Final results of phase II trial of doxorubicin HCl liposome injection followed by bexarotene in advanced cutaneous T-cell lymphoma.

BACKGROUND: High response rates for doxorubicin HCl liposome injection (DLI) in cutaneous T-cell lymphoma (CTCL) have been reported with vague criteria until recently. Approximately 50% of CTCL patients respond to bexarotene (Bex). PATIENTS AND METHODS: A phase II trial was carried out to clarify the true overall response rate (ORR) for DLI and to assess the role of sequential Bex. Patients were treated with DLI 20 mg/m(2) i.v. every 2 weeks for 16 weeks (8 doses) followed by 16 weeks with Bex 300 mg/m(2) orally. Response assessments were carried out after 16 (DLI) and 32 weeks (Bex). Skin responses were measured by the modified Severity-Weighted Assessment Tool (mSWAT) and the Composite Assessment of Index Lesion Severity (CA). RESULTS: Thirty-seven patients were treated: stage IV (22, 8 with Sézary syndrome), IIB (10), earlier stage refractory to skin-directed therapies or radiation therapy (5). For 34 assessable patients: ORR 14/34 [41%: partial response (PR) 12, clinical complete response (CCR) 2]. Maximum responses were all seen after 16 weeks DLI. Median progression-free survival (PFS) was 5 months. There were 22 deaths: 21 of disease and 1 of heart failure. Twenty-seven grade 3 and 5 grade 4 toxic events were observed. CONCLUSION(S): With strict criteria, DLI ORR is among the highest reported for single agents in CTCL. Sequential Bex did not increase the response rate or duration.

Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results.

PURPOSE: Cutaneous T-cell lymphomas (CTCL) are malignancies of T cells appearing as skin lesions and are responsive to retinoid therapy. Safety and efficacy of a novel RXR-selective retinoid (rexinoid) bexarotene (Targretin, LGD1069; Ligand Pharmaceuticals Inc, San Diego, CA) was evaluated as a single-agent oral therapy administered once daily in an open-label study in patients with refractory advanced-stage CTCL. PATIENTS AND METHODS: Ninety-four patients with biopsy-confirmed CTCL in advanced stages (IIB-IVB) were enrolled at 26 centers. Fifty-six patients received an initial dose of 300 mg/m2/d oral bexarotene and 38 started at more than 300 mg/m2/d. RESULTS: Clinical complete and partial responses were reported by Primary End point Classification for the study in 45% (25 of 56) of patients enrolled at 300 mg/m2/d dosing. At more than 300 mg/m2/d, 55% (21 of 38) of patients responded, including 13% (five of 38) clinical complete. For the 300 mg/m2/d initial dose group, the rate of relapse after response was 36% and the projected median duration of response was 299 days. Improvements were also seen in overall body-surface area involvement, median index lesion surface area, adenopathy, cutaneous tumors, pruritus, and CTCL-specific quality of life. The most frequent drug-related adverse events included hypertriglyceridemia (associated rarely with pancreatitis), hypercholesterolemia, hypothyroidism, and headache. CONCLUSION: Bexarotene is the first in a novel class of pharmacologic agents, the RXR-selective retinoids, or rexinoids. Bexarotene is orally administered, safe, and generally well tolerated with reversible side effects, and is effective for the treatment of advanced, refractory CTCL.

Treatment of epidemic Kaposi's sarcoma with etoposide or a combination of doxorubicin, bleomycin, and vinblastine.

An epidemic of disseminated Kaposi's sarcoma in male homosexuals has recently been described. Forty-one evaluable patients with epidemic Kaposi's sarcoma were treated with etoposide. The majority of these patients had early stage disease, no prior opportunistic infections, and no prior therapy. Twelve patients (30%) achieved complete remission, 19 (46%) partial remission, and ten (24%) no response. With follow-up time to 31 months, the median response duration is nine months. The median survival of patients with complete and partial remissions has not been reached. A combination of doxorubicin (Adriamycin, Adria Laboratories, Columbus, Ohio), bleomycin, and vinblastine (ABV) was used in 31 evaluable patients with epidemic Kaposi's sarcoma. The majority of these patients had late stage disease, prior opportunistic infections, or had failed prior treatment. Seven patients (23%) achieved complete remission, 19 (61%) partial remission, and five (61%) no response. With follow-up time to 24 months, the median response duration is eight months. The projected median survival for all patients treated with ABV is nine months. Both regimens were well tolerated, with an overall response rate of 76% for etoposide and 84% for ABV. However, while successfully treating the Kaposi's sarcoma, the underlying immune deficiency in these patients has persisted. Future treatments of Kaposi's sarcoma will need to focus on reversing the underlying immune incompetence as well as controlling the malignant manifestations of Kaposi's sarcoma arising in relation to the acquired immune deficiency syndrome.

