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The effects of treatment with alkylating agents and prednisone on the paraprotein level, the serum viscosity and the clinical symptoms have been studied in four cases of Waldenstrom's macroglobulinaemia and in one case of IgA myeloma. Although the treatment occasionally had some effect, no correlation was observed between the paraprotein level and the clinical condition in the four macroglobulinaemia cases. In the myeloma case there was some correlation, although osteolytic foci appeared at a time when the production of paraprotein was considerably suppressed. It appears that neither the paraprotein level nor the serum viscosity can be used with certainty as an indicator of the activity of the pathological process. It is suggested that the paraprotein may not always be the principal cause of the symptoms of Waldenstrom's macroglobulinaemia.

We searched for criteria that could indicate breast cancer families with a high prior probability of being caused by the breast/ovarian cancer susceptibility locus BRCA1 on chromosome 17. To this end, we performed a linkage study with 59 consecutively collected Dutch breast cancer families, including 16 with at least one case of ovarian cancer. We used an intake cut-off of at least three first-degree relatives with breast and/or ovarian cancer at any age. Significant evidence for linkage was found only among the 13 breast cancer families with a mean age at diagnosis of less than 45 years. An unexpectedly low proportion of the breast-ovarian cancer families were estimated to be linked to BRCA1, which could be due to a founder effect in the Dutch population. Given the expected logistical problems in clinical management now that BRCA1 has been identified, we propose an interim period in which only families with a strong positive family history for early onset breast and/or ovarian cancer will be offered BRCA1 mutation testing.

A cross-sectional study of reverse smoking and its association with pre-malignant and malignant lesions of the palate was conducted in the north coastal areas of Andhra Pradesh, India. A total of 480 randomly selected persons were interviewed. Information about smoking status, diet and access to mass media was obtained in each case and an examination of the oral cavity was performed. Reverse smoking of chutta was practised by 33% of the total rural population. The prevalence rate of all palatal lesions was 55%. The prevalence rates of the separate lesions: leukoplakia palatii, palatal keratosis and palatal cancer, were 9.8%, 18.1% and 1.9%, respectively. The presence of these (pre-)malignant lesions was strongly associated with reverse smoking and also associated with conventional chutta smoking. Reverse smoking induced significantly more lesions than conventional chutta smoking, and was a major determinant of subsequent palatal cancer: all 9 newly diagnosed palatal cancers were observed within the group of reverse smokers. There was an inverse relationship between the incidence of palatal lesions and vitamin A intake. The study of access to mass media indicated that the most favourable medium for promoting a prevention campaign would be the cinema.

Twenty-five assessable patients with metastatic melanoma have been entered in a multicenter phase II study of two induction cycles of human recombinant interleukin-2(IL2), 18 x 10(6) IU/m2/d continuous intravenous (IV) infusion on days 1 to 5 and days 12 to 17. Dacarbazine (DTIC), 850 mg/m2 IV bolus was given on day 26. The cycle was repeated at 5 weeks. Maintenance therapy was scheduled 3 weeks after the completion of induction treatment, consisting of IL2, 18 x 10(6) IU/m2/d for 5 days alternating with DTIC, 850 mg/m2 IV every 3 weeks, for a total of 18 weeks. Six patients responded (24%); two complete and four partial. Stable disease was seen in five patients. None of the six patients with more than two sites of metastases responded. Maximum response was observed in the first 3 months of treatment. Progression-free periods of 6 months and longer were seen in the two complete responders (8 and 17+ months), in two of the four partial responders (7 and 12+ months), and in three of the five patients with stable disease (9+, 15, and 17+ months). Toxicity included fever, skin rash, fatigue, anorexia, and diarrhea in most patients. Two patients had a weight gain of more than 10%. Eight patients needed intensive care for the observation and treatment of a myocardial injury (one patient), ventricular tachycardia (one), hypotension and oliguria (four), and sepsis (two). Sequential treatment with IL2 and DTIC appears to be effective but not clearly better than could be expected of IL2 alone.

