases (75%). A complete remission of initial uT3-carcinoma was diagnosed correctly in only two of eight ypT0-cases. In contrast, CT demonstrated a remission of disease in all cases but was unable to predict the extent of tumour reduction. A remission of lymph node metastasis was accurately shown by rES in 17/19 cases (90%) and by CT in 10/12 cases (83%). Conclusion. The staging of pretherapeutic, locoregional T- and N-status by rES is superior to that by CT (T-status: P=0.0164, N-status: P=0.0035).At restaging, rES offers higher accuracy in the detection of residual tumour infiltration (but not significantly to CT, yT-status: P=0.0833, yN-status: P=0.7962) and assessment of local remission. Therefore rES should be the method of choice in staging to avoid overtreatment in neoadjuvant settings.After neoRT/CT, the predictive efficacy of the rES for the downsizing/-staging of rectal cancer must be evaluated on greater numbers of patients receiving standardised diagnostic procedures and therapy.ZusammenfassungEinleitung. Die neoadjuvante Radio-/Chemotherapie (neoRT/CT) des lokal fortgeschrittenen Rektumkarzinoms erfordert eine genaue prätherapeutische Einschätzung der Tumorinfiltrationstiefe (T-Status) und der lokoregionalen Lymphknotenmetastasierung (N-Status): Zum Staging und Restaging wird allgemein die Kontrastmittelgestützte Computertomographie (CT) und in spezialisierten Zentren die rektale Endosonographie (rES) favorisiert. Methoden. Von 01/98–05/01 wurde bei 102 Patienten (Pat.) mit einem Adenokarzinom des Rektums prospektiv der T- und N-Status per CT und rES bestimmt [Gruppe I: n=61 Pat.ohne neoRT/CT;Gruppe II: n=41 Pat.vor und nach neoRT/CT] und mit dem histopathologischen (y)pTNM-Befund verglichen. Ergebnisse. In Gruppe I traf die rES-Vorhersage bzgl.der Tumorinfiltrationstiefe (uT) in 75% zu (CT: 48%); 10% (CT: 41%) der Malignome wurden falsch zu niedrig (“understaging”) und 15% (CT: 11%) falsch zu hoch (“overstaging”) eingeschätzt.Der N-Status wurde per rES in 75% richtig erhoben (CT: 57%), das “understaging” lag bei 8% (CT: 30%) und das “overstaging” bei 17% (CT: 13%). In Gruppe II entsprach die rES-Vorhersage einer nach neoRT/CT verbliebenen Tumorinfiltration (yuT) in 66% (27/41 Pat.) dem ypT-Befund (CT: 51%).Lediglich 2% der Pat.wurden im Restaging mittels rES falsch zu niedrig (CT: 22%) und 32% (CT: 27%) falsch zu hoch eingeschätzt.Der yuN-Status entsprach in 68% (28/41 Pat.) der Histologie (CT: 76%), wobei ein “understaging” in 20% (CT: 17%) und ein “overstaging” in 12 % vorlag (CT: 7%). Eine komplette Remission (CR) initialer uT3-Rektumkarzinome wurde in 2 von 8 als ypT0 befundeten Fällen erfaßt.Demgegenüber sagte die CT bei allen 20 Pat. – allerdings ohne Festlegung auf das Remissionsausmaß – einen Tumorregress voraus. Eine CR initial vermuteter N-Infiltrationen konnte bei 17/19 Pat.(90%) per rES und bei 10/12 Pat. (83%) per CT korrekt vorausgesagt werden. Schlussfolgerung: Bei der prätherapeutischen T- und N-Beurteilung ist die rES der CT deutlich überlegen (T-Status: p=0.0164, N-Status: p=0.0035).Im Restaging ermöglicht die rES eine genauere, jedoch statistisch nicht signifikante Beurteilung der residuellen Tiefeninfiltration (yT-Status: p=0,0833; yN-Status: p=0,7962) und der lokalen Tumorremission.

Significance of isolated tumor cells in lymph nodes among gastric cancer patients.

PurposeTo determine the frequency and prognostic impact of isolated tumor cells (ITC) in regional lymph nodes judged to be tumor free in conventional histopathology among gastric cancer patients.MethodsAmong 161 patients who underwent gastrectomy and D2-lymphadenectomy, 56 were staged pN0(35%). Archival paraffin blocks of 1148 resected regional lymph nodes of those pN0 patients were reevaluated for ITC using monoclonal antibody Ber-EP4. Patients with and without ITC were compared with regard to the distribution of various clinicopathological factors. Prognostic impact of ITC was tested in uni- and multivariate analysis.ResultsOf 56 pN0 patients, 33 (59%) exhibited single Ber-Ep4 immunoreactive cells or small cell clusters in at least one lymph node. The occurrence of ITC was not dependent on other clinicopathological factors. ITC impaired patients’ prognoses significantly in uni- as well as multivariate analyses [estimated 5-year survival rate: 82% for pN0(i−) vs 58% for pN0(i+) (p=0.059) and 15% for pN1/2 (p=0.0005 and p<0.0001, respectively)].ConclusionITC are a frequent event in apparently tumor-free lymph nodes of gastric cancer patients and are overlooked by conventional histopathology. They are encountered even in limited stages of disease and impair patients’ prognoses. This should be borne in mind when advocating local resection for early gastric cancer.