K. Welvaart

Extended Lymph-Node Dissection for Gastric Cancer

BACKGROUNDnCurative resection is the treatment of choice for gastric cancer, but it is unclear whether this operation should include an extended (D2) lymph-node dissection, as recommended by the Japanese medical community, or a limited (D1) dissection. We conducted a randomized trial in 80 Dutch hospitals in which we compared D1 with D2 lymph-node dissection for gastric cancer in terms of morbidity, postoperative mortality, long-term survival, and cumulative risk of relapse after surgery.nnnMETHODSnBetween August 1989 and July 1993, a total of 996 patients entered the study. Of these patients, 711 (380 in the D1 group and 331 in the D2 group) underwent the randomly assigned treatment with curative intent, and 285 received palliative treatment. The procedures for quality control included instruction and supervision in the operating room and monitoring of the pathological results.nnnRESULTSnPatients in the D2 group had a significantly higher rate of complications than did those in the D1 group (43 percent vs. 25 percent, P<0.001), more postoperative deaths (10 percent vs. 4 percent, P= 0.004), and longer hospital stays (median, 16 vs. 14 days; P<0.001). Five-year survival rates were similar in the two groups: 45 percent for the D1 group and 47 percent for the D2 group (95 percent confidence interval for the difference, -9.6 percent to +5.6 percent). The patients who had R0 resections (i.e., who had no microscopical evidence of remaining disease), excluding those who died postoperatively, had cumulative risks of relapse at five years of 43 percent with D1 dissection and 37 percent with D2 dissection (95 percent confidence interval for the difference, -2.4 percent to +14.4 percent).nnnCONCLUSIONSnOur results in Dutch patients do not support the routine use of D2 lymph-node dissection in patients with gastric cancer.

Randomised comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients

For patients with gastric cancer deemed curable the only treatment option is surgery, but there is disagreement about whether accompanying lymph-node dissection should be limited to the perigastric nodes (D1) or should extend to regional lymph nodes outside the perigastric area (D2). We carried out a multicentre randomised comparison of D1 and D2 dissection. 1078 patients were randomised (539 to each group). 26 allocated D1 and 56 allocated D2 were found not to satisfy eligibility criteria (histologically confirmed adenocarcinoma of the stomach without clinical evidence of distant metastasis). Each of the remainder was attended by one of eleven supervising surgeons who decided whether curative resection was possible and, if so, assisted with the allocated procedure. Among the 711 patients (380 D1, 331 D2) judged to have curable lesions, D2 patients had a higher operative mortality rate than D1 patients (10 vs 4%, p = 0.004) and experienced more complications (43 vs 25%, p < 0.001). They also needed longer postoperative hospital stays (median 25 [range 7-277] vs 18 [7-143] days, p < 0.001). Morbidity and mortality differences persisted in almost all subgroup analyses. While we await survival results, D2 dissection should not be used as standard treatment for western patients.

Inactive Urokinase and Increased Levels of Its Inhibitor Type 1 in Colorectal Cancer Liver Metastasis

BACKGROUND/AIMSnHuman colorectal carcinogenesis was previously found to be associated with an increased urokinase-type plasminogen activator expression, both in antigen and activity, accompanied by simultaneously enhanced levels of plasminogen activator inhibitors type 1 and type 2. This increased proteolytic activity may contribute to invasive growth and metastasis of the tumors.nnnMETHODSnIn the present study, homogenates of liver metastases, primary colorectal carcinomas, and adjacent normal tissues were evaluated regarding the level and composition of urokinase, tissue-type plasminogen activator, and plasminogen activator inhibitors.nnnRESULTSnConcentrations of urokinase were significantly increased in primary carcinomas and liver metastases compared with normal tissues, whereas tissue-type plasminogen activator levels were significantly decreased. Liver metastases showed, in contrast to the carcinomas, hardly any activity of plasminogen activators, which could be attributed to the enhanced presence of the inactive proenzyme form of urokinase in combination with more complexes of plasminogen activators with inhibitors. Furthermore, liver metastases had an eightfold higher content of inhibitor type 1 compared with the primary carcinomas. The excess of inhibitors was confirmed by addition of plasminogen activators to metastasis homogenates, which resulted in increased complex formation.nnnCONCLUSIONSnColorectal cancer metastasis in the liver is associated with an inactivation of the enhanced urokinase cascade, which might allow tumor cells to settle in the liver.

