[Adjuvant treatment for colon carcinoma. Results and perspectives].
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Adjuvants, Immunologic↗
Biomedical subjects
W Hohenberger
Publications and source records attributed to W Hohenberger.
Plasma separation and bilirubin adsorption after complicated liver transplantation: a therapeutic approach to excessive hyperbilirubinemia.
BACKGROUND: Severe hyperbilirubinemia is known to exert multiple toxic effects. Thus, a reduction in bilirubin by use of various adsorbent columns has been reported for a variety of hepatic disorders, but no experience with liver transplant patients is available as yet. METHODS: Plasma separation and bilirubin adsorption by an anion-exchange adsorbent column (BR-350) were performed in two patients with severe jaundice (total serum bilirubin > 55 mg/dl) and multiple organ failure that had developed after orthotopic liver transplantation. RESULTS: The procedure resulted in an 18% to 35% reduction in total bilirubin after each session, accompanied by a remarkable clinical improvement. Both patients finally recovered and had a favorable outcome. No complications or side effects of bilirubin adsorption were observed during any of the six sessions. CONCLUSIONS: Bilirubin adsorption is a safe and effective treatment. It should be considered as supportive therapy for excessive hyperbilirubinemia after liver transplantation. In selected cases, retransplantation may thus be avoided.
Adsorption↗
Rapid RT-PCR-based protein truncation test in the screening for 5' located mutations of the APC gene.
Although in vitro protein synthesis is a rapid method to screen for translational stops in the adenomatous polyposis coli (APC) gene, truncating mutations at the 5' most end are at risk of being overseen due to their small size. The authors describe a reverse transcriptase-polymerase chain reaction (RT-PCR)-based protein truncation test specifically designed for detecting truncated polypeptide chains of less than 10 kDa. Using this detection system, three novel germline mutations in familial adenomatous polyposis (FAP) patients were identified, i.e. a Gly101 Ter non-sense mutation in exon 3, an exon 4 splice acceptor mutation and a 555delC deletion in exon 5. Morever, a patient manifesting congenital hypertrophy of the retinal pigmented epithelium (CHPRE) was detected with an Arg232Ter mutation in exon 6. This is, to the authors' knowledge, the fourth exception to the rule that FAP patients manifesting CHRPE harbour genetic alternations downstream from APC exon 9. Hence, an alternative hotspot for non-sense mutations associated with CHRPE appears to encompass the codons 215, 216 and 232. Patients reported in this study, exhibited relatively mild clinical symptoms with respect to the age of onset of malignancy (> 50 years of age) and the number of polyps (70-100 adenomas). However, manifestation of severe duodenal adenomatosis was independent of the attenuated colorectal FAP phenotype.
Adenomatous Polyposis Coli Protein↗
Possibilities of extensive surgery.
Advances in surgical technique and knowledge of tumor biology have led to an algorithm of surgical treatment of rectal cancer, which offers three options: transanal local excision, sphincter-saving procedures (low anterior resection and, recently, intersphincteric abdomino-peranal resection), and abdomino-perineal resection of the rectum. The choice of operative procedure aiming to fulfill both oncological and functional criteria is determined by the anatomic location of the tumor, the tumor differentiation, the depth of tumor invasion, and preoperative anal sphincter function. Following the algorithm of treatment, a clear decrease can be noted during recent years in the number of abdomino-perineal resections and a shift towards sphincter-sparing procedures, without jeopardizing long-term survival. Although anal sphincter morphology can usually be maintained, preserving the anal sphincter does not necessarily mean preserving the sphincter function. The functional outcome must be judged by objective, measurable parameters and by the impact of operative sequelae on quality of life and its acceptance by the patient. Future work must focus on further improving long-term survival and functional outcome. Technical advances (Goligher et al. 1979; Heald 1980) and an improved understanding of tumor biology, especially metastatic behavior, have resulted in varied strategies for the operative treatment of rectal cancer. The common aims of these techniques are local control, avoidance of local recurrence, and--while still satisfying oncologic requirements--preservation of the anal sphincter. Until the 1970s, abdominoperineal excision was the treatment of choice. Subsequently, a shift toward anterior and low anterior resection of the rectum took place. Initially these procedures were limited to the treatment of tumors in the upper and mid rectum (Table 1) (Gall and Hermanek 1992), but the indication for anterior resection was later extended to tumors of the lower rectum (Table 2) (Hohenberger and Hermanek 1992).
