Discontinuation of proton pump inhibitors during assessment of chromogranin A levels in patients with neuroendocrine tumours.

BACKGROUND: The aim of this prospective study was to examine whether discontinuation of proton pump inhibitors (PPIs) or replacement by H(2)-receptor antagonists (H2RA) resulted in a decrease of chromogranin A (CgA) levels in 196 patients with well-differentiated neuroendocrine tumours (NETs). METHODS: Patients with an unexpectedly high CgA level not connected with NET disease discontinued PPIs, or used H2RA instead; 2 weeks later CgA level was measured again. RESULTS: In all, 19 out of 196 (10%) patients showed unexpected elevated CgA levels, they all used PPI. In 11 out of 19 patients with no evidence of the disease, median CgA decreased from 390 µg l(-1) during PPI treatment to 56 µg l(-1) after discontinuation (P=0.003). In 8 out of 19 patients with stable disease, median CgA decreased from 618 to 318 µg l(-1) (P=0.012). In 12 out of 19 patients who ceased all acid inhibition, CgA levels decreased by 82%, while in the seven patients who replaced PPI by H2RA, CgA decreased by 77% (P=0.967). CONCLUSION: Proton pump inhibitor use causes falsely elevated CgA levels in patients with NET. We recommend to stop, or replace PPI by H2RA, to obtain a reliable CgA value.

An elevated progastrin-releasing peptide level in patients with well-differentiated neuroendocrine tumours indicates a primary tumour in the lung and predicts a shorter survival.

BACKGROUND: Progastrin-releasing peptide (proGRP) is a recently identified biomarker of small-cell lung cancer. In well-differentiated neuroendocrine tumours (WDNETs), this study investigates the association between proGRP and tumour characteristics and the prognostic value of proGRP levels compared with chromogranin A (CgA) levels. PATIENTS AND METHODS: Serum samples were obtained in 282 patients with WDNET. The receiver operating characteristic (ROC) curve technique was used to assess specificity and sensitivity in the identification of a primary tumour location. Cox proportional hazards models and Kaplan-Meier curves were constructed to determine the association of patients' characteristics and tumour markers with survival. RESULTS: For proGRP, the ROC curve indicated a cut-off level of 90 ng/l (approximately twice the upper reference value), with a specificity of 99% and a sensitivity of 43% in distinguishing primary pulmonary tumours from other sites. In the multivariate Cox model, both proGRP and CgA were strongly associated with survival (P < 0.0001 for both variables). CONCLUSIONS: A high-risk proGRP level (more than twice the upper reference value) in patients with WDNETs is a strong indication for a primary tumour in the lung. Besides CgA, proGRP is a complementary tumour marker for prognosis and treatment monitoring in patients with neuroendocrine tumour.

Expression and ligand binding of bombesin receptors in pulmonary and intestinal carcinoids.

INTRODUCTION: Carcinoids are mainly found in the gastrointestinal (65%) and bronchopulmonary tract (25%). These neuroendocrine tumors secrete a wide range of bioactive peptides, including gastrin releasing peptide and neuromedin B, the mammalian analogs of bombesin. The purpose of this study was to investigate the quantity and localization of bombesin receptors in gastrointestinal and pulmonary carcinoids, and to reveal whether bombesin-like peptides (BLP) and their receptors are of any value in distinguishing pulmonary carcinoids from carcinoids of intestinal origin. METHODS: Carcinoid tumors with pulmonary (no.=9) or intestinal (no.=15) localizations were analyzed by immunohistochemistry, autoradiography, and radioimmunoassay, to examine the presence of bombesin receptor subtypes and determine BLP levels in these tumors. RESULTS: All 3 bombesin receptor subtypes (GRPR, NMBR, and BRS-3) were present on pulmonary and intestinal carcinoids by immunohistochemistry. In pulmonary carcinoids, low receptor ligand binding densities together with high and low BLP levels were found. Intestinal carcinoids showed predominantly high receptor ligand binding densities in combination with low BLP levels. CONCLUSIONS: The expression of bombesin receptor subtypes is independent from the carcinoid tumor origin, and is therefore not recommended as a distinction marker, although carcinoids of pulmonary and intestinal origin possess different receptor binding affinities for bombesin and dissimilar BLP levels. The combined presence of bombesin and its receptors might suggest the presence of a paracrine or autocrine growth loop in carcinoids.

