Education and debate

Malignant tumours in patients with HIV infection

^a Centro Regionale di Riferimento Oncologico, Istituto Nazionale di Ricovero e Cura a Carattere Scientifico, 33081 Aviano, Italy

Correspondence to: Dr Tirelli.

One of the most important though somewhat neglected aspects of research in HIV infection concerns the development, clinicopathological characteristics, and treatment of malignant tumours in infected patients. With the improved survival of patients with AIDS owing to the better prevention and treatment of infectious complications there may well be an increase in AIDS related malignancies. This paper reviews the epidemiology, pathology, and treatment of malignant tumours in patients with HIV.

This is the seventh in a series of articles examining developments in cancer and updating what we know about the disease

What are the main types of cancer in AIDS?

At least two malignancies are firmly established as associated with HIV and have long been diagnostic of AIDS--namely, Kaposi's sarcoma and non-Hodgkin's lymphoma (table). When compared with the general population in the same area, the risk of Kaposi's sarcoma in men with AIDS was roughly 900-fold greater in the State of Illinois¹ and 700-fold greater in San Francisco Bay.² Data from the same cancer registry linkage studies for non-Hodgkin's lymphoma showed standardised incidence ratios of 141¹ and 71² respectively (table). More detailed analyses by subtype of non-Hodgkin's lymphoma suggested that the standardised incidence ratio in single men aged 20-49 in 1985-7 as compared with 1973-8 was 43 for the extranodal form but only 8 for nodal disease.³ With respect to histological grade, the increased standardised incidence ratio was restricted to intermediate and high grade lymphomas.³

Risk of cancer in men with AIDS or at risk of AIDS
--------------------------------------------------------------------------------------------------------------------
                               Odds ratios in never      Relative incidence   Standardised incidence ratios
                              married men aged 20-49     ratios in never          among men with AIDS v
                                                         married men aged           general population
                              In 1984 v     In 1985 v    20-49 in 1985-7       ----------------------------
                               1973-8,       1973-6,      v 1973-9 (SEER                       1980-7,
                            San Francisco   Manhattan,      programme,           1986-7,    San Francisco
Type of cancer                  City*       New York@         USA)#             Illinois$       Bay||
--------------------------------------------------------------------------------------------------------------------
Kaposi's sarcoma                2479           1850            5060                972           716
Non-Hodgkin's lymphoma           4.2            6.2            10.4                141            71
Hodgkin's disease                1.6            2.5             1.1                  -           8.8
Rectal and anal cancer            -              -              2.6                  -           3.5
--------------------------------------------------------------------------------------------------------------------
  * Biggar et al (1987).5
  @ Biggar et al (1989).71
  # Rabkin et al (1991) (surveillance, epidemiology, and end results programme).3
  $ Cote et al (1991).1
  || Reynolds et al (1993).2

In the largest cancer registry linkage study² solid tumours as a whole did not occur more often than expected among patients with AIDS, but two types of cancer which are not part of the AIDS case definition occurred with significantly increased frequency. These were Hodgkin's disease (standardised incidence ratio 8.8) and cancers of the rectum, anus, and anal canal (standardised incidence ratio 3.5) (table). The increased frequency of rectal and anal cancer was probably explained by the overwhelming prevalence of homosexual males among AIDS cases in San Francisco, anoreceptive intercourse being an important risk factor for the disease. The excess of Hodgkin's disease in a population based cohort of patients with AIDS confirms other reports*RF 4-6* and suggests that certainly some forms of aggressive Hodgkin's disease with unusual morphology may be part of the malignant presentation of AIDS.⁶

Conversely, significant excesses of a few other rare malignancies, such as non-melanomatous skin cancer and cancer of the nose, nasal cavity, and middle ear, based on two or three cases at most, require cautious interpretation as they may represent misclassifications of Kaposi's sarcoma.

Invasive carcinoma of the cervix uteri, often a more aggressive disease than in the general population, has been part of the AIDS case definition since 1993, but data on it are fairly scanty on account of the vast predominance of male cases in North American series.