Prognostic value of the plasminogen activation system in patients with gastric carcinoma

Patients with gastric cancer have a poor prognosis and can be cured by surgery only if the cancer is detected in an early stage. Extended surgery, down staging with chemotherapy before operation, and new postoperative treatments are recent approaches to increase survival rates. Categorizing patients prognoses as good or poor by pathophysiologic markers, however, may be of great help in selecting therapies for these patients. For example, plasminogen activation (PA) parameters, that play an important role in tumor invasion and metastasis, have prognostic value for several human malignancies.

Contribution of plasminogen activators and their inhibitors to the survival prognosis of patients with Dukes' stage B and C colorectal cancer

Despite the advances in pre-, peri- and post-operative medical care of colorectal carcinoma patients, the prognosis has improved only marginally over recent decades. Thus, additional prognostic indicators would be of great clinical value to select patients for adjuvant therapy. In previous studies we found that colorectal carcinomas have a marked increase of the urokinase-type of plasminogen activator (u-PA), and the inhibitors PAI-1 and PAI-2, whereas the tissue-type plasminogen activator (t-PA) is found to be decreased in comparison with adjacent normal mucosa. In the present study we evaluated the prognostic value of several plasminogen activation parameters, determined in both normal and carcinomatous tissue from colorectal resection specimens, for overall survival of 136 Dukes stage B and C colorectal cancer patients, in relation to major clinicopathological parameters. Uni- and multivariate analyses indicated that a high PAI-2 antigen level in carcinoma, a low t-PA activity and antigen level and a high u-PA/t-PA antigen ratio in adjacent normal mucosa are significantly associated with a poor overall survival. A high ratio of u-PA antigen in the carcinomas and t-PA antigen in normal mucosa, i.e. u-PA(C)/t-PA(N), was found to be predictive of a poor overall survival as well. All these parameters were found to be prognostically independent of the clinicopathological parameters. Multivariate analysis of combinations of these prognostically significant plasminogen activation parameters revealed that they are important independent prognostic indicators and have in fact a better prognostic value than their separate components. Based on these combined parameters, subgroups of patients with Dukes stage B and C colorectal cancer could be identified as having either a high or a low risk regarding overall survival. In conclusion, these findings emphasize the relevance of the intestinal plasminogen activation system for survival prognosis of patients with colorectal cancer and, in the future, might constitute a patient selection criterion for adjuvant therapy.

The splenic red pulp; a histomorphometrical study in splenectomy specimens embedded in methylmethacrylate

The anatomy and pathology of the splenic red pulp was studied in three‐dimensional reconstructions of methylmethacrylate embedded blocks of tissue obtained after splenectomy, as well as by morphometrical analysis of a large number of specimens. The sinuses of the spleen form a plexus of anastomosing vessels with remarkable buds. Capillaries end as sheathed capillaries in the cord tissue, the ‘filtering’ area, but a large proportion of the red pulp cords appear to be ‘non‐filtering’. These might form part of the lymphatic compartment, which is separate from the white pulp and its extension along the capillaries. This area has not yet been described in man. The change in the volume and structure of the various components of the red pulp were studied in 60 controls and in cases of traumatic rupture, idiopathic thrombocytopenic purpura, aplastic anaemia, autoimmune haemolytic anaemia, congenital spherocytosis, splenic congestion, and Hodgkins disease. Significant differences were found in the volume of filtering and non‐filtering areas, the size of the sinus compartment, and the degree of vascularization; these differences were only partially expected, for instance in disorders with excessive erythrocyte sequestration. A decrease of the ‘non‐filtering’ area in Hodgkins disease might indicate an unknown aspect of this disease. In agreement with our previous paper on the amount of white pulp, spleens removed because of traumatic rupture and those incidentally removed during abdominal surgery may not be combined as a single control group, because of significant and probably functional differences in the composition also of the red pulp.