Palliative effect of metaiodobenzylguanidine in metastatic carcinoid tumors.

PURPOSE: To evaluate the therapeutic effect of iodine-131-labeled metaiodobenzylguanidine (131I-MIBG) and unlabeled MIBG in patients with carcinoid tumor. MATERIALS AND METHODS: A therapeutic dose of 7.4 GBq (200 mCi) 131I-MIBG infused over 4 hours was administered to 30 patients with either carcinoid syndrome (n = 20) or tumor symptoms such as pain and fever due to carcinoid tumor (n = 10). In general, two courses were given, 6 weeks apart. Due to radioactivity, patients had to be isolated for 5 to 7 days. Subsequently, we studied the effect of unlabeled MIBG based on the possible pharmaceutic activity of MIBG and to avoid the isolation procedure. A doseescalation study of 8.5, 17, and 34 mg/m2 MIBG infused over 4 hours at 4-week intervals was performed in 20 patients with carcinoid syndrome who were not suitable for treatment with the radioactive compound. RESULTS: Following 131I-MIBG treatment, symptomatic responses were observed in 60% of patients (median duration, 8 months; maximum, 2 years). Side effects were mild and rapidly reversible in 16 patients, and were related to the isolation procedure in seven of these patients. Unlabeled MIBG resulted in symptomatic improvement in 60% of patients (median duration, 4.5 months). Side effects, which included changes in blood pressure, were mild and transient. Symptomatic responses were not accompanied by biochemical responses. CONCLUSION: Both MIBG treatment regimens were equally effective in the palliation of symptoms, but duration of response tended to be much longer with the radioactive compound. However, the unlabeled compound provided a simpler treatment, eg, in elderly patients and those in poor condition, without the need for isolation.

MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families.

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the clustering of colorectal cancer, endometrial cancer, and various other cancers. The disease is caused by mutations in DNA-mismatch-repair (MMR) genes, most frequently in MLH1, MSH2, and MSH6. The aims of the present study were to compare the risk of developing colorectal, endometrial, and other cancers between families with the various MMR-gene mutations. PATIENTS AND METHODS: Clinical and pathologic data were collected from 138 families with HNPCC. Mutation analyses were performed for all families. Survival analysis was used to calculate the cumulative risk of developing cancer in the various subsets of relatives. RESULTS: Mutations were identified in 79 families: 34 in MLH1, 40 in MSH2, and five in MSH6. The lifetime risk of developing cancer at any site was significantly higher for MSH2 mutation carriers than for MLH1 mutation carriers (P < .01). The risk of developing colorectal or endometrial cancer was higher in MSH2 mutation carriers than in MLH1 mutation carriers, but the difference was not significant (P = .13 and P = .057, respectively). MSH2 mutation carriers were found to have a significantly higher risk of developing cancer of the urinary tract (P < .05). The risk of developing cancer of the ovaries, stomach, and brain was also higher in the MSH2 mutation carriers than in the MLH1 mutation carriers, but the difference was not statistically significant. CONCLUSION: Pending large prospective studies, the extension of the current surveillance program in MSH2 mutation carriers with the inclusion of the urinary tract should be considered.

Increased risk of lung cancer, non-Hodgkin's lymphoma, and leukemia following Hodgkin's disease.