Background Ovarian cancer refractory to chemotherapy has a very poor prognosis and no standard treatment options. In a phase I–II study patients with recurrent disease restricted to the peritoneal cavity received intraperitoneal (i.p.) immunotherapy with interleukin-2 (IL-2) and autologous T-cells redirected by bispecific monoclonal antibodies (bs-MAb). Methods A bs-MAb with on the one hand specificity for ovarian cancer cells (the folate binding site MOv 18) and for the CD3 activation site on T-lymphocytes on the other, was produced in large quantities. Lymphocytes, obtained from the patient prior to debulking surgery, were cultured ex vivo and preincubated with the bs-Mab OC/TR (Ovarian Cancer-T cell Receptor) before i.p. administration. IL-2 was given i.p. every 12 hours at a dose of 600.000 IU. The first 4 days increasing numbers of T-cells were administered (106–109 cells), on days 7–11 and 28–32, 109 redirected T-cells were administered each day. Evaluation for tumor response was done by laparotomy 6 weeks after i.p. treatment. Results 11 patients entered the protocol; 10 were evaluable for toxicity; 3 had extracavitary progression without signs of i.p. progression, but were not explored. Therefore in 7 patients i.p. tumor response was evaluated by laparotomy: i.p. CRs were observed in 2 patients, in 1 however there was concurrent PD in retroperitoneal lymph nodes; furthermore 2PRs, 1 SD and 2 PDs were observed. Toxicity was mild, limited to grade 2 fever, abdominal discomfort, tenderness, bloating, and grade 1–2 nausea. Conclusions Immunotherapy with T-cells redirected by bs-Mabs in ovarian cancer has therapeutic potential and should be explored further.

To review the results 5 years after treatment of patients with testicular non-seminoma.Retrospective, descriptive.The records were studied of the 146 patients treated in Leiden University Hospital, the Netherlands, in 1979-1993 for non-seminoma of the testicle. The median age was 27 years (range: 16-76). The median follow-up duration was 65 months (range: 4-172). The Kaplan-Meier method was used to calculate the recurrence and survival rates.In all, 21 of the 146 patients died (5-year survival rate: 84%). Five patients died as a result of treatment. A relapse occurred in 14 of the 49 stage I patients after frequent controls according to the European Organization for Research and Treatment of Cancer (EORTC) standards. One of these patients died after he refused further treatment for his relapse (5-year survival rate: 96%), 92 patients, including 13 from the stage I group, were treated according to protocol with chemotherapy because of metastatic disease, of whom 51 underwent surgery following primary treatment. The histology of the resected material showed vital tumour tissue in 14 of the 51 patients (27%). Seven patients never reached complete remission after chemotherapy and died. In 12 of the 92 patients a relapse occurred after chemotherapy; seven of these died despite further treatment. The 5-year survival rate of the 92 patients with metastatic disease was 82%. None of the surviving patients developed a second primary or major pulmonary, renal or auditory problem.The chance of cure and survival in patients suffering from testicular non-seminoma with the help of chemotherapy and surgery is over 80%. In stage I patients intensive surveillance, and chemotherapy in case of a relapse, is effective. Even patients with metastatic disease have a high probability of being cured with few long-term side effects.

In a retrospective study survival after hypercalcemia in breast cancer patients has been investigated. A group of 72 patients were treated with bisphosphonate APD [3-(amino-1,1-hydroxypropylidene)bisphosphonate] and third-generation amino-containing bisphosphonates between January 1980 and October 1992. A median survival of 4.5 months was found. In a multivariate analysis, four independent prognostic factors for survival have been found: the interval between first relapse and hypercalcemia, sites of metastases at the moment of hypercalcemia, primary treatment, and the level of serum alkaline phosphatase. Patients with a "flare" reaction on tamoxifen treatment and patients with a normal serum alkaline phosphatase level and bone metastases only had a prolonged survival. Hypercalcemia associated with visceral metastases carried a very poor prognosis. The level of serum calcium in this series of patients was no prognostic indicator for survival.

