Bernd Kremer

The retroperitoneal resection margin and vessel involvement are important factors determining survival after pancreaticoduodenectomy for ductal adenocarcinoma of the head of the pancreas

Abstract The prognosis of ductal adenocarcinoma of the pancreas is still poor. We analysed the factors that have a major influence on the survival of patients. Surgical specimens from 51 patients with ductal adenocarcinoma of the head of the pancreas were examined for tumour size, histological type, grade and local extension. In 7 patients the retroperitoneal resection margin was involved either macroscopically or histologically. Their mean survival was 10.6 months (1–17 months), compared with 22.7 months for the 44 patients with curative R0 resection. In 10 patients large vessels (portal and/or mesenteric vein) had to be resected; they survived for only 2-11 months, with a mean of 5 months (P<0.05). Non-R0-resected patients and patients in whom tumour-invaded vessels had to be resected constitute a high-risk group with a significantly shorter mean survival of 8.8 months, compared with 24.3 months for R0 resected patients without vessel invasion (P<0.05). Lymph node metastases were seen in 35 of 51 patients. Survival analysis based on nodal status revealed a mean survival of 33 months for patients staged as N0, 21.4 for N1a patients and 14 month for N1b patients. The differences were not statistically significant, however. Our data suggest that tumour invasion of the retroperitoneal resection margin and large vessel involvement are the major factors determining survival in patients with pancreatic cancer.

Long‐Term Culture and Differentiation of Rat Embryonic Stem Cell‐Like Cells into Neuronal, Glial, Endothelial, and Hepatic Lineages

The in vitro differentiation of mouse embryonic stem cells into different somatic cell types such as neurons, endothelial cells, or myocytes is a well‐established procedure. Long‐term culture of rat embryonic stem cells is known to be hazardous, and attempts to differentiate these cells in vitro so far have been unsuccessful. We herein describe stable long‐term culture of an alkaline phosphatase‐positive rat embryonic stem cell‐like cell line (RESC) and its differentiation into neuronal, endothelial, and hepatic lineages. RESCs were characterized by typical growth in single cells as well as in embryoid bodies when cultured in the presence of leukemia inhibitory factor. RESC expressed stage‐specific‐embryonic antigen‐1 and the major histocompatibility complex class I molecule. For neuronal differentiation, cells were incubated with medium containing 10−6 M retinoic acid for 14 days. For endothelial differentiation, RESCs were grown on Matrigel for 14 days, and for induction of hepatocyte‐specific antigen expression, RESCs were grown in medium supplemented with fibroblast growth factor‐4. Differentiated cells exhibited typical morphological changes and expressed neuronal (nestin, mitogen‐activated protein‐2, synaptophysin), glial (S100, glial fibrillary acid protein), endothelial (panendothelial antibody, CD31) and hepatocyte‐specific (α‐fetoprotein [αFP], albumin, α‐1‐antitrypsin, CK18) antigens. In addition, expression of hepatocyte‐specific genes (αFP, transthyretin, carbamoyl‐phosphate synthetase, and coagulation factor‐2) was detected by reverse transcription polymerase chain reaction. We were able to culture RESCs under stable, long‐term conditions and to initiate programmed differentiation of RESCs to endothelial, neuronal, glial, and hepatic lineages in the rat species.

The grade of pancreatic ductal carcinoma is an independent prognostic factor and is superior to the immunohistochemical assessment of proliferation

Tumour grade is one of the prognostic factors in pancreatic ductal adenocarcinoma, but its value is controversial. In this study, the predictive value and the reproducibility of the WHO grading system were reconsidered and the possibility of supplementing it with the immunohistochemically assessed proliferative activity was investigated. Seventy resected ductal adenocarcinomas of the head of the pancreas were evaluated. A total of 60 HPF fields on two to four sections per tumour were screened for glandular differentiation, mucin production, mitosis, and nuclear atypia by two observers with different degrees of experience. Each criterion was scored and the grade was calculated from the mean value of all single scores. Corresponding slides were immunohistochemically stained with the proliferation marker Ki‐S5. The percentage of positive nuclei was assessed and a proliferation index (PI) assigned (<10%=1; 10–50%=2; >50%=3). Multivariate analysis (Cox regression) identified grade and R stage as the most significant factors for predicting survival. The PI determined on the basis of Ki‐S5 staining did not prove to be an independent prognostic factor. In 30 of 70 carcinomas, it correlated with the tumour grade. Within a given tumour grade, the cases with the least favourable prognosis could be distinguished on the basis of their PI. The inter‐observer variability was considerable, with the main differences occurring in the group of G1 tumours. According to the refined WHO criteria, the histopathological grade of pancreatic ductal carcinoma is an important independent prognostic factor, but reproducibility depends on the expertise of the observer. Criteria that relate to cellular and structural differentiation seem to be more predictive than those related to proliferation. Copyright

