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Biopsies of 13 penile cancers (PC), from patients living in regions of Uganda with a high incidence of genital cancers, were studied for the presence, molecular characteristics and physical state of DNA related to that of human papillomavirus (HPV) types 6, 11, 16, 18, 31 and 33. HPV DNA sequences were detected in all PC specimens by dot/Southern blot analyses and by gene amplification of DNA sequences highly conserved among several HPVs. HPV 16 DNA sequences were found in one PC; DNA sequences with low homology to HPV16 or HPV18 were present in all other samples. Viral DNA is primarily integrated in the cellular DNA. To isolate and characterize a possible highly oncogenic HPV, a genomic library of the DNA extracted from the PC-8 biopsy has been constructed in the EcoRI arms of the EMBL4 phage. A single phage containing 8.30-kb HPV16-related sequences has been identified and the 3 segments of 0.45, 0.65 and 7.2 kb, released by EcoRI digestion, have been independently subcloned in pUC18 for further analysis.

The need for the postgraduate training of medical practitioners in the environment in which they will eventually work is well recognized, and in 1967 it was felt that the University of East Africa had reached sufficient maturity to undertake postgraduate instruction and certification in medicine. This paper describes the evolution and the present structure of the MMed (Surgery) degree at Makerere.

A case of Kaposi's sarcoma involving the brain is described, this being the first of its kind in Uganda. The patient was a 40-year-old woman who presented with a 2-year history of skin tumors on the left ankle that proved resistant to chemotherapy. She therefore underwent an above-knee amputation. Six months after amputation, she developed signs of cerebral involvement, and 6 weeks later she died. Necropsy showed large tumor deposits in bone and lungs as well as in the brain. Histologically the cutaneous tumors consisted of the monomorphic variety, whereas the cerebral and other deposits were anaplastic. In the three cases of cerebral Kaposi's sarcoma hitherto reported from other countries, only minute foci of tumor were found in the brain.

Sera from patients with Kaposi's sarcoma (KS) were examined for antibody titres to cytomegalovirus (CMV), Epstein-Barr virus (EBV) and herpes simplex virus (HSV) types 1 and 2 by four techniques: indirect haemagglutination (IHA), complement fixation (CF), virus neutralization (NT) and indirect immunofluorescence (IF). The patients were classified, according to the stage of disease, as progressive and regressive. Control sera were obtained from healthy adults, matched for age, sex, race, socioeconomic status and geographic location, as well as from patients with melanoma, some of whom were receiving chemotherapy similar to that given to the KS patients. All KS sera contained CMV-neutralizing antibodies. Seventy-five percent of the European KS patients, mainly regressors, showed elevated anti-CMV titres by IHA with a significant increase in the geometric mean over the corresponding healthy adult group and the melanoma group. An overrepresentation of high anti-CMV titres, although less marked, was found by CF. There was no significant association with antibodies to EBV, HSV-1 and HSV-2 related antigens. By contrast, the African KS patients, mainly progressors, did not show a serologic association with CMV or with EBV and HSV-1 and 2. The implication of these results is discussed.

A cell line of penile cancer from a 60-year-old Ugandan black patient has been studied by the authors. Transmission and scanning electron microscopy showed a large number of blebs and microvilli at cell surface; desmosomes were evident at TEM. Cytogenetic investigation (R-, C-, Nor-banding) showed the frequent presence of some markers: del(1p),del(1q),iso(3q),der(4),del(8p),11q+, t rob(13;14), 14p+, t rob(21;21). The epidemiology, geographical distribution, and aetiological role of human papilloma virus type 16 and herpes simplex type 2 are discussed.

In a Phase II clinical trial, 14 patients with histologically proven primary hepatocellular carcinoma were treated with adriamycin administered intravenously at a dose of 75 mg/m2 every 3 weeks. All 11 evaluable patients responded with 3 exhibiting complete tumor regression after two, three, and five courses of adriamycin respectively. The remission durations for these 3 were 3, 6, and 7 months, and their survivals were 8, 9, and 13 months, respectively. The median survival of the evaluable patients is 8 months (range 1-13 months). The side effects encountered included myelosuppression, anorexia, nausea, vomiting, and alopecia. Adriamycin seems to be an effective agent in hepatocellular carcinoma. Further trials are underway to test its true efficacy both singly and in combination with other drugs in the management of this tumor.