Characteristics of patients with AIDS and cancer

Kaposi's sarcoma is severalfold more common among patients who acquire HIV by sexual contact rather than parenterally. Among people with newly diagnosed AIDS in the United States the prevalence of Kaposi's sarcoma ranged from 1% in men with haemophilia to 21% in homosexual men⁷ and similar differences were recorded in European countries.⁸ The case for a sexually transmitted aetiology of Kaposi's sarcoma is strong--for example, clustering of cases in Africa,⁷ faecal-oral contact as main route of transmission in homosexual men⁹--whereas the several infectious hypotheses--for example, with cytomegalovirus, mycoplasmas, and retrovirus-like agents--have never been substantiated. The prevalence of Kaposi's sarcoma among heterosexual AIDS patients is lower in white than Caribbean or African born residents of the United States⁷ or heterosexuals in Italy.¹⁰ Lastly, American⁷ but not Italian data¹⁰ suggest that HIV transmission via whole blood carries an increased risk of Kaposi's sarcoma when compared with transmission by clotting concentrates.

The epidemiology of AIDS associated non-Hodgkin's lymphoma is even less well understood. The disease is rarer (accounting for about 3% of AIDS diagnoses worldwide) and substantially under-estimated in AIDS surveillance statistics (non-Hodgkin's lymphoma is rarely the presenting disease). In the United States intravenous drug users had around half the probability of presenting with non-Hodgkin's lymphoma when compared with homo-sexual and bisexual men and patients with haemophilia. In European countries the difference, if any, seemed much smaller, possibly owing to the more homogeneous access to diagnostic procedures across various strata of the population.¹⁰

Other AIDS associated malignancies (cervical cancer, rectal and anal cancer, Hodgkin's disease, and possibly hepatocellular carcinoma) are known or suspected to be caused by infectious agents whose prevalence or aggressiveness is enhanced in most populations at high risk of AIDS.

Geographical differences and temporal trends in AIDS associated Kaposi's sarcoma and non-Hodgkin's lymphoma

The geographical distribution of AIDS related Kaposi's sarcoma closely reflects the prevalence of sexually acquired AIDS worldwide. Thus the proportion of AIDS patients with Kaposi's sarcoma as a presenting disease tends to be much higher in the United States, Canada, and northern Europe (where homosexual cases predominate) than, for instance, in Italy and Spain (where intravenous drug users account for most reported cases of AIDS). The proportion of AIDS patients with non-Hodgkin's lymphoma as the presenting disease is more homogeneous internationally.

The most consistent finding with respect to temporal trends, noted first in the United States⁷ and then in Europe^{11 12} and Australia,¹³ is a steep decline in the proportion of Kaposi's sarcoma in patients with AIDS. It is unlikely that this reduction is totally artefactual (that is, due to changes in the definition of AIDS). More probable explanations include the early pre-dominant involvement of homosexual men (particularly of the most promiscuous cases) in the epidemic and the tendency of Kaposi's sarcoma to be an early manifestation of AIDS, occurring when immunosuppression is still fairly mild. It has also been predicted that the incidence of lymphoma will rise as more patients prolong their pre-AIDS state with prophylaxis.¹⁴

View larger version (27K): [in this window] [in a new window]   FIG--Kaposi's sarcoma in gingiva

View larger version (23K): [in this window] [in a new window]   FIG--Immunoblastic non-Hodgkin's lymphoma in skin

Pathological and biological aspects

KAPOSI'S SARCOMA

Recently we have substantially improved our understanding of the pathogenesis of Kaposi's sarcoma. Exposure to a still unknown sexually transmitted agent other than HIV and subsequent infection of a mesenchymal cell progenitor could predispose to Kaposi's sarcoma.¹⁵ Moreover, the activation of cytokines such as interleukin 1, tumour necrosis factor (alpha), and interleukin 6 in addition to the HIV related immune function abnormalities could result in proliferation of the mesenchymal progenitor cell and affect the rate of growth of Kaposi sarcoma lesions as well.¹⁵ HIV itself, through the expression of the Tat protein, could directly increase the growth of Kaposi sarcoma cells. The role of cytokines in the modulation of Kaposi sarcoma cell growth has important clinical implications, in that several drugs that modulate cytokines could potentially be of benefit to patients with Kaposi's sarcoma. Clinical studies of retinoids, interleukin 4, HIV Tat inhibitors, and oxpentifylline are under way.

