Loss of Ep-CAM (CO17-1A) expression predicts survival in patients with gastric cancer.

Preoperative staging of gastric cancer is difficult and not optimal. The TNM stage is an important prognostic factor, but it can only be assessed reliably after surgery. Therefore, there is need for additional, reliable prognostic factors that can be determined preoperatively in order to select patients who might benefit from (neo) adjuvant treatment. Expression of immunohistochemical markers was demonstrated to be associated with tumour progression and metastasis. The expression of p53, CD44 (splice variants v5, v6 and v9), E-cadherin, Ep-CAM (CO17-1A antigen) and c-erB2/neu were investigated in tumour tissues of 300 patients from the Dutch Gastric Cancer Trial, investigating the value of extended lymphadenectomy compared to that of limited lymphadenectomy). The expression of tumour markers was analysed with respect to patient survival. Patients without loss of Ep-CAM-expression of tumour cells (19%) had a significantly better 10-year survival (P<0.0001) compared to patients with any loss: 42% (s.e.=7%) vs 22% (s.e.=3%). Patients with CD44v6 (VFF18) expression in more than 25% of the tumour cells (69% of the patients) also had a significantly better survival (P=0.01) compared to patients with expression in less than 25% of the tumour cells: 10 year survival rate of 29% (s.e.=3%) vs 19% (s.e.=4%). The prognostic value of both markers was stronger in stages I and II, and independent of the TNM stage. Ep-CAM and CD44v6-expression provides prognostic information additional to the TNM stage. Loss of Ep-CAM-expression identifies aggressive tumours especially in patients with stage I and II disease. This information may be helpful in selecting patients suitable for surgery or for additional treatment pre- or postoperatively.

Neo-adjuvant chemotherapy for operable gastric cancer: long term results of the Dutch randomised FAMTX trial.

AIMS: Gastric cancer in Western countries is often diagnosed in an advanced stage and prognosis is poor. We performed a randomised trial with pre-operative FAMTX vs. surgery alone in order to evaluate the effect of pre-operative chemotherapy on resectability and survival. METHODS: Patients with proven adenocarcinoma of the stomach were randomised to receive four courses of chemotherapy using 5-Fluorouracil, doxorubicin and methotrexate (FAMTX) prior to surgery or to undergo surgery alone. RESULTS: Fifty-nine patients were randomised; 29 patients were allocated to the FAMTX regimen prior to surgery and 30 patients had surgery alone. Resectability rates were equal for both groups. Complete or partial response was registered in 32% of the FAMTX group. With a median follow-up of 83 months the median survival since randomisation is 18 months in the FAMTX group vs. 30 months in the surgery alone group (p=0.17). CONCLUSIONS: This trial could not show a beneficial effect of pre-operative FAMTX. Until large randomised studies prove otherwise, adequate surgery without delay is the best treatment for operable gastric cancer.

Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial.

PURPOSE: The extent of lymph node dissection appropriate for gastric cancer is still under debate. We have conducted a randomized trial to compare the results of a limited (D1) and extended (D2) lymph node dissection in terms of morbidity, mortality, long-term survival and cumulative risk of relapse. We have reviewed the results of our trial after follow-up of more than 10 years. PATIENTS AND METHODS: Between August 1989 and June 1993, 1,078 patients with gastric adenocarcinoma were randomly assigned to undergo a D1 or D2 lymph node dissection. Data were collected prospectively, and patients were followed for more than 10 years. RESULTS: A total of 711 patients (380 in the D1 group and 331 in the D2 group) were treated with curative intent. Morbidity (25% v 43%; P <.001) and mortality (4% v 10%; P =.004) were significantly higher in the D2 dissection group. After 11 years there is no overall difference in survival (30% v 35%; P =.53). Of all subgroups analyzed, only patients with N2 disease may benefit of a D2 dissection. The relative risk ratio for morbidity and mortality is significantly higher than one for D2 dissections, splenectomy, pancreatectomy, and age older than 70 years. CONCLUSION: Overall, extended lymph node dissection as defined in this study generated no long-term survival benefit. The associated higher postoperative mortality offsets its long-term effect in survival. For patients with N2 disease an extended lymph node dissection may offer cure, but it remains difficult to identify patients who have N2 disease. Morbidity and mortality are greatly influenced by the extent of lymph node dissection, pancreatectomy, splenectomy and age. Extended lymph node dissections may be of benefit if morbidity and mortality can be avoided.