Ten-Year Historic Cohort of Quality of Life and Sexuality in Patients With Rectal Cancer

PURPOSEIn various studies, type of surgery, age, and gender had different impact on sexuality and quality of life in patients with rectal cancer. This study was designed to investigate how sexuality and quality of life are affected by age, gender, and type of surgery.METHODSA total of 516 patients who had undergone surgery for rectal cancer in our department from 1992 to 2002 were included. Within one year after the operation, 117 patients died. Questionnaires were sent to 373 patients 12 to 18 months after surgery. We received quality of life data from 261 patients. Comparisons were made after adjusting age, gender, and type of surgical procedure.RESULTSFor patients receiving abdominoperineal resection sexuality was most impaired. Significant differences were seen in symptom and function scales between males and females. Females reported more distress from the medical treatment insomnia, fatigue, and constipation. Both genders had impaired sexual life; however, males had significantly higher values and felt more distressed by this impairment. Younger females felt more distress through impaired sexuality. In males sexuality was impaired independent of age. Adjuvant therapy had no influence on sexuality but on quality of life one year after surgery.CONCLUSIONSAssessing quality of life with general and specific instruments is helpful to determine whether patients improved through the treatment. The study showed that gender, age, and type of surgery influence sexuality and that quality of life after surgery for rectal cancer is impacted. Because quality of life is a predictor for complications and survival, availability of such data may help to direct supportive treatment to improve outcome.

Surgery for ductal adenocarcinoma of the pancreatic head: staging, complications, and survival after regional versus extended lymphadenectomy.

Abstract. The purpose of this study was to evaluate the influence of regional versus extended lymphadenectomy on survival after partial pancreaticoduodenectomy for pancreatic cancer. From October 1988 to December 1991 (Department of Surgery, University of Hamburg) and from January 1992 to March 1998 (Department of Surgery, University of Kiel) 72 patients with histologically proven ductal adenocarcinoma of the pancreatic head were treated. Partial pancreaticoduodenectomy with regional lymphadenectomy was performed in 26 patients. In 46 patients lymphadenectomy was expanded to include extended retroperitoneal lymphatic and connective tissue clearance. Comparing these two groups and including only patients with R0 resections (n= 58) no significant differences in long-term survival could be shown. The following parameters were shown to have a significant or nearly significant influence on long-term survival: (1) stage of the disease: The 5-year survival of patients with stage I/II pancreatic head cancer was 63%, compared to 15% in patients with stage III/IV a + b of the disease (p= 0.0087). (2) Grading: The 1-year survival of patients with well or moderately differentiated tumors was 55%, compared to 0% for patients with poorly differentiated ductal adenocarcinoma (p= 0.0022). (3) N stage: The 5-year survival of patients in N0 stage was 46.9%, compared with 15% for N1 stage patients. The difference was not quite significant (p= 0.081). (4) Portal vein involvement: The 1-year survival was 0% in patients with R0 resections and histologically proven tumor infiltration of the portal vein, compared to 63% for patients with curative resections without portal vein involvement (p= 0.0063). In conclusion our data indicate that extensive retroperitoneal tissue clearance during pancreaticoduodenectomy for ductal pancreatic cancer does not improve survival compared to regional lymphadenectomy restricted to the right side of the mesenteric artery.

Endoscopic removal of large colorectal polyps

AbstractPURPOSE: Because of the potential risk of malignancy and technical difficulties in achieving complete removal, large colorectal polyps represent a special problem for the endoscopist. The aim of this study was to evaluate the capabilities and risks of endoscopy in complete removal of large colorectal polyps. METHODS: Endoscopic polypectomy of 186 colorectal polyps larger than 3 cm in diameter (range, 3–13 cm) was performed; 141 were sessile and 45 pedunculated. Most of the polyps were located in the rectum (n = 88), sigmoid (n = 63), and cecum (n = 9). The remaining adenomas were situated in other parts of the colon. Sessile polyps were removed using the piecemeal technique. RESULTS: Histology results showed an adenoma in 167 cases, and invasive carcinoma was present in the adenoma in 19 patients. Of the adenomas, 29 were tubulous, 118 tubulovillous, and 20 villous; adenoma with severe dysplasia was found in 49 cases. Complete endoscopic removal was achieved in all sessile and pedunculated polyps. None of the patients with invasive carcinoma who underwent surgical resection (n = 10) had any evidence of tumor in the resected specimen. Bleeding occurred in 4 patients after polypectomy (2 percent). Perforation occurred in 1 patient (0.5 percent), who had an invasive carcinoma of the cecum. There was no procedure-related mortality. During a mean follow-up period of 40 (range, 3–87) months, 6 patients presented with recurrence of a benign adenoma (3 percent), which was treated endoscopically, and 1 patient presented with a recurrent invasive carcinoma, which was treated surgically. CONCLUSIONS: Endoscopic polypectomy is a safe and effective method of treating large colorectal polyps.