Ten-year results of a randomized trial evaluating prolonged low-dose adjuvant chemotherapy in node-positive breast cancer: a joint European Organization for Research and Treatment of Cancer-Dutch Breast Cancer Working Party Study. Cooperating Investigators.

PURPOSEnTo investigate whether treatment with prolonged low-dose adjuvant chemotherapy could improve survival of patients with axillary node-positive breast cancer.nnnPATIENTS AND METHODSnFour hundred fifty-two patients with axillary node-positive breast cancer who received postoperative irradiation were prospectively randomized in a trial (European Organization for Research and Treatment of Cancer [EORTC] 09771) that compared surgery followed by prolonged low-dose chemotherapy versus surgery alone. Chemotherapy was given for a period of 2 years and consisted of monthly courses of cyclophosphamide 50 mg/m2 orally on days 1 to 14, methotrexate 15 mg/m2 intravenously on days 1 and 8, and fluorouracil 350 mg/m2 intravenously on days 1 and 8 (CMF).nnnRESULTSnAt a median follow-up time of 10 years, the overall survival duration was significantly prolonged in the chemotherapy arm (hazards ratio, 0.75; 95% confidence interval, 0.56 to 0.99; P = .04). Ten-year overall survival rates (+/- SE) were 59% (+/- 3.6%) for the chemotherapy arm and 50% (+/- 3.7%) for the control arm. Time to local relapse was significantly prolonged in the chemotherapy arm (hazards ratio, 0.63; 95% confidence interval, 0.42 to 0.94; P = .02). Patients with one to three positive axillary nodes and patients with estrogen receptor-negative tumors especially benefited from chemotherapy. Toxicity was observed in 93% of patients.nnnCONCLUSIONnWe conclude that prolonged low-dose adjuvant CMF can significantly prolong overall survival in patients with node-positive breast cancer. However, considering the fact that toxicity was still considerable despite reducing the dose of chemotherapy by 50%, we believe that conventionally dosed short-term regimens are preferable in the treatment of node-positive breast cancer.

Cutaneous melanoma and precursor lesions

I: Fundamental Aspects.- The epidemiology of melanoma.- The molecular biology of carcinogenesis.- Human melanoma associated antigens identified with monoclonal antibodies: characterization and potential clinical application.- Cellular and molecular parameters of tumor progression in human malignant melanoma.- Immune responses to human malignant melanoma.- II: Diagnosis and Prognostic Factors..- Clinical diagnosis of cutaneous melanomas.- Patients and doctors delay in diagnosing and treating malignant melanoma of the skin.- Histopathology of cutaneous malignant melanoma.- Immunohistopathological aspects of cutaneous melanoma and precursor lesions.- Prognostic factors for cutaneous melanoma.- III: Treatment.- Incidence of recurrence and survival in clinical stage I patients with melanoma after local excision.- Longterm results of randomized trial comparing immediate versus delayed node dissection in stage I melanoma of the limbs.- Local excision and regional perfusion in high-risk stage-I malignant melanoma of the extremities.- The use of chemotherapy in the management of patients with malignant melanoma.- Radiotherapy of malignant melanoma.- IV: Precursor Lesions.- Congenital nevocelular nevi.- Clinical aspects of the dysplastic nevus syndrome.- Histopathological aspects of dysplastic nevi.- Critical remarks on the dysplastic naevus syndrome.- Index of subjects.

GASTRIC-CANCER - A PROSPECTIVE RANDOMIZED TRIAL OF SURGICAL-TREATMENT

Despite declining incidence and improved surgical care, gastric cancer remains associated with high mortality. Incidence and survival show remarkable geographic differences. Japanese patients have a much better chance of cure than Western patients. Whether biological differences between Japanese and Western patients are responsible for this remains unclear. Japanese surgeons, however, generally use a different surgical approach. The so-called R2 resection for gastric cancer has been investigated in a number of retrospective trials and, even in the West, evidence is accumulating that a more extensive resection of lymph nodes might positively influence stage dependent survival rates. Whether this approach indeed improves treatment and not just influences staging is currently being studied in a nation-wide, prospective randomized trial in the Netherlands. The design and the first results of this trial are presented here.