The risk of second cancers (SCs) was assessed in 744 patients with Hodgkin's disease (HD) admitted to The Netherlands Cancer Institute from 1966 to 1983. Sixty-nine SCs were observed one month or more after start of first treatment. These included 14 cases of lung cancer, nine cases of non-Hodgkin's lymphoma (NHL), 16 cases of leukemia, and six cases of the myelodysplastic syndrome (MDS). The median interval between the diagnosis of HD and that of second lung cancer, NHL, and leukemia was 8.1, 13.3, and 5.7 years, respectively. The overall relative risks (RR) (observed/expected [O/E] ratios) of developing lung cancer, NHL, and leukemia were 4.9 (95% confidence limit [CL], 2.7 to 8.2), 31.0 (95% CL, 14.2 to 58.9) and 45.7 (95% CL, 26.1 to 74.2), respectively. At 15 years the cumulative risk of developing an SC amounted to 20.6% +/- 2.9%. The 15-year estimates of lung cancer, NHL, and leukemia were 6.2% +/- 1.9%, 5.9% +/- 2.1% and 6.3% +/- 1.7%, respectively. Increased lung cancer risk following HD has not frequently been clearly demonstrated before; that we were able to demonstrate such risk may be due to the completeness of follow-up over long periods that could be achieved in this study. Excess lung cancer risk was only noted in treatment regimens with radiotherapy (RT); also, all lung cancers arose in irradiation fields. Excess risk of leukemia was only found in treatment regimens involving chemotherapy (CT). For NHL, combined modality treatment was shown to be the most important risk factor. Risk of lung cancer and NHL increased with time since diagnosis. A time-dependent covariate analysis (Cox model) performed on leukemia and MDS showed an increasing risk with intensity of CT, age (greater than 40 years), and a splenectomy.

Developments in diagnosis and treatment of metastatic midgut carcinoid tumors. A review.

Carcinoids are neuroendocrine tumours derived from enterochromaffin cells which are widely distributed in the body and may, therefore, arise from any site. They are traditionally described as originating from the foregut, midgut and hindgut. Localisation in the gastrointestinal tract is the most frequent, among which the appendiceal involvement is often found at laparoscopy for appendicitis and the small bowel is known for the liver metastases with the production of serotonin causing the characteristic carcinoid syndrome with diarrhoea and flushes. The overall incidence of carcinoid disease has increased in the past decades, but whether this is a true increase or due to early detection or better recognition at pathology is not known. The prognosis of metastatic carcinoid tumours has improved during the last decade resulting in a 5 year survival of approximately 50% in the Netherlands. Due to a longer survival, complications such as carcinoid heart disease and new metastatic patterns like skin and bone metastases may become a more important feature in carcinoid disease. New developments are in the field of diagnostics (fine-tuning of the pathology, videocapsule endoscopy to find the primary tumour, positron emission tomography [PET] scanning) and treatment options (radiofrequency ablation, radioactive octreotide, meta-iodobenzylguanidine combinations). The new serum marker of carcinoid, chromogranin A, may play an important role in the follow-up and NT-proBNP for the detection of heart problems. Combining new diagnostic and treatment modalities in metastatic carcinoid patients may result in a better quality of life and a longer survival. The increasing number of therapeutic options and diagnostic procedures requires a multidisciplinary approach focused on tailor-made therapy based on patients' specific conditions preferably in specialised centres and in clinical studies.

Interferon and meta-iodobenzylguanidin combinations in the treatment of metastatic carcinoid tumours.