Abdomen↗
Sphincter preservation with chemoradiation in anal canal carcinoma: abdominoperineal resection in selected cases?
PURPOSE: This study contained herein assessed long-term results, toxicity, and prognostic variables following combined modality therapy of patients with International Union Against (Cancer Classification T1-4, N0-3, M0 squamous-cell carcinoma of the anal canal. PATIENTS AND METHODS: Between 1985 and 1996, 62 patients completed treatment with combined modality therapy. A median total dose of 50 Gy was given to the primary, perirectal, presacral, and inguinal nodes followed by a local boost in selected cases. 5-Fluorouracil was scheduled as a continuous infusion of 1,000 mg/m2 per 24 hours on days 1 to 5 and 29 to 33 and mitomycin C as a bolus of 10 mg/m2 on days 1 and 29. Routinely processed paraffin-embedded sections were stained using monoclonal antibodies for detection of proliferating cell nuclear antigen and MIB1 (Ki-67) antigen to determine the labeling index. In addition, DNA ploidy was assessed after Feulgen staining. RESULTS: Actuarial cancer-related survival, no evidence of disease survival, and colostomy-free survival rates at five years were 81, 76, and 86 percent, respectively. In univariate analysis, T category (T1/2 vs. T3/4) was predictive for no evidence of disease survival (87 vs. 59 percent; P = 0.03) and colostomy-free survival (94 vs. 73 percent; P = 0.05). N category (N0 vs. N1-3) influenced actuarial cancer-related survival (85 vs. 58 percent; P = 0.002) and no evidence of disease survival (80 vs. 53 percent; P = 0.02). A higher proliferative potential as measured by the MIB1 labeling index was associated with a better colostomy-free survival (90 vs. 50 percent; P = 0.04). In multivariate analysis, actuarial cancer-related survival was only influenced by the N category (P = 0.03) and no evidence of disease survival by N category (P = 0.03) and mitomycin C dose (P = 0.04). Salvage abdominoperineal resection achieved long-term control in only four of seven patients with local failures. CONCLUSION: Treatment with a combination of radiotherapy and chemotherapy is safe and effective for patients with anal canal carcinoma. Abdominoperineal resection is indicated as a salvage procedure in nonresponding and recurrent lesions and may be of benefit in a small subgroup of patients with poor prognostic factors.
Adult↗
DCC protein as a predictor of distant metastases after curative surgery for rectal cancer.
PURPOSE: The aim of this study was to determine the value of DCC (deleted in colorectal cancer) protein for predicting metachronous distant metastases after curative surgery for rectal cancer. The DCC protein--for which a gene has been located on chromosome 18q--has recently been reported to have a prognostic value in colorectal cancer. This finding might have implications for treatment of International Union Against Cancer Stage II rectal carcinoma, in which distant metastases will develop in 14 percent of patients despite optimal surgery. METHODS: Paraffin-embedded tissues from 85 patients who developed distant metastases, but no local recurrence, after curative surgery for rectal cancer were matched with 85 samples from patients who remained disease-free. Matching criteria were tumor stage, age, gender, and date of surgery. Expression of DCC protein was assessed using immunohistochemistry. End points of follow-up were recurrence of disease and death. Mean follow-up was 9.6 years. No patient received either local or systemic adjuvant therapy. RESULTS: The DCC protein was found to be expressed in 64.9 percent of tumor samples. Nonexpression of DCC protein had an negative influence on survival (P = 0.03). For all tumor stages together, sensitivity of the test for subsequent occurrence of distant metastases was 42 percent and specificity was 71 percent. In Stage II cancers, the positive predictive value was 19 percent, and the negative predictive value was 88 percent. CONCLUSIONS: Our results confirm that DCC protein is a useful prognostic marker in patients with rectal carcinomas, but the positive predictive value of DCC protein for occurrence of metachronous metastases does not appear to be sufficient to justify adjuvant therapeutic measures in Stage II rectal cancer.
Biomarkers, Tumor↗
Prospective multicenter study of the quality of oncologic resections in patients undergoing laparoscopic colorectal surgery for cancer. The Laparoscopic Colorectal Surgery Study Group.
