hiv infection induces a deficient immunologic milieu that enables other oncogenic viruses such as ebv to escape immune control in a multifactorial way , which can lead to the onset of lymphoma .
the incidence of hiv - related pcnsl has decreased since the widespread introduction of haart .
presentation of the disease is more frequent in persons with reduced performance status , cd4-counts below 100/l and high hiv viremia levels [ 4 - 6 ] . in immunocompetent populations , outcome and toxicity of different therapy regimens are largely agedependent .
significantly reduced survival and neurotoxicity rates of up to 90% occur with combined chemotherapy - radiation regimens in the above 60 year age group . in all age groups , combination radiochemotherapies , with mostly intrathecal ( it ) administration of methotrexate ( mtx ) and/or cytarabine ,
prolong overall median survival rates by up to 55 months [ 7 - 9 ] .
however , they can cause increased treatment - associated mortality , with high rates of infection and neurotoxicity .
intensive chemotherapy - only regimens show less neurotoxicity with similar survival rates [ 7 - 10 ] .
higher response rates are obtained with intensive autologous stem - cell - rescue protocols [ 11 - 14 ] .
in contrast to therapeutic success demonstrated for immunocompetent patients , the outcome of hiv - associated pcnsl is still considered poor .
median survival rates range from four to six weeks with best supportive care alone and 3 to 5 months with cranial radiation treatment [ 4,15 - 17 ] .
most hiv - positive pcnsl patients are in clinically poor condition , and have advanced immunosuppression . moreover ,
hiv - associated leukoencephalopathy in advanced hiv disease is frequent , considering that neurotoxicity is one of the most frequent debilitating side effects in combined chemo - radiotherapy protocols .
haart induced immune recovery improves survival of patients with aids - associated pcnsl and systemic lymphoma , but these patients still have reduced overall survival along with higher treatment - related mortality than hiv - negative patients .
the highest survival rates were reported in a german survey with haart and radiotherapy 40 gy ( n = 5/6 ) or hdmtx/40 gy ( n = 1/6 ) of more than 18 months .
steroids had no prognostic benefit and most pcnsl - patients ( n = 23/29 ) were not eligible for any treatment .
haart has been used alone for hiv - related pcnsl in patients with poor clinical status , patients who have declined other therapies , and in those experiencing failing therapies .
the impact of curative haart of hiv - related pcnsl has been reported in five single cases [ 20 - 23 ] .
antiviral and immune - based therapy of hiv - related pcnsl was suggested by raez et al .
: 5 art - naive hiv - positive patients diagnosed with pcnsl were treated with ganciclovir , azt and interleukin-2 for two weeks and ganciclovir maintenance therapy .
long lasting remission and a marked response after two weeks of treatment was reported in four out of five patients : two patients were alive and disease - free 22 and 13 months later , one died at month seven due to sepsis , one died after four months with progressive disease , and one patient was lost to follow - up in partial remission after changing to radiation - therapy due to ctc grade 4-neutropenia and thrombocytopenia at week four .
aboulafia , et al .   adopted a similar treatment strategy with one out of four patients remaining in complete remission after more than four years of follow - up .
we report three patients who were treated at our institution following a modified treatment plan originally published by raez .
250 mg bid from day 15 ; ongoing haart with one additional nrti as haartbackbones , plus one protease inhibitor ( lopinavir / ritonavir or nelfinavir according to individual conditions ) , orally bid in standard doses ; il-2 subcutaneously two million units bid at days 1 - 14 ; foscarnet bid 90 mg per kilogram body weight on days 1 - 14 in conjunction with one litre of saline bid to prevent renal failure .
maintenance therapy with foscarnet ( alternatively ganciclovir or cidofovir in one patient ) was administered according to patient clinical status and individual toxicities . in case of clinical or radiological disease progression ,
cerebral computerized transaxial tomography ( ctt ) scan controls were performed on days 7 and 14 after the start of treatment , unless there was clinical deterioration , when cct scans were performed earlier .
all patients underwent a brain biopsy that showed large b - cell lymphomas of high malignancy in two patients and lymphoproliferative disease with a large amount of necrotic tissue that was highly suspicious for nhl in the third patient despite lack of proven monoclonality .
a treatment plan was adapted and proposed according to each patient 's clinical status , and informed consent was obtained .