Procalcitonin as a marker of severity in septic shock

Background/aims: Procalcitonin (PCT) was shown to be related to the severity of bacterial infection and is recommended as a new parameter of inflammation and infection. To evaluate the prognostic value in septic shock, PCT levels were repeatedly determined and compared with tumour necrosis factor-α (TNF-α)- and interleukin (IL)-6 bioactivity as well as with C-reactive protein (CRP) serum levels. Patients: Twenty-four surgical patients with septic shock were included. Eight patients died within the study period of 14 days. Methods: Serum levels of TNF- (WEHI 164) and IL-6 (B13–29 subclone 9) bioactivity, CRP and PCT were determined on days 1, 3, 5, 7, 10 and 14 following diagnosis of septic shock. Results: Survivors and non-survivors were comparable in terms of age and severity of sepsis characterized by the APACHE II score and multiple-organ-failure score. Predominant causes of sepsis were peritonitis and necrotiszing pancreatitis. TNF levels increased in non-survivors with no significant difference to survivors. IL-6 bioactivity was increased on day 1 (P = 0.06) and remained elevated in non-survivors, in whom it was significant on day 7 (P<0.05). CRP was constantly elevated with no difference between the groups. In non-survivors PCT remained increased, while the course of survivors was characterized by decreased values which were significantly lower (P<0.05) at every time point compared with those patients who died. A significant correlation could be found on day 1 (P<0.05) and at the end of the observation period (P<0.01) when comparing PCT levels with the multiple-organ-failure score. Conclusions: PCT seems to be a more reliable prognostic parameter in septic shock than IL-6, while TNF and CRP did not show any difference between survivors and non-survivors. These data indicate that PCT may represent a valuable parameter not only in the diagnosis of sepsis but also in the clinical course of the disease.

Pattern of soluble TNF receptors I and II in sepsis.

The serum levels of soluble TNF receptors I (sTNFR I) and sTNFR II were measured frequently in 14 patients with sepsis to evaluate the pattern of these TNF antagonists in relation to TNF alpha, Soluble TNFR I and II could be detected in all samples with significantly higher levels (p<0.001) compared to healthy controls. The concentration of sTNFR I as well as sTNFR II was significantly higher in nonsurvivors compared to survivors during the first 36 h of sepsis (p<0.001). Levels remained elevated throughout the evaluation with maximal values in patients who died. A positive correlation exists between both receptors and between soluble receptors and simultaneously obtained sepsis score (p<0.01) while TNF immunoreactivity detected in 80% of all samples did not correlate to soluble receptor levels or sepsis score. Soluble receptors were constantly found in the circulation representing the inflammatory state throughout the evaluation even when TNF activity was undetectable. Die Serumspiegel der löslichen TNF-Rezeptoren I (sTNFR I) und II (sTNFR II) wurden in kurzen Zeitabständen bei 14 Patienten mit der Diagnose einer Sepsis bestimmt, um die Kinetik der natürlich vorkommenden TNF-Antagonisten in Relation zu TNF alpha zu untersuchen. Die sTNFR I und II waren signifikant gegenüber gesunden Kontrollprobanden erhöht (p<0,001). Die Serumkonzentrationen sowohl des sTNFR I als auch des sTNFR II waren während der ersten 36 Stunden der Sepsis bei den Patienten, die verstarben, signifikant höher als bei den Überlebenden (p<0,001). Die Konzentrationen blieben während der weiteren Messungen erhöht und zeigten maximale Werte bei Patienten mit einem letalen Ausgang. Eine positive Korrelation bestand zwischen den beiden löslichen Rezeptoren sowie den Rezeptoren und dem gleichzeitig bestimmten Sepsis Score (p<0,01), während die Immunreaktivität von TNF alpha, die in 80% aller Proben gemessen wurde, keine positive Korrelation zu den löslichen TNF-Rezeptoren oder dem Sepsis Score aufwies. Die löslichen TNF-Rezeptoren I und II können während der Sepsis zu jedem Zeitpunkt und auch dann nachgewiesen werden, wenn keine meßbare TNF-Aktivität vorliegt.SummaryThe serum levels of soluble TNF receptors I (sTNFR I) and sTNFR II were measured frequently in 14 patients with sepsis to evaluate the pattern of these TNF antagonists in relation to TNF alpha, Soluble TNFR I and II could be detected in all samples with significantly higher levels (p<0.001) compared to healthy controls. The concentration of sTNFR I as well as sTNFR II was significantly higher in nonsurvivors compared to survivors during the first 36 h of sepsis (p<0.001). Levels remained elevated throughout the evaluation with maximal values in patients who died. A positive correlation exists between both receptors and between soluble receptors and simultaneously obtained sepsis score (p<0.01) while TNF immunoreactivity detected in 80% of all samples did not correlate to soluble receptor levels or sepsis score. Soluble receptors were constantly found in the circulation representing the inflammatory state throughout the evaluation even when TNF activity was undetectable.ZusammenfassungDie Serumspiegel der löslichen TNF-Rezeptoren I (sTNFR I) und II (sTNFR II) wurden in kurzen Zeitabständen bei 14 Patienten mit der Diagnose einer Sepsis bestimmt, um die Kinetik der natürlich vorkommenden TNF-Antagonisten in Relation zu TNF alpha zu untersuchen. Die sTNFR I und II waren signifikant gegenüber gesunden Kontrollprobanden erhöht (p<0,001). Die Serumkonzentrationen sowohl des sTNFR I als auch des sTNFR II waren während der ersten 36 Stunden der Sepsis bei den Patienten, die verstarben, signifikant höher als bei den Überlebenden (p<0,001). Die Konzentrationen blieben während der weiteren Messungen erhöht und zeigten maximale Werte bei Patienten mit einem letalen Ausgang. Eine positive Korrelation bestand zwischen den beiden löslichen Rezeptoren sowie den Rezeptoren und dem gleichzeitig bestimmten Sepsis Score (p<0,01), während die Immunreaktivität von TNF alpha, die in 80% aller Proben gemessen wurde, keine positive Korrelation zu den löslichen TNF-Rezeptoren oder dem Sepsis Score aufwies. Die löslichen TNF-Rezeptoren I und II können während der Sepsis zu jedem Zeitpunkt und auch dann nachgewiesen werden, wenn keine meßbare TNF-Aktivität vorliegt.