PURPOSE: Laparoscopic colorectal surgery for cancer is currently under discussion. Results of large, randomized studies will not be available for a number of years yet. This study analyses the results of such resections in consecutive patients operated on by unselected surgeons. METHODS: A prospective, observational, multicenter study was initiated on August 1, 1995, in the German-speaking countries of Europe. One year after initiation of the study, findings are presented with respect to the quality of oncologic resections. RESULTS: Of 500 operations, 231 (46 percent) were performed for cancer, 167 (33 percent) with a curative intent. The most common curative resections were as follows: 63 anterior rectum resections (38 percent), 51 sigmoid resections (30 percent), and 27 abdominoperineal resections (16 percent). Segmental resections were performed in 20 patients (12 percent). Intraoperative tumor spillage was reported in 2 percent. Mean number of lymph nodes harvested was 13 (confidence interval, 5-95 percent; range, 11.5-14.6) and positive lymph nodes harvested was 2.2 (confidence interval, 5-95 percent; range, 0.9-3.4). Significant differences were noted between participating centers in terms of number of lymph nodes resected (P < 0.0001). Distal and proximal resection margins were tumor-free in every case. Lateral margins were tumor free when examined. In the case of 63 curative anterior resections, the mean distal resection margin was 39 (confidence interval, 5-95 percent; range, 33-45) mm, and in 8 of these resections, it was less than 20 min. Mean blood loss was 344 (confidence interval, 5-95 percent; 292-396) ml, and 21 percent of patients received blood transfusion. CONCLUSIONS: These data document that the average quality of laparoscopic colorectal procedures for cancer is satisfactory but differs among surgeons.
Aged↗
Predictive value of nuclear beta-catenin expression for the occurrence of distant metastases in rectal cancer.
PURPOSE: Adenomatous polyposis coli protein, glycogen synthetase kinase-3-beta, T cell transcription factor/lymphoid enhancer-binding factor, and beta-catenin modulate cell differentiation and proliferation via the expression of effector genes. It has recently been postulated that beta-catenin is a potent oncogene of sporadic colorectal carcinogenesis and a prognostic tumor marker. Our aim was to investigate whether the nuclear overexpression of beta-catenin, possibly caused by mutations in exon 3 of beta-catenin (CTNNB1), is correlated with distant metastatic spread or disease-free survival in rectal carcinoma. METHODS: Immunohistochemical analysis was performed with an anti-beta-catenin-monoclonal antibody on paraffin sections of two groups of patients (n = 2 x 77) with rectal carcinoma curatively treated by surgery alone. The patients selected were all free of local disease, to exclude surgical influence. Patient groups were matched for age, gender, International Union Against Cancer stage, and year of operation (1982 to 1991) and differed only in subsequent metachronous distant metastatic spread. Follow-up was prospective (median, 9.6 years). Three staining patterns were defined: membranous (normal), diffuse cytoplasmic (pathologic), and intense nuclear staining (pathologic). When intense nuclear staining was defined, the specimen was microdissected. Then, DNA was isolated, polymerase chain reaction-amplified, and sequenced to detect mutations in exon 3. RESULTS: Nuclear overexpression of beta-catenin correlated neither with distant metastatic spread (chi-squared, 0.37; P = 0.79) nor with disease-free survival (log-rank with trend, P = 0.62). No mutations were found in the area of the serine/threonine-kinase glycogen synthetase kinase-3-beta-phosphorylation site in exon 3 (CTNNB1) of beta-catenin. CONCLUSION: Although beta-catenin seems to play an important role in early colorectal carcinogenesis, its value as a prognostic marker is questionable. It must be assumed that metastatic ability is determined by other factors than the disturbance of the beta-catenin T cell transcription factor/lymphoid enhancer-binding factor cascade and that other mechanisms might cause the observed nuclear translocation of beta-catenin.
Adenocarcinoma↗
Low-field magnetic resonance imaging of the pelvis in patients with anal dynamic graciloplasty: initial experience.