250 mg bid from day 15 ; ongoing haart with one additional nrti as haartbackbones , plus one protease inhibitor ( lopinavir / ritonavir or nelfinavir according to individual conditions ) , orally bid in standard doses ; il-2 subcutaneously two million units bid at days 1 - 14 ; foscarnet bid 90 mg per kilogram body weight on days 1 - 14 in conjunction with one litre of saline bid to prevent renal failure .
maintenance therapy with foscarnet ( alternatively ganciclovir or cidofovir in one patient ) was administered according to patient clinical status and individual toxicities . in case of clinical or radiological disease progression ,
cerebral computerized transaxial tomography ( ctt ) scan controls were performed on days 7 and 14 after the start of treatment , unless there was clinical deterioration , when cct scans were performed earlier .
all patients underwent a brain biopsy that showed large b - cell lymphomas of high malignancy in two patients and lymphoproliferative disease with a large amount of necrotic tissue that was highly suspicious for nhl in the third patient despite lack of proven monoclonality .
a treatment plan was adapted and proposed according to each patient 's clinical status , and informed consent was obtained .
patient 1 was a 33-year - old msm male , who had been diagnosed hiv - positive since 1995 .
his cd4-count was 16/l and at the time lymphoma diagnosis , he was art - naive .
he also had clinical signs of kaposi - sarcoma with lesions on skin , tongue , palate and glans penis that had been treated for four months with systemic liposomal doxorubicin .
he had undergone hospitalization for pneumocystis carinii pneumonia , which had been treated successfully four weeks prior to the lymphoma diagnosis .
this was followed by three weeks of ongoing treatment for histologically proven pulmonary tuberculosis and oral candidiasis .
subsequently , a 5 cm lesion in the basal ganglia with extensive perifocal oedema was demonstrated by cct scan , which had been performed because of a history of headaches and grand mal seizures .
a presumptive diagnosis of cerebral toxoplasmosis was made , and empiric anti - toxoplasmosis therapy was initiated .
a stereotactic brain biopsy was performed and revealed a highly malignant , large b - cell lymphoma ( lca pos .
the patient was treated for 13 days according to the aforementioned treatment plan concomitant to his anti - tuberculosis therapy ( isoniazid , rifampicin , ethambutol , pyrazinamide ) , which was well tolerated .
high dose azt , lamivudine and saquinavir boostered by ritonavir were selected for the haart regimen . due to
tumour regression could not demonstrated by cct scan on days 7 and 13 , so whole brain radiotherapy ( wbrt ) was initiated .
follow - up immune status was not performed . after a cumulative dose of 20 gray ,
the patient expired due to lymphoma progression after discharge to his home , 50 days after diagnosis and 80 days after onset of signs and symptoms .
1 after 2 weeks of treatment with il-2 , azt , haart , foscarnet . patient 2 was a 23-year - old ivdu male ( men sex female ) , who had been diagnosed hiv - positive for two years ( cd4-count 50/l , 13% , ratio 0.2 , art - nave , hiv - viral load 522.600 c / ml ) .
he was hospitalized for a 2 month exacerbation of the chronic paranoid psychosis and fever of unknown origin .
a diagnosis of systemic cryptococcosis , manifested with fever , elevated serum - titre of 1 : 40/1 : 320 and repeated negative csf - findings , was confirmed 2 months before the pcnsl diagnosis .
he had also been diagnosed with pneumonia due to s. pneumoniae , 6 weeks before the pcnsl diagnosis , and was successfully treated with iv ampicillin / sulbactam .
two weeks later , due to a 2 cm contrast enhancing cerebral focus , empiric toxoplasmosis therapy was initiated for 2 weeks . the patient developed left sided paralysis and cct scan revealed that the cerebral focus had developed into a rapidly growing 4 cm parietal mass with accompanying oedema , and normal cytological , hsvconsensus - pcr and microbiological csf findings .
brain biopsy demonstrated an ebv - associated diffuse large b - cell - lymphoma ( cd20 + , mib-1 60% , lmp+ ) .
the initial tumour growth appeared to stop after one week with the aforementioned treatment plan , which included haart with lamivudine and nelfinavir .
however , over the total course of three weeks tumour size progressed to 5 cm with a slight midline shift .
his cd4-count increased two weeks after initiation of haart and il-2 to 810/l ( 52% , cd4/cd8 ratio 1.5 ) , and hiv - viral load decreased to 1840 copies / ml .
however , the patient had minimal signs of improvement of the left sided paralysis and severe psychosis . despite support by nurses in hospice care ,
he continued to worsen clinically , and expired due to lymphoma progression on day 166 after initial lymphoma diagnosis , and 200 days after the onset of signs and symptoms .