Because of the relative rarity of breast cancer in males, data have not been sufficient to support a definitive analysis of pertinent prognostic factors. Remarkably, no studies of male patients with breast cancer have presented survival information based on the number of histologically positive axillary nodes, the most sensitive single indicator of prognosis in women with breast cancer.In this study, the clinical course of breast cancer was documented for 335 male patients registered from 1965 through 1986. For patients to be eligible, diagnoses had to be made within 3 months of registration and the patients had to have histologic confirmation and receive part or all of their initial treatment at 1 of 11 cancer centers participating in the International Patient Data Exchange System.The survival rate at 10 years was 84% for patients with histologically negative nodes, 44% for those with one to three positive nodes, and 14% for the group with four or more histologically positive nodes. The survival rates at 5 years were 90%, 73%, and 55%, respectively. In a multivariable analysis, the risk of death due to breast cancer for a patient with four or more histologically positive nodes was 6.75 times that of a patient with negative nodes.The findings of the authors indicate the following: (1) The number of histologically positive axillary nodes and, to a lesser degree, tumor diameter are significant prognostic factors for breast cancer in male patients. (2) The prognosis of breast cancer is the same in male and female patients when compared on the basis of the number of histologically positive nodes.

Experimental and clinical studies on ifosfamide indicate that fractionated treatment regimens have a higher efficacy compared to a single short-term infusion. In addition, protracted continuous infusion, in general, is often less toxic without loss of antitumour activity. To study the toxicity of a 10-day continuous infusion at increasing dosages of ifosfamide and mesna, 24 patients with a variety of advanced cancers (colon 10, pancreas 5, adenocarcinoma with unknown primary 5, and 4 others) received a total of 60 cycles (range 1-6 cycles, median 2) at 3 to 4 week intervals. The ifosfamide and mesna doses ranged from 654 mg m-2 day-1 to 1562 mg m-2 day-1 for a total of ten doses. Twenty-two patients were chemotherapy-naive. Pharmacia-Deltec CADD-1 pumps and Port-a-Cath implantable venous access devices were used. The dose-limiting toxicity was leucopenia without thrombocytopenia. At a dose of 1300 mg m-2 day-1 in 30% of the cycles in 7 patients leucopenia of WHO grades 3 and 4 was observed, while at higher dosages this percentage increased to 73%. Haemoglobin values usually decreased during the infusion with a mean of 1 mmol/l (range 0.3-2.5 mmol/l), frequently with partial or full recovery by the next cycle. The next most disturbing side-effect was fatigue (50% of patients WHO grades 2 and 3), and nausea and vomiting requiring drug treatment in 75% of patients. Renal failure and haematuria did not occur. There were two catheter-related complications: thrombosis (1 patient) and mechanical obstruction (1 patient). One patient developed severe encephalopathy at day 6 (total dose 18 g ifosfamide) with complete recovery after cessation of the infusion. In summary, a tolerable ifosfamide dose using this regimen in this previously largely untreated patient group appears to be 1200-1300 mg m-2 day-1 for 10 days. Fatigue is a frequent complaint and might be explained as a kind of neurotoxicity. The treatment can be administered to outpatients.

The distribution of the normal differentiation antigen Thy 1 and the mammary tumor virus (MTV)-induced antigens or antigen complexes MLm and MLr were studied in mouse mammary gland cells, mammary tumor cells, and other cell types, by use of ascites leukemia cells of the GR mouse strain as target cells in the cytotoxicity test. The Thy 1.2 antigen was detected by an AKR antiserum to C3Hf thymocytes. MLm was shown by a homologous C57BL antiserum to GRSL2 leukemia (absorbed in vivo in GR mice); MLr was detected by a rabbit heterologous antiserum (absorbed in vivo in C57BL or GR mice and in vitro with BALB/c milk) prepared against Tween 80- and ether-treated purified B particles. Sera from Sprague-Dawley rats bearing murine leukemia virus (MuLV)-producing syngeneic tumors were not cytotoxic or only slightly cytotoxic for GR leukemias transplanted in vivo, which indicated that MuLV-induced antigens were absent or present in very low quantity in such leukemias. The MLr and MLn antigens or antigen complexes were possibly identical to the mammary leukemia (ML) antigen, since they could be detected not only on GR but also on DBA/2 leukemia cells and since their distribution was exactly the same as that of MTV. Both the MLr and MLm antigens were present in purified B particles, and antigenic activity were present in purified B particles, and antigenic activity was enhanced by destruction of the purified virus particles. The antigens were about eightfold enriched in a preparation of B-particle envelopes, as shown by quantitative cytotoxicity absorption (CYTA) tests. Purified nucleoid fractions of B particles were only lightly positive for the antigen, probably due to envelope contamination. One dominant gene was responsible for the expression of MLr, as shown by CYTA tests with mammary glands of individual animals of segregating crosses between the GR strain with high mammary cancer incidence and strains with low incidence. This gene was closely linked with or was possibly identical to 1) the gene for cytoplasmic MTV gs antigen expression as seen by fixed cell immunofluorescence, and 2) the gene causing mammary tumors in the GR mouse strain.

