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Fifty-one adults with acute lymphoblastic leukaemia were entered into a trial of intense initial chemotherapy and early "prophylaxis" of the central nervous system (CNS). Initial treatment with OPAL (Oncovin (vincristine), prednisolone, adriamycin (doxorubicin), and L-asparaginase (colaspase)) followed by craniospinal or cranial irradiation and intrathecal methotrexate produced remission in 36 patients (71%). Seventeen of these patients relapsed three to 18 months after the start of remission; the remainder had been in remission for 12 to 52 months by the end of the study. The predicted median duration of complete remission was 18.5 months. None of the four patients who initially had clinical evidence of CNS disease, three of whom also had leukaemic cells identical to those found in Burkitt's lymphoma, achieved remission. Those patients who initially had hepatomegaly or splenomegaly had a shorter remission than those without. The predicted median survival was 27 months in those who achieved complete remission, one month in those who did not, and 21 months overall. The addition of colaspase and doxorubicin to vincristine and prednisolone and the use of early CNS treatment clearly improved the remission rate among adults with acute lymphoblastic leukaemia, though the presence and length of remission was affected by the extent of disease at presentation. Burkitt-like leukaemia, which had a poor prognosis, is probably a separate disease and may benefit from a different therapeutic approach.

Cytotoxic chemotherapy does not yet have a service role in the management of invasive carcinoma of the bladder, though the minor palliation achievable in patients with symptomatic recurrent primary or metastatic disease does justify its use in patients whose symptoms are not controlled by standard analgesia. For the future, progress will depend on more intense screening of new drugs in centres specializing in undertaking Phase 2 Trials on patients with measurable metastases. However, there is in addition a need for studies measuring primary tumour response to drugs in combination with radiotherapy which still remains the most active single agent in the non-surgical treatment of carcinoma of the bladder.

A group of 29 patients underwent salvage node dissection for residual retroperitoneal masses following orchiectomy and combination chemotherapy for advanced testicular cancer between 1980 and 1988. The results confirm that surgery for residual retroperitoneal masses following combination chemotherapy is worthwhile and whenever possible the sympathetic chain should be preserved.

HLA typing has been performed on a selected series of 29 patients with nasal polyps, with or without asthma. Despite the small series there was a significant incease in the haplotype AI/B8 in patients with both nasal polyps and asthma. No association was found in those with polyps alone. However, those with both conditions, who were positive for AI/B8, had more severe polyp disease. Three out of 4 patients with nasal polyps, asthma and sensitivity to aspirin were positive for AI/B8. In patients with nasal polyps, tissue typing sensitivity to aspirin were positive for AI/B8. In patients with nasal polyps, tissue typing might be of use in predicting both those who are most at risk of developing asthma, and also those who are most likely to have severe polyp disease. The association of AI/B8 with severe polyp disease and asthma, may imply that abnormalities of immune response are likely to be associated with the pathogenesis of both conditions.

The serum expression of the tumour markers hydroxybutyric dehydrogenase (HBD), beta human chorionic gonadotrophin (beta HCG), alphafetoprotein (alpha FP) and placental alkaline phosphatase (PLAP) has been assessed in a consecutive series of 50 patients with pure seminoma. In pre-orchiectomy sera from 15 patients with stage I disease, HBD was elevated in 5, beta HCG in 3, alpha FP in 1 and PLAP in 1 (of 3 only). In 27 patients with stage 2 or 3 disease, prior to chemotherapy, serum HBD was elevated in 19, beta HCG in 11, alpha FP in 2 and PLAP in 10 (of 18). The presence of beta HCG was investigated immunocytochemically in primary tumour tissue from 39 patients. It was demonstrated in 6 of 21 tumours from patients with stage I disease and 5 of 18 with stage 2 or 3 disease.

A phase II study of methotrexate (MTX) treatment of recurrent primary invasive tumors of the bladder is reported. The incidence of measurable response is lower than that seen when the drug is used to treat patients with metastatic disease. However, the overall response achieved when durable symptomatic responses are included, and the absence of major side effects, establishes this drug as a good palliative treatment. Results from a pilot study giving MTX prior to radiotherapy demonstrate that it is possible to combine the two treatments without increasing toxicity. The early results from this study were better than a previously treated historical control series and justify evaluation of adjuvant chemotherapy with MTX in a prospectively randomized trial.

We report a case of bladder cancer developing in a patient after renal transplantation in whom it was possible to demonstrate DNA evidence for infection of the tumour with HPV Type 11. The significance of the observation is discussed in relation to the hypothesis that immunosurveillance can control the development of malignancy.