Interferon (IFN) and meta-iodobenzylguanidin (MIBG) are active in metastatic carcinoids. In a phase II study, we evaluated the effect upon diagnostic 131I-MIBG uptake and the clinical response of the combination. 131I-MIBG scintigraphy was performed prior to treatment, after 8 weeks of IFN and after unlabelled MIBG. The tumour over non-tumour (T/NT) ratios were quantitatively determined by comparing counts in the centre of the tumour (liver metastases) with those in an adjacent area of normal liver uptake (T/NT1) and with abdominal background area (T/NT2). The T/NT1 ratio showed an increase of >10% in only four out of 21 patients (19%) after IFN (P = 0.178) and significantly more often in nine out of 18 patients (50%) after unlabelled MIBG (P = 0.016). The absolute uptake in tumour deposits was also increased if compared with the abdominal background (T/NT2: 23% increase after IFN and 83% increase after unlabelled MIBG). The combination produced 91% of patients with stable disease (using World Health Organisation criteria) at computed tomography scan and a biochemical response (a reduction of at least 50% in urinary 5-hydroxyindolacetic acid excretion) in 39%. IFN-alpha did not significantly improve tumour retention of 131I-MIBG. In contrast, unlabelled MIBG significantly improved biodistribution and tumour uptake in 83%. A synergistic effect was not seen.

Intraperitoneal chemotherapy for malignant peritoneal mesothelioma.

4 patients with malignant peritoneal mesothelioma have been treated with intraperitoneal chemotherapy in the Netherlands Cancer Institute in the recent years. 1 patient achieved a complete remission for 36+ months and another patient had a partial remission that lasted for 10 months. Intraperitoneal chemotherapy alone or in combination with other treatment modalities may yield a response rate of 58% with 24% complete remissions in 70 patients reviewed in the literature. Although these data should be considered with caution because of the heterogenicity of the patient group treated, cisplatin-based intraperitoneal chemotherapy seems to be the best available treatment for malignant peritoneal mesothelioma at present.

Modulation of toxicity following external beam irradiation preceded by high-dose rate brachytherapy in inoperable oesophageal cancer.

To induce fast relief of dysphagia in inoperable oesophageal cancer, we applied high-dose rate (HDR) intraluminal irradiation followed by external irradiation (EBRT) in a phase II study. 15 patients (group A: n = 15; 10 men, 5 women; median age 66 years) were treated with 10 Gy HDR brachytherapy plus 40 Gy EBRT (15 fractions of 2.67 Gy). Severe side-effects were encountered in 60% of patients: 3 late ulceration, 2 pending fistula, 2 fistula and 2 patients with fatal haemorrhage after an interval of 6 months. Overall response was excellent: 9 complete remissions (60%) and 6 partial responses (40%). Because of the high toxicity rate, in a subsequent study (group B: n = 30; 23 men, 7 women; median age 66 years) the EBRT scheme was changed using smaller fractions (2.0 Gy) to reach the same total dose of 40 Gy. The complication rate (17%) was significantly reduced, while the overall response remained excellent (83%): 17 complete and 8 partial responses. The impressive change in complication rate of HDR brachytherapy and EBRT stresses the impact of the fraction per dose and illustrates the small therapeutic margins.

The management of radiation-associated oesophageal carcinoma: a report of 16 cases.

16 patients, presenting with squamous cell carcinoma in previously irradiated sections of the oesophagus, are described. Oesophagectomy could be performed in 2 patients, resulting in long-term disease-free survival (38 and 60 months after diagnosis). 14 patients were treated with palliative radiotherapy (external beam or intraluminal), oesophageal stenting, bougienage or chemotherapy. Although most patients previously received curative dosages of mediastinal irradiation, additional full courses of high-dose radiotherapy could be given on five occasions; no major complications were encountered and adequate palliation for up to 10 months was achieved. Similar results were observed after oesophageal stenting and/or bougienage. Relief of dysphagia following intraluminal radiotherapy or chemotherapy was only minimal (2 months or less). Median survival in the palliative treatment group was 6.5 months (range 2-27 months), which is in keeping with results observed in non-radiation-associated oesophageal carcinoma. We concluded that, in selected cases, both surgery and radiotherapy offer good prospects for patients with radiation-associated oesophageal cancer.

Risk factors for the development of oesophageal cancer as a second primary tumour.