Previous studies have established an association between cytomegalovirus (CMV) and classic and endemic Kaposi's sarcoma (KS) which can be extended to include the epidemic form of KS. The identification of nucleic acid sequences homologous to CMV but not to Epstein-Barr virus (EBV) and Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) as well as the detection of CMV gene products, particularly early antigens, in tumour biopsies and/or early cultures derived from them is an important criterion in the establishment of the type of association. Detection of CMV early antigens but not late antigens as well as the failure to demonstrate virus particles in primary tumour biopsies rule out a simple passenger role of this virus or a preferential site for virus replication in neoplastic tissue. In the setting of a profound immune dysfunction, as in the case of acquired immune deficiency syndrome (AIDS), renal transplant recipients under immunosuppressive therapy, and other iatrogenically immunosuppressed patients (the three groups in which KS has been most frequently observed), the specific involvement of CMV oncogenes, of which at least two have been so far identified in experimental systems, is strongly indicated. Moreover, in vitro transformation experiments indicate that the virus is clearly involved in the initiation of transformation, while other factors (co-carcinogens, activation of cellular oncogenes?) might be required for the maintenance of the transformed phenotype. Endothelial cells, permissive for CMV infection, might be the prime target for these events, since there is evidence that they are a main constituent of KS tissue. Data obtained during 14 years of research on KS are reviewed and possible etiopathogenetic mechanisms giving rise to this type of tumour are discussed.

A staging scheme for hepatocellular carcinoma was presented at an International Symposium on Liver Cancer in Kampala, Uganda in 1971. Historical, clinical, and laboratory aspects of that staging scheme were examined for prognostic significance in 72 untreated patients with this disease studied at the Uganda Cancer Institute. The median survival for the entire group was 1 month. The presence of a serum bilirubin concentration of greater than 2 mg/100 ml or weight loss greater than 25 percent of body weight were the poorest prognostic features. Other factors with prognostic significance were visible abdominal collateral circulation, ascites, tumor differentiation, and serum levels of alkaline phosphatase, SGOT, alpha fetoprotein, and proline hydroxylase. A modified staging scheme is presented which defines three prognostically different groups of Ugandan patients. It is hoped this staging scheme will serve as a stimulus for analysis of similar prognostic features in other populations of patients with hepatocellular carcinoma.

In attempts to encompass multiple events responsible for the development of cancer in man, with a particular interest to the possible involvement of viruses, multidisciplinary studies have been conducted on KS during 1971-1979. There is accumulating evidence associating this malignancy with CMV. African KS patients have high antibody titers to CMV, but they are not significantly different from controls of the same regions (Ag-Ab complexes?). A specific serologic association of European and American KS with CMV was established. CMV-related antigens can be demonstrated in 22% of tumor biopsies and comparably in early passages of cell culture derived from them. Recently, CMV-DNA sequences have been detected in tumor biopsies. Furthermore, a CMV, strain K9V, has been isolated in tissue culture from a KS culture. Cells infected in vitro with K9V have shown some of the characteristics of cells transformed previously by other oncogenic CMV strains. In vivo K9V has induced a fatal disease in old world monkeys, mainly involving the lymphoid system. Moreover, a cluster type of occurrence of KS was detected in the West Nile District of Uganda, an area with as high incidence of KS as BL; and finally, there is a significantly higher incidence of a second primary tumor in KS patients, particularly of the lymphoreticular system. Whether CMV plays a role in the development of KS, a complex neoplasia which involves different cell types cannot be claimed by these results only. However, similarities between CMV and EBV, the latter being closely associated with BL and nasopharyngeal carcinoma are worthy of consideration.

The presence of circulating alpha-interferon and neopterin was investigated in sera of 47 patients affected by African Kaposi's sarcoma, both HIV-seropositive (13 patients) and HIV-seronegative (34 patients). For comparison, analyses were also performed in 20 HIV-seropositive symptomatic African subjects as well as in 20 African and 20 Italian healthy individuals. Alpha-interferon and neopterin levels appeared significantly higher in comparison with healthy control groups (P less than 0.001) but not with HIV-seropositve African individuals without Kaposi's sarcoma. Moreover, alpha-interferon and neopterin levels were significantly higher in progressive Kaposi's sarcoma (27 patients) than in regressive Kaposi's sarcoma (20 patients) (P less than 0.001). A significant correlation between alpha-interferon and neopterin was observed (r = 0.57; P less than 0.01). Furthermore, alpha-interferon levels of HIV-seropositive Kaposi's sarcoma patients resulted significantly higher in comparison with the seronegative ones (P less than 0.05). It is concluded that alpha-interferon and neopterin may be reliable prognostic markers in Kaposi's sarcoma patients.