Retroperitoneal lymph-node dissection or radiotherapy have long been known to provide equivalent survival for early stage I and stage II nonseminomatous germ-cell tumors. Review of the results from intensive radiological and biochemical surveillance with salvage chemotherapy for stage I tumors demonstrates that the long-term survival rate is equivalent to that achievable by conventional treatment (i.e., 98 per cent survival at 4 years). As relapses have continued to occur in the third and fourth years at the rate of 4 per cent annually, and 4 years is the limit of follow-up, further follow-up is required to be sure of the long-term picture. Prognostic factor analysis demonstrates that venous and lymphatic invasion, the absence of yolk sac differentiation, and the presence of undifferentiated cells are independently important in predicting the frequency of relapse. Using these factors, it was possible to define low-risk groups with relapse rates less than that seen after lymph-node dissection and high-risk groups with 58 per cent frequency of relapse who probably are suitable for adjuvant chemotherapy studies. Review of the results from the use of surveillance in stage I seminoma demonstrated no advantages over prophylactic radiotherapy. However, late toxicity is being demonstrated after radiotherapy and evidence is emerging that the less toxic cisplatinum analogue carboplatin may be as good as radiotherapy for metastatic disease. This offers for the first time a viable alternative to radiotherapy for consideration in the adjuvant setting in stage I seminoma.

A study of the effects of human leukocyte and lymphoblastoid interferon preparation on the growth of normal, immune and malignant haemopoietic cells has been carried out. At a standard dose of 10,000 U/ml, incorporation of tritiated thymidine ([3H] TdR) was reduced by 7-92% of control values, and cell survival by 35-82% in acute myelogenous leukaemia cell cultures, whereas in normal bone-marrow cultures interferon showed a 58-62% reduction in [3H] TdR uptake but only up to 13% reduction in cell survival. [3H] TdR incorporation by MLC-stimulated lymphocytes was also significantly reduced by interferon but the blastogenic response to PHA was not. These effects of interferon were shown to be dose-dependent. The problems of using interferon in the treatment of AML in the light of these findings are discussed.

Treatment of a series of 194 patients with T3 (B2/C) tumors by radical radiotherapy, 5,000 to 5,500 rad in four weeks, produced a five-year survival of 40 per cent. Patients whose tumor completely disappeared after treatment (N = 97) had a five-year survival of 69 per cent. These results raise doubts about the necessity of performing elective cystectomy in patients who achieve complete response after radiotherapy, though the significantly better survival of partial responders who underwent salvage cystectomy emphasizes the need for an active policy of cystectomy once failure to respond completely to radiotherapy has been established and a need for techniques to give early indication of nonresponse to radiotherapy.

Peripheral blood leukocytes from 31 out of 48 patients with acute myelogenous leukemia grew in short-term liquid culture. Two distinct types of growth occurred. The first type was dimorphic with supernatant free-floating ("non-sticker") cells and, in addition, a plastic/glass adherent, trypsin resistant, phagocytic population ("stickers"). The second type which occurred less frequently than the first consisted almost entirely of free-floating "non-sticker" cells. Although patients with this second type of growth pattern almost invariably had AML, 44% of AML's produced monocytoid "sticker" cells in culture. Cells from the majority of patients with ALL did not grow in culture.

Fifteen patients with measurable metastatic transitional cell bladder cancer were treated with VP 16-213 100 mg/m2 IV daily for 4 days, repeated every 3 weeks. There were no complete or partial (greater than 50% reduction in area, maintained for 6 weeks) responses. Two patients showed transient reduction by 50% in the area of measurable lesions, and a further five patients showed brief stabilisation of previously progressive disease. The treatment was well tolerated. In two patients, total WBC at the nadir fell below 1.0 X 10(9)/l but without complications from infection. We conclude that VP 16-213 is inactive in metastatic transitional cell urothelial cancer.

259 patients with stage I non-seminomatous germ-cell testicular teratoma who were treated by orchidectomy alone and monitored at one often centres in the United Kingdom were followed for a median of 30 months. 62 of the 70 relapses occurred in the first 18 months after orchidectomy. The 2-year relapse-free rate was 74%, falling to 68% at 4 years. Histological sections from 233 of the orchidectomy specimens were reviewed centrally. Four features independently predicted relapses: invasion of testicular veins, invasion of testicular lymphatics, absence of yolk-sac elements, and presence of undifferentiated tumour. An index, based on the number of these features observed, identified a high-risk subgroup of 55 patients who had a 42% relapse-free rate at 2 years.