There is still uncertainty about the histological nature of Kaposi sarcoma cells. Endothelial cells were first considered the cells of origin¹⁶ because of the presence of factor VIII related antigen in spindle cells. Recently, the identification of smooth muscle specific (alpha) actin¹⁷ both in cultures of cells derived from Kaposi sarcoma lesions and in the lesions themselves favour the hypothesis that the cells of origin may be from a smooth muscle cell progenitor.

HIV ASSOCIATED LYMPHOMAS

The range of HIV associated lymphoid neoplasias includes systemic non-Hodgkin's lymphoma, primary lymphoma of the brain, and possibly Hodgkin's disease.*RF 18-21* HIV associated systemic non-Hodgkin's lymphomas have several pathological features in common. These include a diffuse growth pattern, a high growth rate, and a common B cell derivation, only a minority of non-Hodgkin's lymphomas being of undetermined or T cell phenotype. Moreover, several approaches, including immunophenotypic and immunogenotypic analyses, have defined the clonal nature of most HIV associated non-Hodgkin's lymphomas.¹⁸

View larger version (32K): [in this window] [in a new window]   FIG--Right neck mass of Hodgkin's disease

From our observations²² and other studies*RF 20 23-26* it may be concluded that most HIV associated systemic non-Hodgkin's lymphomas have a "blastic" cell morphology. Many consist of small non-cleaved cells of typical Burkitt's lymphoma and their variants with plasmablastic differentiation,²⁷ or of immunoblasts--usually polymorphic--with plasmacytic features,^{23 26 28} or of centroblasts²⁹ (large non-cleaved cells as defined by the international working formulation for non-Hodgkin's lymphomas) along with their morphological variants.^{23 27} In addition, lymphomas composed of plasmablasts^{18 30} (plasmacytomas) or of blastic cells exhibiting intermediate features between small non-cleaved cells with plasmablastic differentiation²⁷ and immunoblastic plasmacytoid cells²³ (8% in our series²²) may be detected. Finally, anaplastic large cell Ki-1 + lymphomas, a heterogeneous group of high grade lymphomas at the borderline between Hodgkin's disease and non-Hodgkin's lymphoma,³² may occur in HIV infected patients^{18 23 24 28 32 33} (14% in our series²²).

In contrast with the heterogeneity of HIV associated systemic non-Hodgkin's lymphoma, non-Hodgkin's lymphomas arising in the central nervous system represent a more uniform group and in most cases have histological features consistent with immunoblastic plasmacytoid lymphomas.

Conclusive studies on the frequency of Hodgkin's disease in AIDS are lacking and whether Hodgkin's disease should be included among the HIV associated lymphomas is debatable.^{18 20} Recent studies, however, have found a significant difference in the distribution of mixed cellularity and lymphocyte depletion subtypes of Hodgkin's disease in HIV infected patients when compared with Hodgkin's disease in the general population.^{34 35} In particular, several reports have pointed to the high frequency of lymphocyte depletion in series of AIDS associated Hodgkin's disease^{6 18} accompanied by an increase in fibrohistiocytoid stromal cells.⁶

The biological bases and molecular genetics underlying the pathogenesis of these tumours are still largely unclear. A pathogenetic role for Epstein-Barr virus in some HIV associated systemic non-Hodgkin's lymphomas has been proposed.^{28 36 37 38 39 40}

A high prevalence (83-100%) of Epstein-Barr virus has been found in Hodgkin's disease tissue from patients with HIV infection.^{41 42} Applying small non-polyadenylated Epstein-Barr virus RNA (Epstein-Barr virus transcript; EBER) in situ hybridisation to 21 cases of primary central nervous system lymphoma in AIDS patients, MacMahon et al found evidence of Epstein-Barr virus infection of the malignant cells in every case.⁴³ Moreover, Epstein-Barr virus genomes associated with Hodgkin's disease and anaplastic large cell Ki-1 + ⁿon-Hodgkin's lymphoma arising in HIV-1 positive patients have been shown to be episomal and clonal,⁴⁴ even when detected in metachronous multiple biopsy samples,⁴⁵ indicating that Epstein-Barr virus infected cells have arisen from a single infectious agent.