In order to determine whether human cytomegalovirus- (CMV) DNA homologous sequences as well as CMV-specific RNA(s) and antigen(s) exist in tumor biopsies of Kaposi's sarcoma (KS) DNA-DNA reassociation, RNA-DNA in situ cytohybridization and anticomplement immunofluorescence test (ACIF) tests were applied. Three of 10 DNAs extracted from Kaposi sarcoma biopsies contained DNA sequences homologous to radioactively labelled human CMV DNA probe. The amount of CMV DNA in these sarcoma tissues was calculated to range from 0.7 to 1 genome equivalent per diploid cell. The presence of virus-specific RNA was also demonstrated in section from five of 10 tumor biopsies. CMV-determined nuclear antigen(s) CMNA) present in variable degrees were also demonstrated. In contrast, we could not detect any herpes simple virus type II (HSV-2) or Epstein-Barr virus (EBV) DNA sequences in DNA of these tumor biopsies. Furthermore, there were no detectable HSV-2 or EBV-specific RNA or virus-specific antigens in sections of these biopsies. These results provide new lines of evidence for the relationship between CMV and Kaposi's sarcoma.

One hundred and thirty nine patients with histologically proven hepatocellular carcinoma (HC) were admitted to the Uganda Cancer Institute for treatment. The patients were considerably younger and seemed to have more advanced disease than HC patients in Europe and in North America. Of the 99 evaluable patients, 50 received Adriamycin intravenously; of these, 44% responded, with 10% achieving complete responses. Intraarterial Adriamycin tended to increase the response rate to 75%, but this may be merely a reflection of patient selection. Combination of Adriamycin with other drugs (dichloromethotrexate, 5-azacytidine, Rezoxane and cyclophosphamide) did not enhance its therapeutic effectiveness. The alphafetoprotein response curves observed when Adriamycin was combined with dichloromethotrexate suggested possible antagonisms between the two drugs. Hepatic artery ligation (HAL) is a good and simple palliative procedure with response rates similar to i.v. Adriamycin. However, the administration of Adriamycin after HAL tended to improve on response rates and survival. The toxicities observed were mainly myelosuppression, gastrointestinal disturbance, alopecia, and hyperpigmentation of the skin and mucous membranes.

In Uganda, Kaposi's sarcoma is predominantly a disease of the male African with a male:female ratio of 13:1. It is a multifocal disease and all parts of the body may be involved. When confined to the skin in the form of nodular tumour, it runs a slow 'benign' course. The florid, the visceral and bone lesions in adults and lymphadenopathy in children are malignant lesions. The three histological types are useful in determining prognosis and choosing drugs for treatment. A change from benign to malignant forms is associated with loss of cellular immunological status of the host.

Quantitative determinations of serum alpha-fetoprotein (AFP) by radioimmunoassay in 193 patients with hepatocellular carcinoma have demonstrated a wide variation in serum levels that appear to be relatively constant for each patient by the time that diagnosis is made. If there is no therapeutic intervention the serum AFP usually follows a gradual increase as the tumor progresses. A few patients have a fall in serum AFP as a preterminal event. Various forms of chemotherapy cause only minor and transient decrease in serum AFP. Surgical resection of tumor produces an immediate fall that parallels the catabolic decay rate for AFP. All AFP-positive patients treated with surgery had recurrence of their tumor with a rise in serum AFP preceeding clinical discovery. The correlation of serum AFP and effective treatment is demonstration of the usefulness of this oncofetal protein marker as an indicator of neoplastic activity for hepatocellular carcinoma and tumors with embryonal cell components and possibly for some other entodermally derived neoplasms.

Sixteen out of 48 adult African patients with Kaposi sarcoma were found to have tumour tissue in lymph nodes. The evidence suggests that there are probably two main types of involvement. One occurs predominantly in younger patients and involves many groups of glands, probably develops in situ, and is associated with a poor prognosis. The other form is the result of metastasis to a node from an aggressive tumour in the neighbourhood. This occurs more commonly in the older patient and carries a much better prognosis than in those with generalised lymphadenopathy, though worse than in patients with nodular disease without gland involvement. Follow-up over a period of many years will be required to discover the outcome in these cases. Kaposi sarcoma is unusual in women but when it occurs runs a more aggressive course than in men.

An evaluation of humoral and cellular immune mechanisms was performed on patients with Kaposi's sarcoma in Uganda. Antibody responses and immunoglobulin levels were normal in all patients studied. Nevertheless, a striking impairment in the delayed hypersensitivity response to dinitrochlorobenzene was noted in patients with the "malignant" type of tumour.