Prospective Evaluation of Quality of Life of Patients Receiving Either Abdominoperineal Resection or Sphincter-Preserving Procedure for Rectal Cancer

BackgroundStudy results on quality of life (QoL) between patients receiving an anterior resection (AR) or abdominoperineal resection (APR) for rectal cancer vary greatly. A main reason is grounded in unequal methodology. The aims of this study were to assess differences in perceived QoL over time among patients treated with AR or APR with a recommended study design and methodology.MethodsIn a prospective study, the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and a tumor-specific module were administered to patients with rectal cancer before surgery, at discharge, and 3, 6, and 12 months after the operation. Comparisons were made between patients receiving an AR and those receiving an APR.ResultsTwo hundred forty-nine patients were included; 46 patients received an APR and 203 an AR. QoL data were available for 212 patients, of which 112 were female and 100 male. No differences in the distribution of age, sex, or tumor stage were observed between groups. EORTC function scales showed no significant differences, including body image scales, between patients receiving an AR and those receiving an APR. In symptom scores, AR patients had more difficulty with diarrhea and constipation, whereas patients with APR experienced more impaired sexuality and pain in the anoperineal region. At discharge, patients receiving an AR were more confident about their future.ConclusionsQoL in patients receiving an AR and those receiving an APR is not different. Although patients with APR experience more impaired sexuality, patients receiving an AR experience decreases in QoL because of impaired bowel function.

Gender Differences in Quality of Life of Patients with Rectal Cancer. A Five-Year Prospective Study

To determine how quality of life changes over time and to assess gender-related differences in quality of life of rectal cancer patients we conducted a 5-year study. Little is known about how quality of life (QoL) changes over time in patients after surgery for rectal cancer, and whether gender of the patients is associated with a different perception of QoL. The aim of this study was to assess prospectively, changes in quality of life after surgery for rectal cancer, with a focus on gender related differences. Over a 5-year period, the EORTC-QLQ-C-30 and a tumor-specific module were prospectively administered to patients before surgery, at discharge, 3, 6, 12, and 24 months postoperatively. Comparisons were made between female and male patients. A total of 519 patients participated in the study, 264 men and 255 women. The two groups were comparable in terms of surgical procedures, adjuvant treatment, tumor stage, and histology. Most QoL scores dropped significantly below baseline in the early postoperative period. From the third month onward, global health, emotional and physical functioning, improved. Female gender was associated with significantly worse global health and physical functioning and with higher scores on treatment strain and fatigue. Men reported difficulties with sexual enjoyment; furthermore, over time, sexual problems created high levels of strain in men, worse than baseline levels in the early postoperative period. These problems tended to continue over the course of time. The findings in this study confirm that QoL changes after surgery and differs between men and women. Women appear to be affected by impaired physical functioning and global health. Female gender is associated with significantly higher fatigue levels and increased strain values after surgery. Through impaired sexual enjoyment, men are put more under strain than woman.