In a recent study by our group combined in situ hybridisation analyses for viral DNA and EBER (fig 1) and immunohistological detection of Epstein-Barr virus encoded latent membrane protein type 1 showed that there were differences in viral latent gene expression between HIV associated anaplastic large cell Ki-1 + (mostly of B cell phenotype) or immunoblastic lymphomas (latent membrane protein type 1 +) (fig 2) and Epstein-Barr virus infected cells of small non-cleaved cell lymphomas (J group; see box) (latent membrane protein type 1 -).²²

With respect to additional genetic events contributing to HIV associated non-Hodgkin's lymphoma, activation of the c-myc oncogene has been detected in most small non-cleaved cell lymphomas. By contrast, in immunoblastic plasmacytoid lymphomas c-myc activation is detected in only a minority of tumours.^{36 46 47} Another genetic event recorded in HIV associated non-Hodgkin's lymphoma is p53 inactivation. This is specifically associated with Burkitt's lymphoma (fig 3) and is consistently absent in all other

View larger version (60K): [in this window] [in a new window]   FIG 1--EBER (short non-protein coding Epstein-Barr virus transcripts) in situ hybridisation signal shown as dense grains over nuclei of tumour cells of anaplastic large cell (CD30/Ki-1 + lymphoma. (Nuclear fast red counterstain)

View larger version (60K): [in this window] [in a new window]   FIG 2--Latent membrane protein type 1 staining with variable intensity within cytoplasm of several tumour cells of immunoblastic lymphoma. (Haematoxylin counterstain)

View larger version (71K): [in this window] [in a new window]   FIG 3--Small non-cleaved cell lymphoma stained with DO7 (which recognises wild and mutant p53 antigen) showing strong nuclear staining (brown) of tumour cells. (Haematoxylin counterstain)

From the pathological and biological data we can formulate a pathological classification of HIV associated systemic lymphomas based on the morphological features of the two main types--that is, blastic and anaplastic cell lymphomas, which include specific cytomorphological subtypes and possibly Hodgkin's disease (box). This classification uses the terminology of the international working formulation and the updated Kiel classification²⁹ and includes morphological variants of the high grade B cell non-Hodgkin's lymphoma described by Hui et al.²⁷ It defines precise morphological categories and their association with genetic lesions (box), thus providing a reliable basis for further biologically oriented investigations of the pathogenesis of HIV associated lymphomas.

Clinical manifestations and treatment

KAPOSI'S SARCOMA

At the beginning of the AIDS epidemic Kaposi's sarcoma frequently occurred as an indolent manifestation in patients without any evidence of severe immunosuppression and often as a presenting sign of HIV infection. Now, however, Kaposi's sarcoma is frequently seen as a late manifestation of AIDS and is likely to be associated with an aggressive course.

The lesions usually begin as macular or papular eruptions, sometimes in clusters. These progress to plaque or nodular lesions, which may spontaneously disappear while others appear. Lymphoedema of the legs and face may be severe and heralds the need to start treatment. Kaposi's sarcoma confined to the skin is never a cause of death in AIDS but may cause severe cosmetic problems needing treatment. The outcome of patients with Kaposi's sarcoma is usually determined by the severity of the immunosuppression present and by the related opportunistic infections. Kaposi's sarcoma has been recorded in every site in the body and may be found in gastrointestinal tract, lungs, or lymph nodes without any evidence of cutaneous lesions. Pulmonary Kaposi's sarcoma usually occurs in advanced disease, and when symptomatic an aggressive form of therapy is required. Gastrointestinal Kaposi's sarcoma occurs in almost half of patients with cutaneous lesions but usually does not cause symptoms.

The treatment of Kaposi's sarcoma must be tailored to individual needs. Treatment is not curative and rarely induces complete remission. In patients with Kaposi sarcoma lesions that are not disfiguring and in whom there are no other symptoms no treatment is required. When symptoms occur or cosmetic problems are present various effective (but not curative) treatments are available. Localised cutaneous lesions may effectively be treated with radiotherapy for pain or cosmetic problems with temporary complete remission of lesions in 70% of cases.⁴⁹ Appreciable toxicity, however, occurs with oral radiotherapy.⁵⁰ Intralesional vinblastine, interferon alfa, and laser photocoagulation are reportedly effective in single, especially intraoral, Kaposi sarcoma lesions, with good cosmetic and symptomatic results.⁵¹ These treatments are much better tolerated than radiotherapy. In patients with disseminated and progressive Kaposi sarcoma lesions, or when systemic lesions become symptomatic, chemotherapy or biological response modifiers should be tried. High doses of interferon alfa (10-18 MU daily) have been used, but adverse effects of this drug that are dose dependent and include fever-like symptoms should be weighed carefully against benefit.