Exposure to irradiation or chemotherapy as well as prolonged exposure to risk factors, such as alcohol and tobacco, may induce a second primary carcinoma of the oesophagus. To estimate the potential risk of previous treatment regimens, we performed a case-control study. In the Tumour Registry of The Netherlands Cancer Institute, from 1955, 27 cases of squamous cell carcinoma of the oesophagus were identified following treatment for malignant lymphoma (n = 11), breast cancer (n = 8) and lung cancer (n = 8). The median interval was 6.6 years (range 1-16). Preferably 3 controls from the same tumour registry were matched to each case on the basis of sex, age, primary tumour, location of primary treatment (academic or general hospital), calendar year at diagnosis of primary tumour and duration of follow-up. Clinical data and details of treatment were obtained from the medical records. In patients who had smoked for more than 5 years, there was a 3.2-fold increased risk of oesophageal carcinoma (P = 0.04); for those with a regular alcohol intake the relative risk was 3.3 (P = 0.01). There was no significant relationship between irradiation of the mediastinum and subsequent risk for oesophageal cancer. The number of chemotherapy-treated patients was too small to calculate the relative risk associated with cytostatic drugs. In conclusion, oesophageal cancer as second primary cancer is extremely rare. Risk factors include the well known abuse of alcohol and tobacco. No significant relationship with previous mediastinal irradiation could be demonstrated.

Combined diagnostic imaging with 131I-metaiodobenzylguanidine and 111In-pentetreotide in carcinoid tumours.

Carcinoid tumours derived from the neural crest are usually associated with the symptoms of flushing and diarrhoea in the presence of liver metastases. Scintigraphs with 131I-metaiodobenzylguanidine (131I-MIBG) which is accumulated in the argentaffin granules of the cell, as well as with 111In-pentetreotide for the imaging of somatostatin receptors on the cell surface, are positive in a large proportion of carcinoid patients. To evaluate the complementary role of both radionuclide tests, we studied 20 consecutive carcinoid patients: 14 with the characteristic carcinoid syndrome and 6 with tumour symptoms, such as pain or obstruction. A positive test was found in 84% with either 131I-MIBG or 111In-pentetreotide; the combination yielded a sensitivity of 95%. A positive correlation was found with the presence of the carcinoid syndrome, but not with 5-HIAA excretion. A positive test may help in adjusting treatment: either to predict the response to octreotide or to select patients for 131I-labelled MIBG treatment. Application of a therapeutic dose of 111In-pentetreotide may be limited by the high normal uptake in the kidneys.

Hereditary nonpolyposis colorectal cancer: results of long-term surveillance in 50 families.

A surveillance programme comprising either colonoscopy of sigmoidoscopy plus barium enema every 2-3 years was instituted in 50 hereditary nonpolyposis colorectal cancer (HNPCC) families. The families included 238 patients with colorectal cancer (CRC) (mean age at diagnosis: 43.7 years; range: 16-86 years). These patients had 597 first-degree relatives of whom 493 could be traced and 388 (79%) accepted the invitation for screening. The control group were relatives (index patients) with symptomatic CRC. The average follow-up duration was 5 years (1-20 years). Screening led to the detection of adenomas in 33 patients and CRC in 11 patients. Pathological examination revealed 1 Dukes' A, 7 Dukes' B and 3 Dukes' C cancers. In contrast, among the control group 47% had advanced CRC (Dukes' C or distant metastases). The 5-year survival of the screen-detected cases was 87% versus 63% in the control group. Of the 11 CRC cases in the screening group, 4 were detected within 1-4 years after a negative colonic examination. A large proportion of the polyps found in the screening and control groups showed a villous growth pattern and/or a high degree of dysplasia. We conclude that periodic examination of HNPCC families allows the detection of cancer at an earlier stage than in patients not under surveillance. Because of the possibly more aggressive nature of polyps associated with HNPCC, we recommend a screening interval of 1-2 years.

A dose-escalation study of recombinant interferon-alpha in patients with a metastatic carcinoid tumour.