The chemotherapy of advanced ovarian cancer is reviewed. Treatment with single agents results in low remission rates and few complete remissions. The results have been improved with modern combination chemotherapy, which includes cisplatin, although a longer follow up is needed for definite conclusions to be made concerning survival. Toxicity and drug resistance remain important problems. The future prospects of treatment with emphasis on intraperitoneal chemotherapy are discussed.

Cell suspensions prepared from lymph nodes, spleen or peripheral blood of patients with non-Hodgkin's lymphoma (NHL) often contain a high percentage of residual nonmalignant cellular elements. By E-rosette sedimentation, it was possible to enrich such suspensions from patients with various types of lymphoma for malignant cells. In patients with a B- or non-B/non-T-cell lymphoma, the neoplastic cells were found in the non-T fraction. The capacity to respond to stimulation by various stimuli was then confined to the T-cell fraction, which contained the residual normal T-cells. In patients with T-cell lymphomas, in which the malignant cells had retained the capacity to form E-rosettes, lymphoma cells were found in the T fraction. These cells usually did not respond to mitogenic stimuli. Using this separation method, small proportions of neoplastic cells could be identified in mixed cell populations. Thus, in the blood from nine out of 23 lymphoma patients without abnormalities in routine blood tests, a population of abnormal cells was detected after cell separation. This included a monoclonal B-cell population in the blood of four patients, a questionably monoclonal B-cell population in the blood of two patients and in increased non-B/non-T cell population in the blood of three patients.

DNA/cell distributions were recorded by automated cytofluorometry (=pulse cytophotometry) in bone-marrow aspirates of leukaemia and lymphosarcoma patients subjected to chemotherapy. In most cases, early perturbations in DNA/cell histographs were observed, characteristically reflecting the known mode of action of the drugs. These changes in general preceded the clinical observation of drug response. In a series of 23 measurements in 19 patients, a positive correlation between early cytophotometric changes and clinical effects of chemotherapy was observed in 17 patients. Five patients were negative for both cytophotometric and clinical reactions and one patient was probably false-positive. The validity of the assay for early detection of drug resistance in acute leukaemia and related diseases is discussed.

Twenty-four evaluable patients with metastatic melanoma have been entered in a multicentre Phase II study of two induction cycles of human recombinant interleukin-2 (rIL-2) 18 x 10(6) IU/m2/day continuous i.v. bolus on days 1-5 and days 12-17. Dacarbazine (DTIC) 850 mg/m2 i.v. bolus was given on day 26. The cycle was repeated at five weeks. Maintenance therapy was scheduled three weeks after the completion of the induction treatment, consisting of rIL-2 18 x 10(6) IU/m2/day for five days alternating with DTIC 850 mg/m2 i.v., every three weeks, for a total of 18 weeks. Median age was 44 years (range 23-80), and Karnofsky index was 100 (range 80-100). One patient had received prior chemotherapy with hydroxyurea and one patient had prior radiotherapy. Six patients responded (25%): two had complete responses (CR) and four had partial responses (PR). Stable disease (SD) was seen in five patients. Responses occurred in the following sites: liver 2/9 (22%), lung 3/14 (21%), skin 2/11 (18%), and lymph nodes 3/12 (25%). Duration of CR was 11+ and 13 months. PRs lasted 2, 5, 7, and 11+ months. Of note, time to progression in patients with SD was similar to that of responders: 4, 4, 11+, 11+, and 14+ months. Toxicity included fever, skin rash, fatigue, anorexia, and diarrhoea in most patients. Two patients had a weight gain of more than 10%. Hypotension requiring vasoactive agents or interruption of rIL-2 occurred in four patients, creatinine elevations WHO grade 1-2 in seven patients, and bilirubin elevations WHO grade 1-3 in six patients. One patient developed transient ventricular tachycardia. It appears that rIL-2 and DTIC in this schedule is feasible and effective, but not clearly superior to rIL-2 alone.