Effect of isosorbide dinitrate ointment on anal fissure.

BACKGROUND/AIMS: Until recently, the treatment of choice for anal fissure was surgery, consisting of a partial lateral internal sphincterotomy. This treatment has a high complication rate: impaired continence is reported in 8-30% of the patients in the literature. Therefore, recently nonsurgical treatment modalities have been developed, such as local application of isosorbide dinitrate (ISDN) ointment. This treatment has comparable effectiveness with lower complication rates. To study the effect of ISDN on the healing of anal fissures in a general surgical practice, a prospective study was performed in our hospital. METHODS: In the period between June 1997 and January 2000, 100 consecutive patients with anal fissure were treated with ISDN. RESULTS: Of these 100 patients, 93 were healed within 8 weeks and 7 patients had no response and were operated. Of the 93 patients with primary healing fissures, 13 patients had recurrence during the 1-year follow-up. Seven of them were cured with ISDN, and the remaining 6 patients needed surgery. The only complication observed in this study was temporary headache which was observed in 7 patients. CONCLUSIONS: The primary healing rate of anal fissures was 93% with ISDN. In case of recurrence, 54% (7/13) could again be treated successfully with ISDN. Therefore, we recommend ISDN as first choice treatment for primary and recurrent anal fissures.

Extent of thyroidectomy in nodular thyroid disease.

OBJECTIVE: To find out which procedure was the safest for each indication for operation in diseases of the thyroid gland. DESIGN: Retrospective study. SETTING: Two teaching hospitals, The Netherlands. SUBJECTS: 599 consecutive patients who had 601 thyroid operations between 1 October 1985 and 1 June 1993. MAIN OUTCOME MEASURES: Incidence of complications, particularly postoperative hypocalcaemia and injuries to the recurrent laryngeal nerve. RESULTS: Accidental injuries to the recurrent laryngeal nerve occurred in 0.7% of the nerves at risk (7/948) and the incidence of permanent hypocalcaemia was 5.2% (31/599). In subtotal procedures (bilateral subtotal thyroidectomy with the remnant left dorsally or total hemithyroidectomy combined with subtotal hemithyroidectomy on the other side with a remnant left at the upper pole) the rate was 11/390 (2.8%) compared with 18/525 (3.4%) after total resections. The corresponding numbers of accidental injuries to the recurrent laryngeal nerve were 2 and 4. CONCLUSIONS: Total thyroidectomies are more likely to be done for malignant disease, so the slightly higher complication rates probably reflect the nature of the disease, which requires more radical resection. Both subtotal procedures can be done with comparable low morbidity.

Chemotherapy for operable gastric cancer: results of the Dutch randomised FAMTX trial. The Dutch Gastric Cancer Group (DGCG).

The aim of this trial was to investigate whether pre-operative chemotherapy leads to a 15% higher curative resectability rate in patients with operable gastric cancer. In this randomised trial, patients were allocated to receive either four courses of chemotherapy using 5-fluorouracil, doxorubicin and methotrexate (FAMTX) prior to surgery or to undergo surgery only. Patients younger than 75 years of age with a good physical and mental condition and a histologically proven adenocarcinoma of the stomach without clinical or radiographic (computed tomography scan) evidence of distant metastases were eligible for this trial. Early gastric cancer or cardia carcinoma were excluded. The response to chemotherapy was evaluated after two and four courses. In case of progressive disease (PD) after two courses, patients were operated upon as soon as possible. Otherwise complete response (CR) partial response (PR) or stable disease (SD), two more courses were scheduled. The standard surgical procedure was a limited lymphadenectomy (D1) with staging biopsy of the para-aortic lymph nodes. Between September 1993 and February 1996, 56 eligible and evaluable patients were entered: 27 were randomised to receive FAMTX before surgery and 29 to undergo surgery only. In the FAMTX + surgery treatment group, 15/27 (56%) had curative resections versus 18/29 (62%) in the surgery only arm. There was no difference in the frequency of TNM stages I + II in both treatment arms: 15/27 versus 15/29. Due to PD and/or toxicity, 12 patients (44%) could not complete the planned four courses of FAMTX. Response evaluation after chemotherapy was possible in 25 patients: 2 CR, 6 PR, 8 SD and 9 PD. The difference in curative resectability rate was 6.5% (95% confidence interval -32 to +19%) in favour of surgery only. Downstaging for stages I + II did not occur. PD was more often the reason for not completing the planned four courses than toxicity. More active regimens than FAMTX are required for future randomised trials.