. pat . 2 after 2 weeks of treatment with il-2 , azt , haart , foscarnet .
patient 3 was a 44-year old male ( men sex male ) , who had been diagnosed hiv - positive for 7 years ( cd4-count 120/l , cd4/8-ratio 0.2 , viral load 793.000 copies / ml ; art - nave ) .
he had a history of seasonal allergies , primary syphilis , gonorrhoea , and condylomata accuminata .
a cct scan revealed a contrastenhancing temporal mass with a diameter of 1.2 cm accompanied with perifocal oedema .
despite one week of empiric toxoplasmosis therapy , the mass had expanded to a diameter of 2 cm .
stereotactic brain biopsy showed an ebv induced lymphoproliferation ( lmp+ , ebna-2 + , cd30- , cd20 + , high proliferation - index ki-67 ) . due to the presence of massive necrosis and high proliferation index ,
highly malignant lymphoma was suspected , but could not be confirmed with the biopsy specimen material . since a repeat biopsy would have put the patient at further risk , these highly suspicious results were deemed consistent with the clinical presentation , and treatment was initiated with foscarnet , interleukin-2 , high dose azt for 18 days , with lamivudine and lopinavir/ ritonavir bid added for haart in standard doses . due to a second seizure on day 7 , gabapentin , which had been administered since the first seizure ,
overall , he tolerated the treatment regimen well except for limb edema , which improved with xipamid 10 mg , and one episode of local induration at an interleukin injection site that resolved without sequelae .
a cct scan on day 18 showed a tumor diameter of 2.53 cm with no change in perifocal oedema .
his cd4-count on day 11 was 550/l , cd4/cd8 ratio 2.0 , and on day 30 it was 180/l , with a ratio of 0.7 , and a viral load of 790 copies / ml .
haart ( azt , 3tc , lpv / r ) was continued , and ganciclovir maintenance therapy ( once daily 5 mg per bodyweight ) was initiated .
forty two days after treatment initiation , the patient underwent whole brain radiotherapy with a 30 gy cumulative dose .
six months after start of treatment , his hiv viral load was constantly below detectable levels , and after 4 months , cct scan showed cr with leukencephalopathy .
after completion of 3 months of ganciclovir maintenance therapy , the patient received cidofovir monthly for one year after the induction period ( cumulatively 20 times ) against ebv proliferation because of his relatively low cd4-count ( nadir 100/l after 6 months ) .
the cidofovir was then discontinued due to a steadily improving immune response ( cd4count 306/l ) .
ophthalmological and neurological examinations as well as renal function tests were within normal limits 2 years after the start of treatment .
four years from time of diagnosis , cct restaging demonstrated constant marked demyelinization of the cerebral medullary layer , which was most likely radiotherapy - associated . the patient has been clinically and mentally stable 53 months after diagnosis .
he remained on haart with azt , 3tc , lpv / r with cd4-counts above 300/l and without a detectable viral load . a year after diagnosis the patient retired from work .
. pat . 3 after 5 years of treatment with il-2 , azt , haart , foscarnet .
patient 1 was a 33-year - old msm male , who had been diagnosed hiv - positive since 1995 .
his cd4-count was 16/l and at the time lymphoma diagnosis , he was art - naive .
he also had clinical signs of kaposi - sarcoma with lesions on skin , tongue , palate and glans penis that had been treated for four months with systemic liposomal doxorubicin .
he had undergone hospitalization for pneumocystis carinii pneumonia , which had been treated successfully four weeks prior to the lymphoma diagnosis .
this was followed by three weeks of ongoing treatment for histologically proven pulmonary tuberculosis and oral candidiasis .