Classification of systemic lymphomas occurring during HIV-1 induced immunosuppression

Blastic cell lymphomas not associated with Epstein-Barr virus encoded
latent membrane protein type 1 expression

* Centroblastic (G (international working formulation))

* Small non-cleaved cell (J (international working formulation);
associated with c-myc deregulation + p53 inactivation) with or without
plasmablastic differentiation27

* Plasmablastic (plasmacytoma; it is debatable whether extramedullary
plasmacytomas should be included among HIV associated lymphomas)

* Blastic cells with intermediate features22 23

Blastic cell lymphomas that may be associated with Epstein-Barr virus
encoded latent membrane protein type 1 expression

* Immunoblastic (H (international working formulation); included as
separate entity as different in Epstein-Barr viral latent gene
expression from other blastic cell systemic lymphomas)

Anaplastic cell lymphomas (associated with monoclonal Epstein-Barr virus
infection and latent membrane protein type 1 expression)

* Anaplastic large cell Ki-1 +31

* Hodgkin's lymphoma (mixed cellularity and lymphocyte depletion; it is
debatable whether Hodgkin's lymphomas should be included among HIV
associated lymphomas)

Though zidovudine has no antitumour activity, it is often combined with interferon alfa for its anti-HIV effect.⁵² Bone marrow colony stimulating factors have been used successfully to ameliorate neutropenia and allow combination chemotherapy in this setting.⁵³ Combination chemotherapy has been found effective been used successfully to ameliorate neutropenia and allow combination chemotherapy in this setting.⁵³ Combination chemotherapy has been found effective in patients with disseminated symptomatic and pulmonary Kaposi's sarcoma. The most effective agents are bleomycin, vinblastine, vincristine, cyclophosphamide, etoposide, and doxorubicin.⁵⁴ These agents may be given in various combinations. A randomised study showed that a combination of low dose doxorubicin, bleomycin, and vincristine was more effective than doxorubicin alone.⁵⁵ More intensive therapy is not always associated with increased survival, as the immunosuppressive effects of chemotherapy may increase the number of opportunistic infections in such severely immunocompromised patients. Liposomal doxorubicin⁵⁶ and liposomal daunorubicin⁵⁷ are interesting new approaches in this setting and together with colony stimulating factors are under investigation at present. Angiostatic agents also look hopeful, based on laboratory data.⁵⁸

View larger version (22K): [in this window] [in a new window]   FIG--Kaposi's sarcoma on penis

View larger version (19K): [in this window] [in a new window]   FIG--Kaposi's sarcoma lesions in skin over arms

View larger version (25K): [in this window] [in a new window]   FIG--Invasive squamous carcinoma in skin rising from posterior region of right axilla in patient with HIV infection

NON-HODGKIN'S LYMPHOMA

Most patients with AIDS related non-Hodgkin's lymphoma present with fever, loss of weight, and night sweats (B symptoms), widespread disease, and extranodal involvement, the most common sites being the central nervous system, gastrointestinal tract, bone marrow, and liver. Any site of the body, however, may be affected.^{59 60} On account of the unfavourable presentation of non-Hodgkin's lymphoma and the prevalence of high grade subtypes in addition to the underlying HIV infection with associated opportunistic infections, the overall outcome of these malignancies is poor. Nevertheless, some prognostic factors for survival have been identified, and some patients with AIDS related non-Hodgkin's lymphoma can obtain long term survival and even cure with appropriate therapy.

Levine et al identified Karnofsky performance score less than 70%, AIDS being diagnosed before non-Hodgkin's lymphoma, bone marrow involvement, and low CD4 counts as associated with a poorer prognosis.⁶¹ Patients who presented with one or more of these features had a significantly shorter survival than those who had none (median survival four months (upsilon) 11 months).⁶¹ Kaplan et al identified a CD4 count of fewer than 1000 cells/l as the most important factor in predicting survival, though performance score, development of AIDS before the lymphoma, and presence of advanced disease were also recorded as relevant.⁶² Lastly, Gisselbrecht et al identified low performance score, CD4 count less than 1000/l, and AIDS diagnosis before non-Hodgkin's lymphoma as important in predicting survival, half of patients with none of these features being alive two years after the diagnosis of non-Hodgkin's lymphoma.⁶³