Mycosis fungoides metastasizing to the brain parenchyma: case report.

OBJECTIVE AND IMPORTANCE: Mycosis fungoides is a rare T-cell lymphoma of the skin that can, in one-half to three-quarters of patients suffering from this disease, involve the viscera in late stages of the disease. Although autopsy series performed more than 2 decades ago showed that the incidence of metastatic mycosis fungoides to the central nervous system is approximately one of seven, a total of only several dozen cases have been reported to date. As compared to meningeal involvement, intraparenchymal metastases are even rarer. We describe a biopsy-proven case of intraparenchymal central nervous system mycosis fungoides in a patient with nonprogressive skin involvement and no detectable visceral involvement, and we present a review of the relevant literature. CLINICAL PRESENTATION: A 68-year-old man, 3 years after the diagnosis of his skin disease, developed fatigue, confusion, and frontal lobe signs without the presence of cerebriform cells in the peripheral blood or any other clinical evidence of visceral involvement. Magnetic resonance imaging revealed a diffuse area of increased T2-weighted signal involving the white matter of both cerebral hemispheres as well as a focal area of T2 abnormality along the body of the corpus callosum. The radiological differential diagnosis was either leukodystrophy caused by chemotherapy, progressive multifocal leukoencephalopathy, or glioma with associated white matter changes. INTERVENTION: A stereotactic serial brain biopsy revealed diffuse perivascular infiltrates of atypical lymphocytes, as well as several large cells with cerebriform nuclei consistent with mycosis fungoides. The cells were immunoreactive for LCA, MT1, UCHL1, and CD3. CONCLUSION: We stress the importance of including mycosis fungoides as part of the differential diagnosis for a brain lesion in patients with cutaneous T-cell lymphoma, because treatments do exist, and we conclude that a serial stereotactic biopsy may be necessary to provide a definitive diagnosis.

A new infrared spectral library of controlled and noncontrolled drug standards using internal reflection spectroscopy.

An infrared spectral library containing 455 controlled and noncontrolled solid drug standards was generated using internal reflection spectroscopy. All attenuated total reflection (ATR) spectra were obtained with small diamond internal reflection elements. ATR spectra will have minor variations from transmission spectra commonly found in commercial infrared libraries.

In vitro suppressor T lymphocyte dysfunction in autoimmune thrombocytopenic purpura associated with a complement-fixing antibody.

Ig secretion of peripheral blood mononuclear cells (PBMC) was measured in Epstein Barr virus (EBV) seropositive autoimmune thrombocytopenic purpura (ATP) patients and controls following in vitro infection with EBV. EBV infected PBMC from patients with ATP secreted Ig for a longer period of time than EBV infected control cells and had higher peak Ig production. Removal of T cells or CD8 cells from control PBMC increased the duration and level of Ig production to that achieved by ATP PBMC. Total T or CD8 cell depletion of ATP PBMC had no effect on the enhanced level or duration of Ig secretion. Depletion of control CD4 lymphocytes decreased Ig production. Treatment of EBV infected control PBMC with either ATP sera or purified IgG (plus complement) increased the duration and level of production of Ig to that observed in ATP PBMC, control PBMC depleted of all T cells or control PBMC depleted of CD8 cells. This antibody effect could be reversed by reconstitution with control T cells. Thus, patients with ATP produce an antibody which leads to suppressor cell dysfunction. Defective function of these cells may lead to a disorder of immune regulation in which autoantibodies are produced against platelets.

A solid-phase radioimmunoassay for bound anti-platelet antibody: studies on 45 patients with autoimmune platelet disorders.