Classification of gastric carcinoma using the Goseki system provides prognostic information additional to TNM staging.

BACKGROUND: Due to the high variability of the epidemiology, genetics, morphology, and biologic behavior of gastric carcinoma, many classification systems are in use, e.g., the World Health Organization (WHO) classification; tumor differentiation; the criteria of Ming, Mulligan, and Laurén; and the recently introduced Goseki classification. In the authors' opinion, the TNM staging is the most valuable classification system, with a prognostic value for survival. METHODS: To assess the reproducibility and usefulness of these systems in clinical practice, material from 285 gastric carcinoma patients entered in the Dutch Gastric Cancer Trial was analyzed by a panel of 5 experienced gastrointestinal pathologists. The presence of eosinophilic and lymphocytic infiltrates was analyzed in addition to the TNM staging. RESULTS: Of the analyzed classification systems, only TNM stage, tumor differentiation, eosinophilic infiltrate, and the Goseki system contained information associated with the survival of patients with gastric carcinoma. The reproducibility was perfect for tumor differentiation (Kappa 1.00), nearly perfect for the WHO and Goseki classifications (Kappa 0.86 and 0.87, respectively), reasonably good for Laurén and lymphocytic infiltrate (Kappa 0.70), and reasonably good for eosinophilic infiltrate (Kappa 0.42). CONCLUSIONS: Of all these systems, the Goseki classification was the only system with prognostic value that is additional to TNM staging.

Extended lymph-node dissection for gastric cancer.

BACKGROUND: Curative 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. METHODS: Between 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. RESULTS: Patients 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). CONCLUSIONS: Our results in Dutch patients do not support the routine use of D2 lymph-node dissection in patients with gastric cancer.

Role of fine-needle aspiration biopsy and frozen section examination in determining the extent of thyroidectomy.

Traditionally the extent of thyroidectomy in patients with nodular thyroid disease has been based on peroperative frozen section examination (FS). Fine-needle aspiration biopsy (FNAB) and FS were evaluated with regard to the reliability to determine whether an operation for cancer is necessary. Both methods were performed in 240 patients operated for nodular thyroid disease and compared with the final histology on paraffin sections. Altogether 72 (30%) patients were found to have a malignant lesion on final histology. Only a malignant FNAB diagnosis and a malignant FS diagnosis were considered positive results for determining the extent of thyroidectomy. The test characteristics were equal: the sensitivity of FNAB and FS was 67%, the specificity 99%, and the accuracy 89%. The positive predictive value was 96% for FNAB and 98% for FS; the negative predictive values were 88% and 87%, respectively. Further analysis of the results indicates that FS is not necessary for patients with a malignant FNAB result. These patients should undergo a therapeutic operation for malignancy. When the FNAB result is uncertain, patients should undergo diagnostic surgery, and definitive surgery should be based on the final histology. Routine use of FS can be omitted.

Expression of oncoproteins and the amount of eosinophilic and lymphocytic infiltrates can be used as prognostic factors in gastric cancer. Dutch Gastric Cancer Group (DGCG).

Preoperative staging of gastric cancer is difficult. Several molecular markers associated with initiation and progression of cancer seem promising for obtaining preoperative prognostic information. To investigate whether these markers are indicative especially for the presence of lymph node metastases in patients with gastric cancer, we have examined primary tumour specimens from 105 patients with primary adenocarcinoma of the stomach entered in a surgical trial. In this trial, lymph node status was determined by strictly quality-controlled lymph node dissection and examination. The selected markers were growth regulators (p53, Rb and myc), metastasis-suppressor gene product (nm23), adhesion molecules (Ep-CAM, E-cadherin, CD44v5 and CD44v6) and urokinase-type plasminogen activator (u-PA). Also, the amount of eosinophilic and lymphocytic infiltrates available post-operatively was analysed with respect to its prognostic value for lymph node status. Moreover, the association of these parameters with survival and disease-free period (DFP) was evaluated. Of all molecular markers investigated, only Rb expression had a significant association with the presence of lymph node metastasis in both univariate and multivariate analysis. For curative resectability, a significant association was found with Rb and E-cadherin expression, while in multivariate analysis Rb and myc were selected as the combination with additional independent prognostic value, and E-cadherin had no additional independent value. For overall survival in univariate analysis, the amount of both eosinophilic and lymphocytic infiltrates and Rb and myc expression were of significant prognostic value. Only the amount of lymphocytic infiltrate had a prognostic significance for DFP. In stepwise multivariate analysis, TNM stage (I + II) and marked lymphocytic infiltrate were associated with better overall survival and longer DFP. We conclude that, if these results are confirmed in a larger series of patients, molecular markers can provide useful prognostic information.