The efficacy of interferon alpha-2b in doses up to 12 x 10(6) IU three times weekly was studied in 21 patients with a metastatic carcinoid tumour. Of these 21 patients, 19 were evaluable for response. Patients were treated with escalating dosages of interferon alpha-2b: 3 x 10(6) IU, 6 x 10(6) IU and 12 x 10(6) IU. The escalation was performed every 8 weeks when no objective tumour regression was observed. Patients were also evaluated for biochemical response and symptomatic improvement. One objective tumour regression was observed. Of the 15 patients with elevated 5-hydroxyindole acetic acid (5-HIAA) excretion, 5 (33%) had a more than 50% decrease in 5-HIAA excretion. Relief of symptoms occurred in 11 patients (58%). This improvement was already apparent during the initial 8 weeks of treatment. Increasing the dose to 6 or 12 x 10(6) IU interferon alpha-2b did not result in further symptomatic improvement. In contrast toxicity was considerable with the higher dosages of interferon alpha-2b. It is concluded that low dose interferon alpha-2b (3 x 10(6) IU) three times weekly is as effective as higher dosages of interferon alpha-2b at ameliorating symptoms of the carcinoid syndrome.

Metastatic ovarian or colonic cancer: a clinical challenge.

Clinical problems arise when histology is unable to differentiate between an ovarian carcinoma infiltrating into the rectosigmoid region and a colonic cancer with ovarian metastases. To evaluate the discriminative value of immunohistochemistry we studied four groups: (A) ovarian carcinoma (n = 21), (B) ovarian carcinoma with sigmoid stenosis (n = 18), (C) colonic carcinoma (n = 20) and (D) a group in which the differential diagnosis was a problem (n = 19). Paraffin sections stained with a panel of monoclonal antibodies revealed specific patterns: in group A and B a negative Parlam-4 and positive OC-125; in group C the opposite; in group D the 'colonic' pattern in 15 cases, and the 'ovarian' pattern in only 2. The clinical diagnosis in group D during follow-up was ovarian carcinoma in 7, colonic carcinoma in 8, double tumour in 1 and still unknown in 3. This was based on high levels of serum tumour markers such as carcinoembryonic antigen (n = 5) and CA-125 (n = 4), laparotomy (n = 4), autopsy (n = 1), barium enema and/or endoscopy (n = 5). The response to chemotherapy in group D was extremely poor.

Results of a phase II trial of epirubicin and cisplatin (EP) before and after irradiation and 5-fluorouracil in locally advanced pancreatic cancer: an EORTC GITCCG study.

The objective of the present study was to define the role of chemotherapy, in the form of the EP regimen, consisting of epirubicin (E) and cisplatin (P) in addition to irradiation in combination with 5-fluorouracil (5-FU) for treatment of pancreatic cancer. 53 eligible patients with histologically or cytologically proven locally advanced pancreatic cancer were treated with three cycles of E 60 mg/m2 (if this dose was well tolerated then the dose of E was increased by 10 mg/m2 in the next cycle; 80 mg/m2 was the maximum dose for the following cycles) and P 100 mg/m2 once every 3 weeks, followed after 4 weeks by a split course of irradiation of 40 Gy with 5-FU 500 mg/m2 on each of the first 3 days of each 20 Gy treatment segment. This was followed by another three cycles of EP in patients who achieved stable disease (SD) or a better response after the first three cycles. The treatment given with standard anti-emetics was moderately tolerated. The chemotherapy related toxicity consisted mainly of myelosuppression and the chemoradiotherapy related toxicity of gastrointestinal side-effects. However, due to the long duration of treatment which made the whole treatment difficult to endure, only 18/53 (34%) actually completed the full treatment regimen. Responses were evaluated after the first three cycles and 4 weeks after the completion of the treatment by serial CT-scans using standard criteria. The results in 53 evaluable patients after the first three cycles of EP were as follows: 1 patient achieved a clinical complete response (CR), 7 a partial response (PR) (CR + PR: 15%; 95% confidence interval (CI): 11-33%), 36 patients (68%) had stable disease (SD) and 6 patients progressive disease (PD). There was 1 early PD, 1 toxic death and 1 patient could not be evaluated. The response at the end of the treatment was 3 CR, 11 PR (CR + PR: 14/53 (26%); 95% CI: 15-40%), 30 SD and 6 PD. The median time to progression was 8.9 months and the median duration of response 13.1 months. The median survival of all treated patients was 10.8 months (range 7 days to 41.5 months), of responders 15.1 months and, of the patients with SD 10.3 months. These results are comparable to other combined modality regimens reported in the literature for locally advanced disease. The addition of the systemic treatment with E and P offers no additional advantage to combined modality treatment alone.