A highly sensitive, solid-phase radioimmunoassay has been developed for detecting platelet-bound immunoglobulin, which employs 125I-staphylococcal protein A. The assay detects platelet IgG at the picogram level, which is 10- to 50-fold more sensitive than currently available procedures. It is relatively simple and can be performed on frozen extracts from as little as 2 X 10(5) platelets. Washed platelets are frozen, thawed, sonicated, and centrifuged at 20,000 X g. The supernatant, which contains 7S IgG, is applied in serial dilution to the wells of a plastic microliter plate capable of adsorbing protein. Commercial rabbit anti-human IgG is added and then "sandwiched" to 125I-staphylococcal protein A. The wells are removed from the plate and assayed for radioactivity. Thirty-two of 35 thrombocytopenic patients (92%) with ATP had platelet IgG values greater than those of controls by 2 S.D. and averaged 150 +/- 145 (S.D.) ng/10(6) platelets; 11 healthy controls, 11.4 +/- 7.4 ng; five "thrombocytopenic" controls, 9.7 +/- 13 ng. The platelet count (X) correlated inversely with IgG/platelet (Y) according to the equation: Log Y = -0.66 log X + 4.8; r = -0.71, p less than 0.001. Elevated platelet IgG levels were also found in 5 ATP patients in "apparent remission"; two of four had evidence for compensated thrombocytolysis (increased megathrombocytes). Elevated platelet IgG levels were also found in six patients with thrombocytopenia secondary to lymphoproliferative disorders.

Heavy-chain subclass of round antiplatelet IgG in autoimmune thrombocytopenic purpura.

The gamma heavy-chain subclass of bound antiplatelet antibody was examined in six patients with autoimmune thrombocytopenic purpura (ATP) by a solid-phase radioimmunoassay. Monospecific antisera for gamma G1, gamma G2, gamma G3, and gamma G4 subclasses were employed in a "sandwich" technique, utilizing the binding of 126I-staphylococcal protein A. We have previously reported that serum antiplatelet antibody was restricted to be gamma G3 subclass in ATP. In contrast, all 4 IgG subclasses were found bound to platelets of ATP patients in the same distribution as that present in normal serum. It is suggested that the differences noted between serum antiplatelet IgG and platelet-bound IgG may represent different mechanisms of platelet injury.

Regulation of autoimmune anti-platelet antibody-mediated adhesion of monocytes to platelet GPIIb/GPIIIa: effect of armed monocytes and the Mac-1 receptor.

Platelet autoantigen-autoantibody-monocyte interaction was studied by utilization of a specific monoclonal antibody (MoAb) 10E5 to trap and immobilize the GPIIb-GPIIIa complex on microtiter plates. Peripheral blood mononuclear cells (PBMC) or purified monocytes formed distinct morphologic clusters after incubation with immobilized antigen for 18 hours at 37 degrees C. PBMC of 18 and 19 patients with autoimmune thrombocytopenic purpura (ATP) formed 48 +/- 6.8 (SEM) clusters/well compared with 7.4 +/- 1.0 for control subjects, P less than .001. The number of clusters per well correlated inversely and exponentially with platelet count, r = -.8, n = 21, indicating that the GPIIb-GPIIIa autoantigen is pathophysiologically relevant. Binding of ATP PBMC to immobilized GPIIb-GPIIIa could be inhibited by F(ab')2 fragments of immunoglobulin (Ig) G of ATP patients, indicating that monocyte IgG bound to autoantigen by its F(ab')2 domain. Optimal cluster formation could be obtained with normal monocytes if preincubated with ATP IgG but not with F(ab')2 fragments of ATP IgG, indicating that ATP IgG binds to monocytes by its Fc domain. Armed monocytes (ie, normal monocytes preincubated with ATP IgG) bound to immobilized autoantigen 5.8-fold greater than normal monocytes incubated with immobilized autoantigen opsonized with ATP IgG. Armed monocyte adhesion could be inhibited 81% from 18.9 +/- 1.6 to 3.6 +/- 0.5 clusters/well by prior fixation with 0.1% formalin, whereas fixation of IgG before arming of monocytes was not inhibitory. MoAb MM41, directed against the alpha m-chain of the Mac-1 adhesive protein receptor of monocytes, inhibited cluster formation by 79%. Thus, (1) armed monocyte interaction with autoantigen is considerably more effective than monocyte interaction with opsonized autoantigen; (2) armed monocyte interaction requires specific F(ab')2-antigen recognition; and (3) monocyte-autoantigen interaction requires a secondary nonimmunologic adhesive event.