subsequently , a 5 cm lesion in the basal ganglia with extensive perifocal oedema was demonstrated by cct scan , which had been performed because of a history of headaches and grand mal seizures .
a presumptive diagnosis of cerebral toxoplasmosis was made , and empiric anti - toxoplasmosis therapy was initiated .
a stereotactic brain biopsy was performed and revealed a highly malignant , large b - cell lymphoma ( lca pos .
the patient was treated for 13 days according to the aforementioned treatment plan concomitant to his anti - tuberculosis therapy ( isoniazid , rifampicin , ethambutol , pyrazinamide ) , which was well tolerated .
high dose azt , lamivudine and saquinavir boostered by ritonavir were selected for the haart regimen . due to
tumour regression could not demonstrated by cct scan on days 7 and 13 , so whole brain radiotherapy ( wbrt ) was initiated .
follow - up immune status was not performed . after a cumulative dose of 20 gray ,
the patient expired due to lymphoma progression after discharge to his home , 50 days after diagnosis and 80 days after onset of signs and symptoms .
. pat . 1 after 2 weeks of treatment with il-2 , azt , haart , foscarnet .
patient 2 was a 23-year - old ivdu male ( men sex female ) , who had been diagnosed hiv - positive for two years ( cd4-count 50/l , 13% , ratio 0.2 , art - nave , hiv - viral load 522.600 c / ml ) .
he was hospitalized for a 2 month exacerbation of the chronic paranoid psychosis and fever of unknown origin .
a diagnosis of systemic cryptococcosis , manifested with fever , elevated serum - titre of 1 : 40/1 : 320 and repeated negative csf - findings , was confirmed 2 months before the pcnsl diagnosis .
he had also been diagnosed with pneumonia due to s. pneumoniae , 6 weeks before the pcnsl diagnosis , and was successfully treated with iv ampicillin / sulbactam .
two weeks later , due to a 2 cm contrast enhancing cerebral focus , empiric toxoplasmosis therapy was initiated for 2 weeks .
the patient developed left sided paralysis and cct scan revealed that the cerebral focus had developed into a rapidly growing 4 cm parietal mass with accompanying oedema , and normal cytological , hsvconsensus - pcr and microbiological csf findings .
brain biopsy demonstrated an ebv - associated diffuse large b - cell - lymphoma ( cd20 + , mib-1 60% , lmp+ ) .
the initial tumour growth appeared to stop after one week with the aforementioned treatment plan , which included haart with lamivudine and nelfinavir .
however , over the total course of three weeks tumour size progressed to 5 cm with a slight midline shift .
his cd4-count increased two weeks after initiation of haart and il-2 to 810/l ( 52% , cd4/cd8 ratio 1.5 ) , and hiv - viral load decreased to 1840 copies / ml . radiation therapy ( 40 gy ) was initiated followed with concomitant dexamethasone .
however , the patient had minimal signs of improvement of the left sided paralysis and severe psychosis . despite support by nurses in hospice care ,
he continued to worsen clinically , and expired due to lymphoma progression on day 166 after initial lymphoma diagnosis , and 200 days after the onset of signs and symptoms .
. pat . 2 after 2 weeks of treatment with il-2 , azt , haart , foscarnet .
patient 3 was a 44-year old male ( men sex male ) , who had been diagnosed hiv - positive for 7 years ( cd4-count 120/l , cd4/8-ratio 0.2 , viral load 793.000 copies / ml ; art - nave ) .
he had a history of seasonal allergies , primary syphilis , gonorrhoea , and condylomata accuminata .
a cct scan revealed a contrastenhancing temporal mass with a diameter of 1.2 cm accompanied with perifocal oedema .
despite one week of empiric toxoplasmosis therapy , the mass had expanded to a diameter of 2 cm .
stereotactic brain biopsy showed an ebv induced lymphoproliferation ( lmp+ , ebna-2 + , cd30- , cd20 + , high proliferation - index ki-67 ) . due to the presence of massive necrosis and high proliferation index ,
highly malignant lymphoma was suspected , but could not be confirmed with the biopsy specimen material . since a repeat biopsy would have put the patient at further risk , these highly suspicious results were deemed consistent with the clinical presentation , and treatment was initiated with foscarnet , interleukin-2 , high dose azt for 18 days , with lamivudine and lopinavir/ ritonavir bid added for haart in standard doses . due to a second seizure on day 7 , gabapentin , which had been administered since the first seizure , was raised from 1200 mg to 2100 mg daily .