Results in a series of 60 patients with recurrent or metastatic transitional cell carcinoma of the bladder confirm that methotrexate is active as a single agent. Over-all, 43 per cent of the patients with measurable metastases and 28 per cent with recurrent primary tumors responded for an average of 6 months. Response rates in both groups were influenced by the stage of the primary tumor.

Analysis of patients with germ cell tumours of the testis treated at the London Hospital during the last 30 years has shown that the incidence of pure seminoma has fallen from 69 to 39%. Coincident with this, the incidence of patients with metastases detectable at presentation in all other types of germ cell tumour has increased from 19 to 62%. These observations may explain why the relapse rate of the most recently treated patients with Stage 1 malignant teratoma was the same whether or not they received prophylactic radiotherapy and substantially less than that reported in the literature 30 years ago for orchiectomy alone. These changes justify the use of a surveillance policy for Stage 1 tumour in studies by specialist centres.

Leucocyte suspensions from some cases of acute myelogenous leukaemia produced large numbers of macrophages when cultured in vitro. The macrophages increased steadily in number during the first 1-2 wk of culture. The increase was partly derived from division of the macrophages themselves, partly from augmentation from supernatant cells not adherent to the surface of the culture flask. This augmentation occurred mostly in the first 24 hr of culture. The leukaemic macrophages had many features of normal macrophages as regards light microscopy, surface receptors, phagocytic activity and cytochemistry. Under the electron microscope, however, they had many abnormal characteristics, all of which have been recorded previously as features of malignant transformation. Cultures containing the abnormal macrophages and their precursor cells caused local solid tumours when injected into immune-deprived mice. The tumours were composed of rather uniform cells many of which resembled neoplastic reticulum cells. It is concluded that human leukaemic monocytes or promonocytes can develop into macrophages with ultrastructural features of malignancy. This appears to be the first demonstration of the development of neoplastic macrophages. It is suggested that some lymph node tumours of man may be composed of similar neoplastic macrophages and their precursor cells.

Nucleated cells other than sperm (NCOS) were isolated from human semen by centrifugation on a Ficoll density gradient. Using tissue-specific monoclonal antibodies (mAb) greater than 99% of the NCOS were found to be sperm cell precursors (SpP). These cells were tested for the expression of class I and II (DR, DP and DQ) HLA antigens by using specific mAb. The anti-HLA class I and II and anti-beta 2-microglobulin mAb reacted with less than 1% of the NCOS. This was demonstrated by indirect immunofluorescence microscopy and fluorescence-activated cell sorter analysis. These results were similar to those obtained from testing germ cells in frozen sections of normal adult testis using the same panel of mAb. In mixed lymphocyte-NCOS cultures, the SpP failed to stimulate allogeneic lymphocytes even when different concentrations of cells were used. These results indicate little or no expression of HLA class I and II including the HLA-D (T cell-defined) determinant on the SpP, a phenomenon which could be of biological importance.

Leukaemia cells were collected from the blood of 72 untreated patients using a continuous-flow blood cell separator. The yield of cells was proportional to the number circulating in the patient, and up to 1 x 10(12) could be obtained in three hours. Complications of the procedure were mild, consisting of chills and shivering in 18% of patients. Leucopheresis at the time of diagnosis is an essential part of setting up a specific immunotherapy programme for patients with acute myelogenous leukaemia, and the lack of harmful side effects makes the collection of these cells ethically justified. The need for a centralized service to provide cells for this form of therapy is emphasized.

Following preliminary studies suggesting that some patients with metastatic renal cell carcinoma had accelerated tumor growth after entry into chemotherapy studies, 73 patients with measurable metastatic disease referred to a tertiary referral center for consideration for experimental treatment protocol have been observed to attempt to establish the incidence of spontaneous regression. Initially, patients went off study if metastases showed greater than 25% increase in products of bidimensional measurement but with increasing confidence patients only went into therapy protocols with the development of symptomatic progression. In this selective series, on observation, three complete (histologically documented) and two partial unexplained "spontaneous" regressions were observed and a further four patients had prolonged stable disease for more than 12 months. On progression, 52 were entered into treatment protocols (BCG n = 19, Mitozantrone n = 12, and Welferon n = 21). A further two complete and five partial responses (14%) and four prolonged stable disease were observed confirming that the previously reported responses with these agents are not totally explicable on the basis of "spontaneous" response.