Immunologic thrombocytopenic purpura after heterosexual transmission of human immunodeficiency virus (HIV).

We report four cases of immunologic thrombocytopenic purpura related to human immunodeficiency virus (HIV) transmitted through heterosexual contact in persons who were not homosexual, addicted to intravenous narcotic drugs, or hemophilic. Each transmission occurred in a different setting. A 23-year-old white woman had immunologic thrombocytopenic purpura in July 1985, with a platelet count of 11 X 10(9)/L. In January 1987, she had prominent submandibular and posterior cervical adenopathy. A careful social-sexual history revealed several sexual contacts with a male narcotic addict before July 1985. A 27-year-old heterosexual white man had a platelet count of 8 X 10(9)/L in December 1986. A social-sexual history revealed that his fiancée had been an intravenous narcotic addict 6 years ago. A 64-year-old white woman had a platelet count of 75 X 10(9)/L in May 1986, approximately 2 years after she had resumed having sexual intercourse with her husband who had had a triple coronary bypass in October 1983. The husband had received HIV-seropositive blood. A 42-year-old white man had a platelet count of 45 X 10(9)/L, which was associated with a cutaneous eruption refractory to antibiotics and antifungal agents. He had had sexual contacts with several women, who, to the best of his knowledge, were neither prostitutes nor intravenous narcotic addicts. He denied homosexuality or drug abuse. All four patients were HIV-seropositive and had circulating immune complexes and platelet-associated IgG, C3C4, and IgM values that were considerably higher than those usually measured in patients with classic autoimmune thrombocytopenia, averaging 2.4-, 2.2-, 6.5- and 5.2-fold higher, respectively. Thus, HIV-related immunologic thrombocytopenic purpura can be heterosexually spread and should become part of the differential diagnosis of unexplained thrombocytopenia. Obtaining a careful social-sexual history is mandatory in such patients.

Sequestration of anti-platelet GPIIIa antibody in rheumatoid factor immune complexes of human immunodeficiency virus 1 thrombocytopenic patients.

Human immunodeficiency virus 1-related idiopathic thrombocytopenic purpura (HIV-1-ITP) patients have a 4-fold increased percentage of CD5+ B cells and a 4.8-fold increased percentage of serum immune complexes precipitated by polyethylene glycol (PEG-ICs) compared to control subjects, as reported previously. Since CD5+ B cells produce predominantly IgM rheumatoid factor (RF) vs. Fc of IgG and PEG-ICs contain high levels of IgM, we looked for the presence of RF in the immune complexes of HIV-1-ITP patients. PEG-ICs were adsorbed to protein A and dissociated with acid, and IgM and IgG were purified by gel filtration and affinity chromatography. Solid-phase ELISA was used to measure antibody specificity vs. platelets, Fc, and HIV-1 gp120, p24, and CD4. Dissociated IgG antibody reacted with platelets, HIV-1 gp120, p24, and CD4, but not with Fc. Serum IgG did not react with platelets or Fc but did react with HIV-1 gp120, p24, and CD4. Both PEG-IC IgM and serum IgM reacted with Fc as well as the other four antigens. Control IgM and IgG were unreactive. Isolated IgM from PEG-ICs relocated approximately 50% of the IgG preincubated with IgM to the Vo region of a G200 gel-filtration column. Anti-platelet IgG but not IgM could be affinity-purified from fixed platelets. Both F(ab')2 fragments of anti-platelet IgG and the total PEG-IC bound to platelets in a saturation-dependent manner. F(ab')2 of anti-platelet IgG inhibited 50% binding of PEG-IC to platelets at an F(ab')2/complex ratio of 3:1 (wt/wt). Scatchard analysis revealed two classes of binding sites: high-affinity Kd values of 0.8-1.8 nM and lower-affinity Kd values of 6.6-12.3 nM with respective numbers of binding sites of 44,000-57,000 and 122,000-256,000 (n = 4). Anti-platelet IgG of 6/6 patients precipitated GPIIIa from platelet lysates of surface 125I-labeled platelets. Platelet count correlated inversely with anti-platelet IgG (r = -0.73; P < 0.01; n = 27). Thus, PEG-ICs of HIV-1-ITP patients contain IgM RF, which sequesters serum anti-platelet IgG containing anti-GPIIIa. Anti-platelet IgG contributes to binding of immune complexes to platelets and correlates with thrombocytopenia.