The aim of this study was to determine whether low-field magnetic resonance (MR) imaging can safely and accurately depict inflammatory changes in patients with anal dynamic graciloplasty, in whom high-field MR imaging is contraindicated and ultrasonography and computed tomography are inadequate. A 0.2-T field-strength MR examination was performed in six patients with anal dynamic graciloplasty malfunction in whom reoperation was contemplated. The following sequences were applied: T2-weighted turbo spinecho with fat saturation, T1-weighted conventional spin-echo, and contrast-enhanced T1-weighted conventional spin-echo with fat saturation. Results indicated that none of the patients experienced relevant discomfort, pacemaker malfunction, or electrode dislocation with low-field MR imaging. Inflammatory pelvic changes were visualized in four patients and atrophy of the transposed gracilis muscle in another. Surgery was thus avoided in the four, who underwent conservative treatment for their pelvic inflammation. It was concluded that these preliminary results demonstrate the feasibility of MR imaging with a low field strength in patients with anal dynamic graciloplasty. In such patients, in whom diagnostic imaging had been problematic, the potential for safe and accurate visualization will be a boon to treatment planning.
Adult↗
[Adjuvant and neoadjuvant therapy of rectal carcinoma. The current status].
BACKGROUND: The Consensus Conference of the German Cancer Society (CAO/AIO/ARO, 1.7.1998) has recently updated recommendations for patients with rectal cancer. Instead of a former reservation regarding the indication of adjuvant therapy for rectal cancer the actual version of the consensus particularly emphasizes the role of postoperative radiochemotherapy for stage-II/III tumors. This article reviews the most recent and ongoing trials of adjuvant and neoadjuvant therapy of rectal cancer. RESULTS: To avoid local recurrence is the most important aspect in the primary treatment of rectal cancer. In some series, e.g. the results of the Surgical Department of the University of Erlangen, a significant correlation between local control and survival was noted. The final results of the Swedish Rectal Cancer Trial with 1168 randomized patients not only confirmed the potential of radiotherapy to reduce local recurrence rate, but also demonstrated a significant survival advantage for patients receiving short-course preoperative radiation therapy. Postoperative combination therapy is usual in the United States and in most European countries since the publication of two randomized trials of the Gastrointestinal Tumor Study Group (GITSG) and the North Central Cancer Treatment Group (NCCTG). The survival advantage resulting from an adjuvant radiotherapy with conventional doses and concurrent fluorouracil-based chemotherapy as compared to surgery alone was recently confirmed in a Norwegian trial. Protracted venous 5-fluorouracil infusion should further improve treatment results. Numerous phase-II studies have demonstrated the efficacy of preoperative radiochemotherapy with high rates of pathological response. Thus, neoadjuvant radiochemotherapy is recommended for patients with locally advanced tumor primarily not amenable to curative surgery. Prospective randomized trials are ongoing to clarify the role of preoperative versus postoperative combined treatment for patients with resectable rectal cancer. CONCLUSION: Radiochemotherapy for rectal cancer is recommended as standard treatment outside clinical trials for stage II/III patients after curative treatment and for patients with T4-tumor prior to surgery. The optimal use of chemotherapy and the sequence of treatment modalities remains to be elucidated.
Carcinoma↗
Monitoring of immunotherapy by measuring monocyte HLA-DR expression and stimulated TNFalpha production during sepsis after liver transplantation.
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Fatal Outcome↗
Gastric fundectomy in the rat: effects on mineral and bone metabolism, with emphasis on the gastrin-calcitonin-parathyroid hormone-vitamin D axis.
In humans, gastric surgery results in in osteopenia via mechanisms that are insufficiently understood; surgery-induced changes in the hormonal axes involving the stomach, thyroid, and the parathyroids may play a role. To study this in more detail, we evaluated calcium (Ca), magnesium (Mg), and phosphorus (P) metabolism as well as physical, chemical, and histomorphometric bone parameters in rats rendered hypergastrinemic by fundectomy (FX). In independent experiments, the response to an oral Ca challenge was investigated in intact rats versus FX, and in thyroidectomized versus thyroid-intact FX rats. Sixteen weeks following FX, body weight was approximately 80% that of sham-operated controls. In urine, P excretion was elevated fivefold, the pH was significantly decreased, and cAMP excretion was elevated as compared with controls; serum parathyroid hormone (PTH), calcitonin, 25OHD, Ca, Mg, and P were normal; gastrin and 1,25(OH)2D were elevated. On the basis of bone ash mineral content, FX rats developed significant osteopenia, and histomorphometry indicated only slightly elevated bone turnover and mineralization. Following oral Ca, thyroid-intact FX rats developed hypercalcemia, serum gastrin decreased, and calcitonin increased significantly; in thyroidectomized FX rats, calcitonin remained at baseline levels although there was a similar degree of hypercalcemia; PTH decreased during the hypercalcemic period in both groups. Serum gastrin did not correlate with calcitonin or PTH, and in multivariate regression analysis the only predictor of serum 1, 25(OH)2D was urinary phosphorus. It was concluded that in the FX rat (1) osteopenia is not caused by intestinal Ca malabsorption, vitamin D, Ca deficiency, or secondary hyperparathyroidism; (2) osteopenia may be related to PTH-independent urinary hyperexcretion of P, followed by a rise of serum 1,25(OH)2D; (3) the existence of endocrine axes among gastrin, calcitonin, and PTH cannot be substantiated. FX osteopenia appears to be related to gastric acid abolition, and the reactive hypergastrinemia probably stabilizes the mass and turnover of bone.