Expression of beta human chorionic gonadotropin (beta hCG) by bladder tumours has been shown to be associated with increased metastases and resistance to treatment with radiotherapy and chemotherapy. Preliminary results from typing frozen tumours using monoclonal antibodies against HLA determinants show reduced or lost expression of one or more antigens in two thirds of patients studied with a trend for more malignant behaviour and inability to generate tumour infiltrating lymphocyte expression using Interleukin-2 in those patients whose tumours demonstrate loss. In this series beta hCG expression was only seen in a subgroup of those demonstrating loss of HLA antigen expression. Studies of beta hCG secreting bladder cancer cell lines showed that it was possible to induce class II HLA antigen expression with gamma Interferon, and that this treatment but not alpha Interferon reduced beta hCG production by the cell line.

Immunocytochemical screening of bladder tumors with an antibody to beta-human chorionic gonadotrophin (hCG) demonstrates a correlation with malignant behavior in that 0 of 20 G1M0, 5 of 20 G3M0, and 11 of 20 G2/3M + showed strong staining, while only 2/20 G3 Ca prostate and 0/18 renal cell carcinoma showed weak staining. There was a suggestion that hCG positive bladder cancer responded less well to chemotherapy (1 of 12 hCG positive and 6 of 13 hCG negative patients achieved a complete or partial response) and also patients whose tumors showed strong hCG staining did less well after radiotherapy, though paradoxically patients showing only occasional stained cells did better than patients whose tumor showed no staining. The possible significance of these observations in relation to recent observations on the mechanisms of trophoblast escape from immune surveillance is discussed.

A monoclonal antibody (H17E2) against placental alkaline phosphatase (PLAP) and testicular placental-like alkaline phosphatase was labelled with indium-111 and used in radioimmunoscintigraphy of 15 patients known or suspected to have germ-cell carcinoma of the testis or carcinoma of the ovary or cervix. Good images of neoplastic lesions were obtained in most patients with active disease. In 1 patient with testicular teratoma and elevated human chorionic gonadotropin who had a normal computed tomography scan, the labelled antibody located microscopic disease in a lymph node, which was then removed. No false positive localisation was seen in patients with PLAP-negative tumours or sites of inflammation. This method may be helpful in the diagnosis, staging, and monitoring of PLAP-positive neoplasms of testicular, ovarian, and cervical origin.

Severe neurological complications (either peripheral neuropathy, subacute combined degeneration of the cord or cerebral changes) are a characteristic feature in some patients with marked vitamin B12 deficiency. Although Addisonian pernicious anaemia (PA) is the major cause of this neurological syndrome, the disorder has been described in association with other conditions in which there is a profound depletion of vitamin B12 stores. Sixteen patients with vitamin B12 neuromyelopathy, associated with PA, have been HLA-typed for 27 alleles of the A and B loci and compared with 53 cases of PA without neurological damage and 60 controls of the same ethnic group. There is a significantly increased frequency of the HLA phenotype. A12;B12 (44% instead of 4% in PA patients without neurological damage) in the disease group studied (P less than 0.0005). The signficance of these findings in relation to the pathogenesis of vitamin B12 neuromyelopathy is discussed.

A series of 73 patients with measurable metastatic disease referred to a tertiary referral centre for consideration for an experimental treatment protocol were entered into a surveillance protocol in order to establish the incidence of spontaneous regression. Initially, patients were taken off the study if metastases showed greater than 25% increase in products of bidimensional measurement but with increasing confidence patients went into therapy protocols only following the development of symptomatic progression. We observed 3 complete and 2 partial unexplained spontaneous regressions and a further 4 patients had prolonged stable disease for more than 12 months. A group of 21 patients on progression subsequently received treatment with alpha-interferon (Wellferon) as part of a multicentre study which included an additional 61 cases; 12 responded (3 surveillance relapse patients and 9 others). Patients with lung metastases only had the highest response rate (10/17 compared with 5 unexplained responses seen in 38 such patients on surveillance). These results confirm that alpha-interferon is active against metastatic renal carcinoma and that the responses are not totally explicable by spontaneous regression.