1. Stable phenotypic expressions of transformed and tumor cells.- 2. On the correlation between mutagenicity and carcinogenicity.- 3. DNA repair and its relationship to the origins of human cancer.- 4. RNA tumour viruses: interesting interactions with the host genome.- 5. Structure and functions of adenovirus 5 transformation genes.- 6. Plant tumours caused by bacterial plasmids: crown gall.- 7. Histocompatibility genes and neoplasia.

The exact cause of cancer is not known, but considerable evidence has been accumulated in favour of the somatic mutation hypothesis. This means that a genetic change in somatic cells is thought to be the initiating event in the origin of cancer. Both environmental and constitutional factors are involved in the origin of cancer. It has been estimated that 80 percent of human cancer is determined by the environment via ionizing radiation, ultraviolet light, chemical carcinogens and dietary factors. This hypothesis is supported by the finding of large geographic differences in the frequency of certain tumour types. The convenient term for the sum of these factors is ‘life style’.

The detection of a liver metastasis means a poor prognosis for any cancer patient. The consequences of diagnostic procedures should therefore be carefully considered before any attempt at screening is made.

Major histocompatibility complex is a set of closely linked genes controlling cell surface antigens, immune response, and complement activity. MHC was found in every vertebrate species which was sufficiently studied and it is involved in a number of biological processes including defence against viral infections. We discuss the structure and function of the major products of the MHC and list a number of other functions of the MHC of the mouse (H-2) and of man (HLA).

Most orbital tumours will be treated by surgery or radiotherapy. Only a few tumours will metastasize and as a consequence be considered for chemotherapy. Medical oncologists therefore have a limited experience in the treatment of such tumours. This is a good reason to concentrate patients with orbital tumours in centres, where surgeons, radiotherapists, pathologists and medical oncologists can combine their efforts to provide optimal treatment. A similar situation exists for several other rare tumours, where the multidisciplinary approach has led to better results.

Future scenarios on cancer in The Netherlands were made with the help of existing trends, demographic changes and expected developments in cancer research, prevention, screening and treatment. Until the year 2000, cancer incidence will probably increase by 1.5% per year, by nearly 3% per year and the need for health care facilities accordingly. Upon the request of Parliament, the Dutch government used this information to formulate a long-term cancer control policy. Faced with a restricted budget and a growing demand for care, the government plans to increase its efforts in the areas of prevention and screening and to improve the efficiency of cancer care. More attention will be paid to the quality of life of those patients who cannot be cured. Support for cancer research will be maintained at its present level.

Cell suspensions prepared from lymph nodes, spleen or peripheral blood of patients with non-Hodgkin's lymphoma (NHL) often contain a high percentage of residual nonmalignant cellular elements. By E-rosette sedimentation, it was possible to enrich such suspensions from patients with various types of lymphoma for malignant cells. In patients with a B- or non-B/non-T-cell lymphoma, the neoplastic cells were found in the non-T fraction. The capacity to respond to stimulation by various stimuli was then confined to the T-cell fraction, which contained the residual normal T-cells. In patients with T-cell lymphomas, in which the malignant cells had retained the capacity to form E-rosettes, lymphoma cells were found in the T fraction. These cells usually did not respond to mitogenic stimuli. Using this separation method, small proportions of neoplastic cells could be identified in mixed cell populations. Thus, in the blood from nine out of 23 lymphoma patients without abnormalities in routine blood tests, a population of abnormal cells was detected after cell separation. This included a monoclonal B-cell population in the blood of four patients, a questionably monoclonal B-cell population in the blood of two patients and in increased non-B/non-T cell population in the blood of three patients.