Animals↗
Reduced TNFalpha and IL-6 production in patients who mount a preoperative acute phase response.
BACKGROUND/AIMS: In some patients postoperative infective complications are related to a reduced resistance to the operative trauma and the perioperative microbiological challenge. To investigate preoperative alterations in the immune responses in patients who had mounted an acute-phase response before the operation, we measured the capacity of tumor necrosis factor alpha and interleukin-6 production in whole blood. PATIENTS/METHODS: Serum concentrations of C-reactive protein, alpha1-antitrypsin, albumin, and prealbumin were measured in 89 patients submitted for major abdominal surgery on their admission to hospital. RESULTS: In 23 patients (26%) we found concentrations of at least one, and in 16 patients (18%) of two or more of these variables beyond the reference range. Patients who mounted an acute-phase response released 37% less TNFalpha (1339 vs. 848 pg/ml) and 31% less IL-6 (24293 vs. 16900 pg/ml) when whole blood was stimulated with lipopolysaccharide 0.5 microg/ml. CONCLUSION: Patients who mount an acute-phase response before operation may thus have a downregulated immune response at the level of proinflammatory cytokines. This is likely to alter their resistance to invasive micro-organisms in the perioperative period.
Acute-Phase Reaction↗
Mesorectal lymph node dissection: is it beneficial?
Locoregional recurrences and distant metastases are the determinants of the long-term prognosis following curative resection of rectal carcinoma. While distant metastases cannot be affected by the surgical treatment of the primary tumor, avoidance of local recurrence by the surgeon is of special significance as the predominant prognostic factor. Analysis of the long-term results achieved by various surgeons led to the concept of mesorectal excision - the removal of the rectum together with all additional tissue invested by the adjacent visceral fascia, that is, fatty tissue, lymph nodes, and lymphatic vessels, by sharp dissection of the appropriate anatomical plane. In our own patient material the 5-year survival rate following R0 resection was 85% for all stages, provided no local recurrence developed. This contrasts with a figure of only 23% in those who did develop local recurrence. The local recurrence rate decreased from 39.4%, with a 50% 5-year survival rate in 1974, to 9.8% and a 71% survival rate in 1991, although the rate of distant metastases remained constant. Among the patients treated between 1988 and 1994 the local recurrence rate was determined by depth of infiltration (1987 UICC classification: pT1 0%, pT2 10%, pT3 14%, pT4 28%), extent of lymph node infiltration (pN0 6%, pN1 15%, pN2 26%, pN3 25%), grading (G1 9%, G2 12%, G3 21%), and location within the rectum (upper third 13%, middle third 8%, lower third 17%), with combinations of unfavorable initial factors leading to higher local recurrence rates. The elevated local recurrence rates seen in the 1970s, in particular in the case of tumors of the lower third, were traced retrospectively to incomplete mesorectal excision, the implementation of which reduced the local recurrence rate initially to less than 10%, and then to the current 4.1%. From the oncological point of view, mesorectal excision must be considered to confer considerable benefit. In the case of carcinomas of the upper third of the rectum, mesorectal resection carried out to just 5 cm below the lower tumor edge is sufficient, however, without coning, while deeper carcinomas mandate total mesorectal excision.
Humans↗
Early results of a prospective multicenter study on 500 consecutive cases of laparoscopic colorectal surgery. Laparoscopic Colorectal Surgery Study Group (LCSSG).