overall , he tolerated the treatment regimen well except for limb edema , which improved with xipamid 10 mg , and one episode of local induration at an interleukin injection site that resolved without sequelae .
a cct scan on day 18 showed a tumor diameter of 2.53 cm with no change in perifocal oedema .
his cd4-count on day 11 was 550/l , cd4/cd8 ratio 2.0 , and on day 30 it was 180/l , with a ratio of 0.7 , and a viral load of 790 copies / ml .
haart ( azt , 3tc , lpv / r ) was continued , and ganciclovir maintenance therapy ( once daily 5 mg per bodyweight ) was initiated .
forty two days after treatment initiation , the patient underwent whole brain radiotherapy with a 30 gy cumulative dose .
six months after start of treatment , his hiv viral load was constantly below detectable levels , and after 4 months , cct scan showed cr with leukencephalopathy .
after completion of 3 months of ganciclovir maintenance therapy , the patient received cidofovir monthly for one year after the induction period ( cumulatively 20 times ) against ebv proliferation because of his relatively low cd4-count ( nadir 100/l after 6 months ) .
the cidofovir was then discontinued due to a steadily improving immune response ( cd4count 306/l ) .
ophthalmological and neurological examinations as well as renal function tests were within normal limits 2 years after the start of treatment .
four years from time of diagnosis , cct restaging demonstrated constant marked demyelinization of the cerebral medullary layer , which was most likely radiotherapy - associated .
he remained on haart with azt , 3tc , lpv / r with cd4-counts above 300/l and without a detectable viral load . a year after diagnosis
. pat . 3 after 5 years of treatment with il-2 , azt , haart , foscarnet .
combined first - line therapy with haart , il-2 , foscarnet and azt - high - dose was not effective in reducing tumour growth in the 3 patients .
therefore , standard radiation therapy was indicated after 2 weeks of therapy in all patients .
after 4 months of radiation therapy , patient 3 showed a complete remission of the tumour mass 53 months after diagnosis and a stabilized immune response by haart as well as cidofovir maintenance - therapy ( 20 cycles ) .
lymphoma was suspected because of the high proliferation index and necrotic tissue masses . retrospectively , based upon the positive response to radiation and absence of an early response to immunomodulating therapy ,
a ) , b ) diffuse large b - cell lymphoma within the central nervous tissue penetrating a blood vessel .
c ) the large tumor cells express the b - cell marker cd20 and reveal a high proliverative activity d ) .
e ) in a further case h&e stained section shows a diffuse large b - cell lymphoma .
h ) the proliferation marker mib1 ( ki67 ) labels more than 50% of the tumor cells .
i , j ) the h&e stained sections reveal necrotic cns tissue with reactive astrocytes , macrophages and inflammatory cells .
although these case reports shared comparable clinical characteristics to those treated by raez et al . , they did not have similar results despite having received optimized antiviral medication with foscarnet instead of ganciclovir and demonstrating excellent immune responses in 2 of the 3 patients ( patient 1 was not evaluated for an immune response ) .
combined therapy with il-2 , azt , foscarnet and haart had no effects on reducing tumour growth in our art - naive hiv - positive patients with pcnsl in the short time of administration . by comparison , this differs from raez et al , who reported at least partial remission within two to three weeks in 4 out of 5 patients .
these case reports suggest that this was probably due to rapid pcnsl tumour growth and that azt , which was the only anti - neoplastic agent , was ineffective against lymphoma cell lines .
this finding is concordant to different highly toxic treatment experiences both in hiv - positive and hiv - negative pcnsl patients .
haart was effective in immune reconstitution , but patient 2 did not take it regularly from the time of radiation therapy due to poor adherence . replacing ganciclovir by foscarnet during
foscarnet has been shown to be effective in ebv - associated lymphoproliferations and is activated independently of viral encoded thymidine - kinase , which is an advantage over ganciclovir . however , it was not effective in halting rapid tumor growth in these patients , which had already become independent from the original multifactorial pathogenesis of polyclonal ebv - and hiv - induced lymphoproliferation .