Samples of 37 fresh human ovarian tumor biopsies were screened to detect proto-oncogene amplification and ras mutations. Three samples showed c-K-ras2 amplification; none of the other oncogenes tested revealed any gene amplification. 5-, 25-, and 120-fold amplifications were assessed by dilution experiments and soft laser densitometry. Corresponding elevated levels of c-K-ras2 mRNA and p21 ras protein were found in the three tumors. Analysis by the polymerase chain reaction method to detect point mutations of codon 12 or codon 61 of Harvey-, Kirsten-, or N-ras showed only the wildtype sequence in all specimens. No correlation was found between ras activation and degree of tumor progression or histological subtype. DNA from one of the tumors with c-K-ras2 amplification proved to have high transforming activity in the NIH 3T3 tumorigenicity assay, but the transforming gene was not c-K-ras2.

The epidemiology of cancer is reviewed with particular emphasis on the geographic variations in the incidence of certain types of cancer. Several new developments in the prevention and treatment of cancer are discussed. The main advance in the results of treatment is due to chemotherapy, preferably in conjunction with radiotherapy and surgery. Much is expected of this procedure for the future.

SummaryVindesine, desacetyl vinblastine amide sulfate (DVA) is a new semi-synthetic Vinca alkaloid. Thirty heavily pretreated patients, 17 with breast cancer, 3 with testicular teratoma and 10 with a non-Hodgkin lymphoma received 3 mg DVA/m2 i. v. every week for 6 weeks and biweekly thereafter. All had been treated with Vinca alkaloids before, vincristine in the breast cancer and non-Hodgkin lymphoma patients, vinblastine in the testicular teratoma patients.Trial was considered adequate if more than 3 weekly cycles were given. Neurotoxicity was seen in 20 patients, varying from muscle weakness to severe paresthesias (14 patients) and paralytic ileus (1 patient). Mucositis was encountered in 5 patients, nausea in 6. Leukopenia was not a severe side effect, only 1 patient had a WBC below 1500/ccm. One patient developed a macular skin rash, and three ran a fever.No response was found in the teratoma patients. Two partial remissions (PR) were seen in the 17 breast cancer patients and 1 complete remission, and 1 PR in the non-Hodgkin lymphoma patients.According to the literature, previous treatment with Vinca alkaloids seems to influence response to DVA negatively in breast cancer but not in non-Hodgkin lymphoma patients. The study is to be continued in non-Hodgkin lymphoma.

Approximately 1/3 of all mammary carcinomas are hormone-dependent. Therefore in approximately 30% of these cancer patients transient regression of the tumor may be obtained by means of endocrine therapy. Ablative procedures such as ovariectomy, adrenalectomy, hypophysectomy, roentgen castration, and destruction of the hypophysis by isotope implantation have been used. Administration of such hormones as estrogens, androgens, and corticosteroids and of hormone antagonists have been attempted. Remissions have been observed under the influence of L-dopa. A method to determine the hormone dependency of a mammary tumor is now available. The presence of estrogen receptors in human mammary carcinomas has a distinct correlation with the response to adrenalectomy. In the absence of receptors the chance of success of hormone therapy is minimal. Currently 51 patients have been found suitable for analysis. Remissions occurred in 21 of 24 patients with receptor-positive tumors but in only 3 of 27 with receptor-negative tumors. It was noted that those with cutaneous metastases more often respond favorably to endorcrine therapy than do those with skeletal or visceral metastases. No complete parallelism was found between hormone dependency and the presence of receptors. In 2 of the 3 receptor-positive patients who did not show an objective remission, a distinct subjective remission was noted. It is recommended that receptor determinations be done in every mammary tumor case operated on in the primary stage.

In the last ten years more refined procedures in blood-group immunology and blood banking have enabled us to treat more patients with refractory anaemia over a prolonged period. Multiple transfusions, however, inevitably burden the body with large amounts of iron, and clinical manifestations of iron overload are observed with increasing frequency. While the clinical signs and the histological features of transfusional iron overload may vary considerably from one patient to another, it is apparent that the deposition of excessive amounts of iron in the cells may in some instances be associated with tissue damage and impairment of organ function. The exact pathogenesis of this acquired condition has not yet been clarified, and it is difficult to understand why some individuals appear to be more susceptible than others.