Thymidylate synthase expression in patients with colorectal carcinoma using a polyclonal thymidylate synthase antibody in comparison to the TS 106 monoclonal antibody.

Colorectal cancer is one of the most common human cancers, for which 5-fluorouracil (5FU) is usually part of the treatment. Thymidylate synthase (TS), the target enzyme for 5FU, can be predictive for the outcome of 5FU-based therapy. TS levels in tumor samples can be determined with radiochemical enzyme assays, RT-PCR, and immunohistochemical staining. We validated TS immunohistochemistry with a polyclonal rabbit anti-human TS antibody using the avidin-biotin method. This antibody can be used on paraffin-embedded, formalin-fixed material using an antigen retrieval method with citrate buffer and microwave treatment. The antibody shows a granular cytosolic staining pattern. The reproducibility in cross-sections from colorectal tumors from 50 patients was 90% and the interobserver variability was acceptable with a kappa of 0.45. On Western blotting it detects purified TS at 36 kD, while in 5FU-treated cells the ternary complex between FdUMP, TS, and 5, 10-methylene-tetrahydrofolate is clearly visible at 38 kD, with no other interfering bands. In a separate set of tumors, immunostaining was compared with enzyme levels; Western blots correlated with enzyme levels. Because both this polyclonal antibody and the monoclonal antibody TS-106 are being used for large-scale studies, we also determined whether they could be used interchangeably. No differences were observed. This polyclonal antibody is specific and gives reproducible results. A study on a larger scale is ongoing to determine the role of TS as a predictive parameter in patients with colorectal cancer treated either with postoperative adjuvant 5FU/levamisole or with surgery only.

Treatment results of primary stage I and II non-Hodgkin's lymphoma of the stomach.

Gastric lymphoma in stage I or II was usually treated by partial gastrectomy and total abdominal irradiation in our institute since 1970. Since 1978, a number of patients were also treated without laparotomy, in clinical stage I with radiotherapy only and in clinical stage II with combined modality treatment. Treatment results of 58 patients are reported. A relapse-free survival rate of 85% was reached for 24 patients treated with resection and irradiation either in stage I or II, and for seven patients in stage I who did not undergo surgery. For these patients, survival in stage I was 85%, in stage II, however, survival dropped to 60% due to intercurrent deaths. Seven stage II2 patients received intensive chemotherapy and radiotherapy with 58% relapse-free survival. Twenty patients could not be treated according to the outlined treatment protocol. For the total group, survival in stage I is 65% and in stage II 35%. In the Addendum, an additional group of 17 patients is mentioned with the same result.

Non-allelic heterogeneity of familial adenomatous polyposis.

Linkage studies on familial adenomatous polyposis (FAP) reported so far suggest that FAP is a genetically homogeneous disease. Recently, we found that the putative gene for Turcot syndrome, an apparently autosomal recessive clinical variant of FAP, is not allelic to FAP. Here we describe another family, segregating for an autosomal dominant disease clinically indistinguishable from FAP but genetically not linked to the APC locus, adding further evidence for the occurrence of non-allelic heterogeneity of FAP. These observations have implications to the linkage-based genetic counselling of persons at risk for FAP especially when they are drawn from small families giving insufficient information.