Patients with primary central nervous system non-Hodgkin's lymphoma had a significantly shorter median survival than patients with peripheral systemic lymphomas,⁶¹ possibly related to their substantially lower CD4 counts and consequent more severe immunosuppression. It is important to emphasise that leptomeningeal disease is not associated with poorer survival, though it is not unusual to find asymptomatic leptomeningeal lymphomas during the staging procedure. Hence lumbar puncture should be performed routinely in the staging of these patients. On account of the aggressive course of non-Hodgkin's lymphoma, intensive chemotherapy regimens should be used. The risk of severe side effects--particularly bone marrow toxicity--is of special concern in patients with aggressive non-Hodgkin's lymphoma. Gisselbrecht et al showed that HIV positive patients in a low risk category--that is, without opportunistic infections and full blown AIDS and with good performance status--could be treated with intensive chemotherapy such as LNH 84.⁶³ A complete response was obtained in 90 (64%) of 141 patients, a rate not significantly different from that in HIV negative non-Hodgkin's lymphoma (75%). Twenty (14%) patients died during treatment, half due to the toxicity and half due to the progression of the disease.⁶³ For patients with CD4 counts less than 1000/l and performance score less than 80% the probability of survival at two years was 50%.

Levine et al have evaluated a low dose methotrexate-bleomycin-doxorubicin-cyclophosphamide-vincristine-dexamethasone (M-BACOD) regimen in patients with and without adverse prognostic factors.⁶⁵ Their findings showed that less intensive regimens of combination chemotherapy with early central nervous system prophylaxis may be comparable to more intensive regimens, which are associated with a high rate of opportunistic infections. Other workers have found that high risk patients respond poorly to low dose chemotherapy with a cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP)-like regimen in association with zidovudine with complicating opportunistic infections and with disappointing overall survival.⁶⁶ Use of bone marrow growth factors, however, might overcome some of these problems. Kaplan et al reported benefit with granulocytemacrophage colony stimulating factor in association with cyclophosphamide-doxorubicin-vincristine-prednisone with a substantial decrease in bone marrow toxicity.⁶⁷ Tirelli et al have shown that granulocyte colony stimulating factor in association with chemotherapy greatly decreases bone marrow toxicity and thus the delay between cycles of chemotherapy without any increase in the overall cost of treatment.⁶⁸

The European Organisation for Research and Treatment of Cancer's AIDS and Tumor Study Group has undertaken a multicentre European study of non-Hodgkin's lymphoma in order to compare chemotherapy regimens of different intensity in patients with low, intermediate, and high risk category disease. High risk was defined as the presence of one or more of the following: CD4 count less than 1000/l; performance score >/=80%; diagnosis of AIDS. Granulocyte colony stimulating factor will be given to all these patients and zidovudine will be given after the induction of chemotherapy.

OTHER TUMOURS

It is now evident that Hodgkin's disease in HIV positive patients presents with special clinicopathological characteristics, including higher frequency of mixed cellularity and lymphocytic depletion subtypes and more widespread disease, and has subsequent poorer outcome than in HIV negative patients.⁶⁹ In the Italian series (the largest published so far) the median CD4 count at diagnosis of Hodgkin's disease was 249x10⁶/l, therefore requiring the use of antiretroviral therapy.⁶⁹ Preliminary data show that the combination of tailored chemotherapy regimens and zidovudine in these patients may result in a substantial decrease in opportunistic infections when compared with patients treated with conventional chemotherapy like mustine-vincristine-procarbazine-prednisone (MOPP) or doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD) without zidovudine.⁶⁸

Women with HIV infection have a high risk of cervical dysplasia and cervical carcinoma. Similarly, there is an increase in anal carcinoma, especially in association with a history of anal intercourse in homosexual or bisexual men. Numerous single case reports and small series have described the development of miscellaneous cancers in HIV infected patients.⁷⁰ The largest group of solid cancers in the series of Monfardini et al consisted of germinal testicular cancers in 12 patients without, however, any unusual adverse prognostic factors when compared with those observed in the general population.⁴

This work was supported in part by the Istituto Superiore di Sanita, AIDS project 1993, Rome, and by the Associazione Italiana per la Ricerca sul Cancro, Milan.

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