Easy bruising, thrombocytopenia, and elevated platelet immunoglobulin G in Graves' disease and Hashimoto's thyroiditis.

Platelet IgG levels, count, and function and easy bruising or bleeding were studied in 25 patients with Graves' disease and 12 with Hashimoto's thyroiditis (normal value for platelet IgG 10.7 +/- 4.5 ng [SD]/10(6) platelets). Eight of 22 patients with Graves' disease and normal platelet counts had elevated platelet IgG averaging 38 +/- 4.0 ng (SEM) (range, 24 to 60). Four of 10 patients with Hashimoto's thyroiditis and normal platelet counts ahd elevated platelet IgG averaging 45 +/- 7.2 ng (range, 27 to 66). Five patients with thrombocytopenia had platelet counts averaging 53000 +/- 12000/microL (SEM) and elevated platelet IgG averaging 154 +/- 40 ng (range, 27 to 300). Twelve of 15 patients with a history of easy bruising or bleeding had elevated platelet IgG compared to five of 22 without easy bruising (p < 0.001). Four of six with elevated platelet IgG had one or more abnormal in-vitro platelet aggregation measurements (particularly with epinephrine) compared to none of six with normal platelet IgG levels (p = 0.03). We conclude that elevated platelet IgG is associated with easy bruising and thrombocytopenia in about half of patients with Graves' disease or Hashimoto's thyroiditis.

Role of leuCAM integrins and complement in platelet-monocyte rosette formation induced by immune complexes of human immunodeficiency virus-type 1-immune thrombocytopenic purpura patients.

Patients with human immunodeficiency virus-type 1-immune thrombocytopenic purpura (HIV-1-ITP) have elevated polyethylene glycol (PEG)-precipitable immune complexes (ICs) composed of IgG, IgM, and complement that are threefold to sevenfold higher than in healthy control subjects. These complexes contain anti-F (ab')2 as well as anti-idiotype antibodies versus anti-HIV-1gp120. Because anti-F (ab')2 and anti-idiotype antibodies correlate with thrombocytopenia (r = .83 [J Clin Invest 77:1756, 1986] and r = .90 [J Clin Invest 89:356, 1992], respectively) we studied the binding of ICs to platelets and monocytes as well as their role in platelet-monocyte rosette formation. ICs bind to platelets in a saturation-dependent manner (optimum at 10 micrograms/mL; 0.5% of serum conc). Binding to platelets could not be inhibited with platelet saturating concentrations of aggregated IgG or with monoclonal antibody (MoAb) IV.3 versus FcR gamma II. Platelet binding could be inhibited with Fab anti-C3, anti-Clq, or anti-C4 by 57%, 40%, and 46% respectively, not with control Fab (P < .001). Monocytes from HIV-1-ITP patients form rosettes with normal platelets 16.8 +/- 5.2 rosettes/100 monocytes compared with 4.8 +/- 0.8 control monocytes plus normal platelets (P = .009). Gel-washed HIV-1-ITP platelets formed 19 +/- 2.0 rosettes with U937 cells compared to 6.3 +/- 1.0 for normal platelets (P = 0.001). Arming of U937 cells with HIV-1-ITP ICs (5 micrograms/mL) formed 36.7 +/- 2.5 rosettes compared with 10.6 +/- 1.2 for control ICs (P < .01). Rosetting of armed U937 cells could be inhibited with MoAbs versus the alpha chains of CD11a (LFA-1), 11b (Mac-1), or 11c (p150,95) by 67%, 70%, and 61%, respectively (P < .007), whereas binding of ICs to U937 cells was unaffected. Isotype-matched control as well as MoAbs versus antigens on U937 cells (CD13, CD33) or the anti-FcR gamma II receptor had no effect. However, Fab fragments of polyclonal anti-C3 inhibited rosette formation by 78% (P < .01); control Fab had no effect. Thus, platelet-monocyte rosette formation is not Fc dependent. It is complement receptor dependent and requires the cooperation of all three leuCAM integrins.