Prognostic value of positive cytology findings from abdominal washings in patients with gastric cancer.

The poor prognosis of patients with gastric cancer with free abdominal tumour cells on cytological examination has been described in Japan. In a randomized trial in the Netherlands comparing D1 and D2 lymphadenectomy for gastric cancer, patients were subjected to cytological examination of abdominal washings on an optional basis; findings were of no consequence for scheduled treatment. Cytology results in 535 patients were obtained, in 457 (85.4 per cent) after curative resection and in 78 (14.6 per cent) after palliative operation. There was a clear association of positive cytology results with serosal invasion (12 per cent positive cytology) and lymph node infiltration (7.5 per cent positive cytology). Survival of those with positive cytology results was significantly lower than that of those with negative findings, irrespective of the procedure employed (curative or palliative). Cytological examination of abdominal washings increases the accuracy of staging and improves the selection of patients suitable for curative or palliative resection.

[Extensive lymph node dissection in stomach cancer? Initial results of the Dutch Stomach Cancer Study]. / Uitgebreide lymfklierdissectie bij maagkanker? Eerste resultaten van het Nederlandse maagkankeronderzoek.

The five-year survival rate after curative resection for gastric cancer is higher in Japan (62%) than in the Netherlands (30%). In Japan, extensive D2 resection surgery is performed, in the Netherlands D(1) resection in which only the perigastric lymph nodes are removed. In a large prospective randomised trial, surgical departments of 80 Dutch hospitals compared the results of both resection types. A Japanese surgeon gave instruction in the D2 technique. D2 patients suffered more complications than D(1) patients and hospital mortality was 10% as against 4%. Demographic characteristics and concomitant morbidity might explain these differences. A change in current therapy is not advised at present. However, the surgical protocols and standards developed in connection with the trial reduced the overall death rate and morbidity of surgical treatment of gastric cancer in the Netherlands.

Prognostic value of resection-line involvement in patients undergoing curative resections for gastric cancer.

Prognostic value of microscopical resection-line involvement of the proximal and distal resection lines was examined in patients undergoing potentially curative resection in a multicentre trial with strict quality control. Tumour-positive resection lines were seen in 41 of the 699 evaluable patients (5.9%). Resection-line involvement was associated with T stage (P < 0.001), N stage (P = 0.003), tumour location (P < 0.001) and tumour differentiation (P < 0.001). Presence of resection-line involvement was also associated with significantly worse survival. Together with T3 and T4 stage (relative risk (RR) 2.04), N(+) stage (RR 4.02) and tumour differentiation (RR 1.33), resection-line involvement (RR 2.28) was also an independent prognostic factor for survival. Survival in patients with resection-line involvement was comparable with patients with positive cytology. In patients undergoing potentially curative resection for gastric cancer, peri-operative frozen-section examination should be mandatory, especially in those with poorly differentiated, signet ring cell or anaplastic tumours, with tumours covering the entire stomach and T3 or T4 tumours. In case of tumour-positive margin(s) at final histology, re-laparotomy could be considered if achieving tumour-free resection lines seems realistic.

Can Surgical Treatment Results in Gastric Cancer Be Improved?