since the herpes - virus consensus pcr was negative in two of the patients ' csf prior to therapy , and not performed in one patient ( histological diagnosis ) , ebv - viral load was not measured .
the reason for the reduced effectiveness of foscarnet compared to ganciclovir against ebv could be not be discerned , and it is unclear why raez and aboulafia elected to utilize ganciclovir .
interleukin-2 was administered to induce an acceleration of immune response , and to decrease ebvdna .
the observed rapid immune reconstitution of cd4 cells by combined antiretroviral and interleukin-2 administration in 2 patients was impressive , nevertheless it had no impact on tumour progression .
of note is that this did eventually contribute to stopping lymphoproliferation after radiation in patient 3 , which is similar to four reported patients with longer lasting remissions by haart and radiation .
even though only lymphoproliferation had been diagnosed in patient 3 , the lymphoproliferative polyclonal tumor with impressive necrotic tissue mass , which is pathognomonic for high grade lymphoma in the brain , was highly suspicious for pcnsl .
polyclonal lymphoproliferation as a pre - lymphoma stage could not be completely ruled out . additionally , patient 3 was the only patient with a relatively stable immune status and without previous aids - defining illnesses at the time of diagnosis .
herpes - consensus pcr in his csf was negative with ebv - positivity in histology , corresponding to a latent infection pattern without active ebv - replication .
ritonavir has been reported to have antiangiogenic and radiation sensitizing effects in a mouse carcinoma model , and could eventually have had an influence on response , but only in this patient . however , after responding to radiation he continued haart with long - term antiviral ebv therapy and was clinically stable over the following years
haart plus whole brain radiation appears to be the mainstay of treatment for hiv - associated pcnsl patients with highly impaired immune and performance status . in
selected cases of hiv - positive pcnsl patients with sufficient performance status , systemic chemotherapy should be considered .
haart and systemic chemotherapy , possibly even in patients with impaired immune status , can be considered in an attempt to induce immune reconstitution and thus improving both neurological and overall clinical status .
combination chemo - radiotherapies in immunocompetent patients ( most of them with intrathecal mtx and/or cytarabine , systemic methotrexate , procarbazine , vincristine , thiotepa , teniposide or carmustine ) cause high rates of hematologic toxicity , treatment - related deaths in up to 10% , infection rates up to 19% and leukoencephalopathy rates of up to 30% ( without radiation 3% ) .
systemic rituximab alone does not generally seem to be beneficial , but may be so only in selected patients . in a small series with relapsed or progressive disease in hiv - negative persons , intrathecal rituximab was shown to be safe and partially effective [ 34 - 36 ] and therefore stands as a possible option .
systemic methotrexate ( mtx ) alone , 3 - 8 g / mand delayed radiotherapy are most frequently used in hiv negative patients , and show median survival times of 22 to 47 months with low neurotoxicity rates [ 7 - 9 ] .
select hiv patients are reported to benefit from high - dose mtx alone : seven out of 15 patients treated with 3 g / m2 intravenous mtx without haart showed a complete response after six cycles , with two of 15 patients dying from septicaemia .
only a few hiv - positive patients with pcnsl were treated with systemic mtx . in the pre - haart era , combined radio - chemotherapy with procarbazine , lomustine and vincristine ( pcv-3 ) for hiv - related pcnsl patients with more than 200 cd4-cells/l , who had a good performance status and without history of opportunistic infection , showed a median survival of 13 months .
autologous stem - cell rescue with high - dose chemotherapy protocols were given successfully in immunocompetent pcnsl patients under the age of 60 years and achieved median survival rates of up to 60 months .
hiv - positive patients were excluded from high - dose studies due to safety reasons .
temozolomide plus systemic mtx/ prednisone in an elderly patient group showed overall survival rates of 36 months , but severe nephrotoxicity and hematological toxicity occurred in 20% and 13% respectively   which is too toxic for aids - patients . a promising schedule for the elderly that utilizes three cycles of rituximab , methotrexate , lomustine , and procarbacine ( r - mcp ) has been described .