In Caucasoids the third locus antigen Hu (FJH or T-2) shows a 91% association with W27 and W10. Less than 10% of the Hu positive cells had an unknown antigen at the second locus. In a Negroid population from Zambia studied with 1972 Workshop data W27 was absent and W10 present in low frequency. Hu in contrast was present with twice the frequency seen in Caucasoids. Eighty-six % of positive cells had an unknown antigen at the second locus. Data from the use of platelet complement fixing sera suggests that this unknown allele was Da(6), an antigen present in very low frequency in Caucasoids. Recombination between second and third locus alleles has been proposed as an explanation for these associations. Associations of HL-A12 and Hu with 4a, W5 with 4b in Caucasoids and vice versa in the Negroids was demonstrated, and the possibility that this finding may be an indication of recombination between a separate 4a/4b locus and the second and third loci was discussed.

The iridium mould technique was used as the method of choice whenever possible in a series of 80 cases of cancer of the penis. When the growth was confined to the glans penis the survival rate was 89% but local recurrence called for subsequent amputation in 22%. When tumour had invaded the corpus cavernosum, irradiation improved the survival rate but amputation was required in 75 to 80%. Prognosis correlated well with histology, patients with a "cord" pattern having the worst prognosis.

Analysis of 101 patients with germ cell tumours of the testis who have been typed for HLA DR antigens has provided confirmatory evidence for an association of DR5 with the development of seminoma and demonstrated an association of DR7 with metastases. These observations taken with the suggestion of HLA linkage in the small numbers of familial cases reviewed, does suggest that there is an HLA linked gene involved in the clinicopathological behaviour of germ cell tumours. Though of only theoretical interest at present these observations may be of considerable importance in the future given the observation in mice that transfection of missing MHC genes into a malignant tumour can produce a vaccine that enables previously unexposed animals to resist the original malignant tumour (Hui et al., 1984).

In nonmalignant disease, there have been two mechanisms implicated in the association of HLA antigens with disease. In ankylosing spondylitis, evidence is accumulating for cross tolerance between a bacterial antigen and the HLA-B27 antigen; while in the autoimmune diseases, the involvement of an abnormal immune response gene, associated with A1/B8 haplotype, is strongly suspected. The same haplotype has also been associated with recovery from hepatitis B infection and survival of patients with Hodgkin's disease and acute myeloid leukaemia. At present, there are no techniques to study directly immune response genes in man and so these observations are still strictly academic. However, with increasing interest in the use of immunotherapy in cancer and the demonstration in mice that the major histocompatibility system may be the site of action of soluble mediators of immune memory, understanding the mechanisms of action of the HLA associated resistance factors may enable a more rational approach to immunotherapy in man.

A review of 78 previously untreated patients with bidimensionally measurable metastatic bladder cancer who were entered into a series of studies of cytotoxic chemotherapy has shown that complete response occurred in 1 of 23 patients receiving methotrexate, none of 15 receiving cisplatin, none of 20 receiving the platinum analogue carboplatin and 3 (2 with histological confirmation) of 20 receiving methotrexate in combination with cisplatin. WHO/UICC performance status 3 and 4, though a prediction of lower response, did not provide a means for excluding patients who might benefit from chemotherapy. Studies using serial cytology showed that 5 of 8 responders according to standard criteria had complete loss of malignant cells from the urine compared with none of 10 non-responders and there was a suggestion that duration of response was longer in those whose urine was negative for malignant cells than in those which remained positive.

Prompted by recent reports of the increasing incidence of late relapses in Stage 1 patients with both malignant teratoma and seminoma on surveillance, a low toxicity regimen combining etoposide, bleomycin and cisplatin [EBCi(3)] with prolonged infusion of bleomycin, given daily for 3 days, has been developed for possible use as adjuvant treatment. Forty of 44 patients treated remain free of disease with a median follow-up of 21 months and actuarial disease free survival at 2 years of 91%. There have been no respiratory problems attributable to bleomycin lung toxicity in this study compared with four (3 associated with patient deaths) seen in 91 previously treated patients. The relatively low toxicity and high efficacy of this regime indicate that it may be suitable as adjuvant treatment.

Improved definition of seminoma using step sections and tumour markers makes such patients a more selected group than when radiotherapy was first introduced. This and the improvements in radiological staging and the exquisite sensitivity of metastatic seminoma to chemotherapy justifies reappraisal of the role of prophylactic radiotherapy. To investigate this, twenty-six patients have been entered onto a programme of prospective biochemical and radiological surveillance. Though only four (15%) have relapsed, and all easily salvaged by chemotherapy, the relative difficulty and lateness of establishing the diagnosis makes this approach unsuitable for service use. Whether given the chemosensitivity of seminomas, radiotherapy would remain the treatment of choice compared to short courses of adjuvant carboplatin requires testing in a randomized trial.