BACKGROUND: Prospective randomized multicenter studies comparing laparoscopic with open colorectal surgery are not yet available. Reliable data from prospective multicenter studies involving consecutive patients are also lacking. On the basis of the personal caseloads of specialized surgeons or of retrospective analyses, it is difficult to judge the true effectiveness of this new technique. This study aims to investigate the results of laparoscopic colorectal surgery in consecutive patients operated on by unselected surgeons. METHODS: This observational study was begun August 1, 1995, in the German-speaking part of Europe (Germany and Austria) and 43 centers initially agreed to participate. All consecutive cases were documented. All data were rendered anonymous. Analysis was performed on an intention-to-treat basis. The study committee was blinded to the participating center. RESULTS: By the end of the 1st year, 500 patients (M:F ratio 0.83, mean age 62.9 years) had been treated by 18 centers; 269 operations were performed for benign indications and 231 for cancer (palliative and curative). Most operations were done on the distal colon or rectum. An anastomosis was performed in 84%, with an overall leakage rate of 5.3% (colon 3.6% and rectum 11.8%), which required surgical reintervention in 1.7%. The mean operating time was 176 min and showed a decreasing tendency over the period under study. The conversion rate was 7.0% and the overall complication rate 21.4%. The reoperation rate was 6.6%; the most common cause was bleeding. There was one ureteral lesion (0.2%), but urinary tract infections were fairly common (4.8%). A postoperative pneumonia was diagnosed in 1.6% of the cases. No thromboembolic complications were reported. The 30-day mortality rate was 1.4% and overall hospital mortality 1.8%. CONCLUSIONS: Laparoscopic colorectal operations are still rare (about 1% of all colorectal operations in Germany). Laparoscopic procedures are more common on the left colon and rectum than on the right colon. The surgical complication rate is acceptable, comparable with rates reported by others for open surgery. Cardiopulmonary and thromboembolic complications were rarely seen. Mortality and surgical morbidity rates do not differ significantly among participating centers. A learning curve, reflected by a shortening of the operating time and a somewhat lower conversion rate, was observed over the observation period.
Aged↗
Low rejection rate after hepatic transplantation achieved with a cyclosporine-based quadruple immunosuppressive regimen.
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Adult↗
Nuclear overexpression of the oncoprotein beta-catenin in colorectal cancer is localized predominantly at the invasion front.
Sixty to eighty percent of all colorectal cancers are characterized by mutations in the APC tumor suppressor gene. Recently, it was shown that these mutations lead to a nuclear overexpression of beta-Catenin by disruption of the wingless/WNT signal pathway. Since nuclear beta-Catenin functions as a transcriptional activator of hitherto unknown tumor genes, this form of beta-Catenin is now considered a major oncoprotein in colorectal cancer. Using immunohistochemistry, we investigated the distribution of overexpressed beta-Catenin within individual colorectal carcinomas. In the majority of the tumors, we found no homogeneous staining, but a strong nuclear expression of beta-Catenin predominantly localized at the invasion front with strongest nuclear staining of isolated, scattered tumor cells. In contrast, cells in the tumor center often showed no nuclear staining, but retained a membranous expression of beta-Catenin, comparable to normal colon epithelium. It is, therefore, likely that in addition to the overexpression of beta-Catenin caused by defects in the APC locus, regulatory events in the tumor itself lead to a different distribution of this oncoprotein. Possibly, surrounding tissue at the invasion front can give signals to the tumor cells, leading to a nuclear translocation of beta-Catenin, where it may play a direct role in tumor invasion processes.
Cell Nucleus↗
Improvements in staging of gastric carcinoma from using the new edition of TNM classification.
AIMS: To recognize possible advantages of the 5th edition of TNM of gastric carcinoma in comparison to the former edition. METHODS: Data from Erlangen Cancer Center for 898 patients with gastric carcinoma treated surgically by total or subtotal gastrectomy with en bloc lymphadenectomy were analysed. RESULTS: The prognostic significance of TNM has been improved by the new edition as demonstrated by the likelihood ratio test. In addition, uncertainties of method in the pathological classification of regional lymph-node metastasis inherent in the 4th edition can now be avoided. CONCLUSION: The changes in the TNM classification introduced by the 5th edition are justified by data from the Erlangen Cancer Center, have methodic advantages in determining the N classification, and lead to an improvement in estimation of outcome.
Adult↗