the regimen is without radiation , has an acceptable safety profile , and a 12 month overall and disease - free survival of 81% in 16 patients .
this treatment modality could eventually become an option for hiv - positive pcnsl patients , considering that the oldest patient was 83 years old and that a reduced performance status was not an exclusion criteria .
salvage regimens have been performed with topotecan , pcv ( procarbacine , lomustine , vincristine ) , antracyclines , high - dose cytarabine , etoposide , ifosfamide , thiotepa , temozolomide , temozolomide / rituximab , radiotherapy and surgery .
il-2 , haart , azt - high - dose and foscarnet were safe , but ineffective when used as the only therapy for hiv - associated pcnsl based on our experience with these 3 patients .
the numbers of patients treated with similar regimens have been too few to allow any final conclusion .
the deterioration of the overall clinical status in 2 out of 3 patients was rapid , and corresponded to the frequently encountered clinical course of newly diagnosed hiv - associated pcnsl patients , who often have co morbidities .
nevertheless , in select patients with advanced disease and without a systemic chemotherapeutic option , this type of regimen could be considered .
raez and aboulafia et al reported similar cases to the 3 patients that we have described .
a favourable clinical course may more likely occur in select hiv infected patients with good performance status .
two of the 3 patients had severe co morbidities ( tbc , kaposi - sarcoma , cryptococcosis , psychosis ) , so chemotherapy was not a reasonable option .
, patients within clinical studies who have adequate performance status could qualify for more intensive systemic chemotherapy options combined with haart to avoid late leukencephalopathy caused by radiation .
it remains uncertain if interleukin-2 , azt high - dose and/or foscarnet can be added or be given sequentially with chemotherapy , especially in severe compromised patients at the beginning of therapy . despite a substantial and sustained increase in the cd4-count , as compared with antiretroviral therapy alone , interleukin-2 plus antiretroviral therapy yielded no clinical benefit in hiv positive persons .
if chemotherapy is utilized , multidisciplinary teams including specialists in haematology - oncology and infectious diseases will be needed to manage toxicities , drug - interactions , and specific infectious and other complications that can occur during and after therapy .
clinicians should be diligent about detecting and treating cns - lymphoma and other types of cancer in hiv positive patients , and should be encouraged by the improved prognosis due to haart to treat cns - lymphomas more intensively .
finally , we emphasize the importance of performing clinical trials in hiv - positive patients with malignancies .
 purposecombined immunomodulatory and antiviral treatment was administered to three patients with newly diagnosed hiv - associated primary central nervous system lymphoma ( pcnsl ) in an attempt to improve outcomes.patients and methodsthree patients from our institution who were recently diagnosed with hiv - associated pcnsl received intravenous azidothymidine ( azt ) 1.6 gr . 
 bid for two weeks , followed by oral azt 250 mg bid from day 15 . 
 in addition , complementary highly active antiretroviral therapy ( haart ) with a second nucleoside reverse transcriptase inhibitor ( nrti ) plus one protease inhibitor ( pi ) and interleukin 2 ( il-2 ) subcutaneously 2 million units twice daily ( bid ) plus foscarnet 90 mg / kg bid were administered on days 1 - 14 . 
 one patient received anti - epsteinbarr virus ( ebv)-maintenance therapy with ganciclovir , followed by cidofovir [ 1].resultsall patients experienced progressive disease while on induction therapy , and switched early to whole - brain radiation therapy ( wbrt ) as second linetreatment . no grade 3 or 4 toxicities were observed . 
 two patients died on days 50 and 166 respectively due to progressive disease . the third patient with histologically proven lymphoproliferation and only suspected pcnsl remained alive at 53 months . 
 he was on haart and remained clinically and neurologically stable.conclusionalthough il-2 , haart , high - dose azt and foscarnet are used for other hiv - related conditions , they did not demonstrate benefit in lymphoma remission for 2 hivassociated pcnsl patients . 
 the third patient went into delayed remission after additional radiotherapy and was in good clinical and neurological health status over 53 months after diagnosis . 
Introduction
Methods - 3 case reports
Doses and regimens
Results
Patient 1
Patient 2
Patient 3
Overall Results
Discussion
Conclusion
Conflict of interests statement