Patients with gastric cancer have a poor prognosis. Surgery is the only treatment modality offering hope for cure. However, even after curative surgery, the five-year survival rate is still about 30%. Even though the incidence of early gastric cancer is up to 40% of all cases (surgically curable) in Japan, in Western countries most of the patients are diagnosed at an advanced stage, when curative surgery is no longer possible. Most patients die of locoregional recurrence or distant metastasis. Therefore, every attempt should be made to increase early diagnosis and to find additional prognostic factors which can be determined preoperatively. Operations with extended lymphadenectomy are associated with higher morbidity and mortality rates, while a possible survival benefit is not proven in Western countries. The five-year survival results of two large prospectively randomized, controlled trials (the Dutch Gastric Cancer Trial and the British Medical Research Council Trial) comparing limited lymphadenectomy (D1) to extended lymphadenectomy (D2) are still being awaited. In light of increased morbidity and mortality rates associated with extended lymphadenectomy, the limits of surgical possibilities for the treatment of gastric cancer seem to be reached. Adjuvant radiotherapy and chemotherapy are demonstrated to not give an additional survival advantage compared to surgery only. Development of more active combination chemotherapy regimens and results in locally advanced gastric cancer are encouraging. Therefore, to evaluate the place of preoperative chemotherapy in potentially operable gastric cancer, two randomized trials have been initiated in the Netherlands and Great Britain. Gastric cancer should be considered a malignancy which requires a multidisciplinary approach of a specialized team consisting of committed specialists. New treatment modalities should only be applied to patients in clinical trial settings with dedicated clinicians.

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.

Complications of thyroid surgery.

BACKGROUND: The morbidity of thyroid surgery is low. Despite this, some authors advocate a subtotal thyroidectomy instead of a total thyroidectomy, to avoid the higher morbidity associated with a total thyroidectomy. METHODS: We retrospectively evaluated the complications of thyroid surgery in Leiden between January 1, 1982 and October 1, 1990. Three hundred forty-one patients--261 women and 80 men--had 356 operations; 15 patients were operated on twice; there were 152 total hemithyroidectomies, 3 subtotal hemithyroidectomies, 33 total thyroidectomies, 122 bilateral subtotal hemithyroidectomies, 12 combinations of total and subtotal hemithyroidectomies, and 34 other operations. RESULTS: Calculated for the nerves at risk (n = 489), the percentage of permanent recurrent nerve lesions was 3.1 (in the 5 most recent years it was 1.2%). There was no significant difference between total or subtotal (hemi)thyroidectomies. Initial symptomatic hypocalcemia necessitating supplementation was encountered 42 times (12.5%). The occurrence of permanent symptomatic hypocalcemia (6%) was not significantly different between total and subtotal (hemi)thyroidectomies (p = 0.06). The duration of surgery was 137.8 min for bilateral subtotal thyroidectomies and 182.9 min for bilateral total thyroidectomies (p < 0.0001). There was no difference in blood loss between total and subtotal (hemi)thyroidectomies. CONCLUSIONS: Because total thyroidectomy carries a risk of complications similar to that for subtotal thyroidectomy, it is not logical to avoid total resections. If the number of total resections were increased, it is anticipated that fewer reoperations, which involve a relatively high morbidity rate, would have to be performed.

Preoperative diagnostic tests for operable thyroid disease.

Although the availability and acceptance of fine-needle aspiration biopsy (FNAB) of thyroid nodules has increased, many physicians still use thyroid scintigraphy for distinguishing benign from malignant lesions. We evaluated these diagnostic tests in 350 patients who had thyroid surgery in our institution between 1977 and 1990. Histologic confirmation of FNAB was obtained in 265 patients. In the group of patients having surgery, 247 thyroid scintigraphies were performed. Our patients were divided into two groups (1977-1986 and 1986-1990). The first group comprised 173 patients with 173 FNABs and 126 scintigrams. The second group consisted of 177 patients having 92 FNABs and 121 scintigrams. Results of scintigrams were analyzed in the second group only. In 5 out of 120 cases where the FNAB result was "benign or probably benign" the lesion appeared to be malignant postoperatively. If the FNAB result was "malignant or probably malignant" (n = 83) the pathology report confirmed a malignancy in 68 cases (81.9%). In 56 instances of all 265 FNABs the cytology report was not conclusive ("uncertain"); in 21.4% of these cases a malignancy was found postoperatively. An FNAB-result "(probably) malignant" had a positive predictive value of 0.819 while the negative predictive value of a result "(probably) benign" is 0.950. An "uncertain" result does not take away our concern so this result should have the same consequences as those of a result "(probably) malignant". In that case, FNAB-sensitivity is 93.0% and specificity 66.1%. Eighty-five of the last 116 scintigraphies showed a solitary node. Eleven of these nodes were hot while 74 were cold.(ABSTRACT TRUNCATED AT 250 WORDS)