Large-cell variants of mantle cell lymphoma: cytologic characteristics and p53 anomalies may predict poor outcome.

Large-cell variants are uncommon in mantle cell lymphoma (MCL). Here we describe the pathologic and clinical findings in five patients with large-cell lymphoma related to MCL (L-MCL), and compare them to a group of classic small-cell MCL (s-MCL) cases. Histologically, the MC origin of the large cells was evinced by their association with a small mantle cell component in the same tissue, or their distribution in a classic mantle zone pattern, or their development in a patient with previous s-MCL. The large cells were either pleomorphic mantle cells (case 1) or transformed blast-like cells (case 2-5). The median nuclear diameter, median nuclear area and proliferation index of L-MCLs and s-MCLs, were statistically different. Immunophenotypic characterization of four specimens of L-MCL and 10 of s-MCLs with a large panel of antibodies showed the classic findings of MCL, i.e. the IgM+ D+/-, CD5+, CD10-, CD23- phenotype in all cases except two (one CD5- and one CD23+), and the association with a loose follicular dendritic cell network. Two of four L-MCLs and 5/10 s-MCLs demonstrated rearrangements of the bcl-1 gene by Southern blot or by polymerase chain reaction (PCR); 2/4 L-MCLs and 1/9 s-MCLs had p53 mutations on single-strand conformation polymorphism analysis; none of the 14 specimens showed rearrangement of bcl-2 by PCR or bcl-6 and c-myc by Southern blot. All patients with 'transformed' histology (versus 37% of all others) died of lymphoma; their survival (15-18 months; median 17) was much shorter than that of all the others (28-117+ months; median 43) (P=0.0035). All three patients with p53 anomalies, two of whom had tumours with transformed histology, died of their disease in a short time (15, 18 and 28 months). In contrast, the presence of bcl-1 rearrangements did not have prognostic implications. This study documents the existence of large-cell variants of MCL and the poor prognosis associated with the 'transformed' cytologic type and/or p53 abnormalities.

Kaposi's sarcoma in homosexual men-a report of eight cases.

The clinical findings in eight young homosexual men in New York with Kaposi's sarcoma showed some unusual features. Unlike the form usually seen in North America and Europe, it affected younger men (4th decade rather than 7th decade); the skin lesions wee generalised rather than being predominantly in the lower limbs, and the disease was more aggressive (survival of less than 20 months rather 8-13 years). All eight had had a variety of sexually transmitted diseases. All those tested for cytomegalovirus antibodies and hepatitis B surface antigen of anti-hepatitis B antibody gave positive results. This unusual occurrence of Kaposi's sarcoma in a population much exposed to sexually transmissible diseases suggests that such exposure may play a role in its pathogenesis.

Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma.

BACKGROUND: The median survival for adults with glioblastoma multiforme (GBM) is 12 months, despite surgery, radiation, and chemotherapy. Regimens using interleukin-2 (IL-2) plus lymphokine-activated killer (LAK) cells have been beneficial against systemic cancers, albeit with significant toxicity. METHODS: Nineteen adults with recurrent malignant glioma (5 GBMs, and 4 anaplastic astrocytomas (AA)), Karnofsky performance status 60 or greater, were treated with intracavitary autologous LAK cells plus IL-2 after reoperation. Lymphokine-activated killer cells and IL-2 were given on day 1, and IL-2 alone was given 5 times during a 2-week cycle. This cycle was repeated at 2 weeks to constitute one 6-week course of therapy. Each two-cycle course of treatment was repeated at 3-month intervals for patients with stable disease or response to therapy. At the conclusion of immunotherapy, all patients were offered chemotherapy, generally carmustine or procarbazine, including responders. Corticosteroids were strictly limited during immunotherapy. Sequential reservoir aspirates were obtained for microbiologic and cytologic analyses. RESULTS: The maximal tolerated dose for a 12-dose course of therapy was 1.2 million international units (MIU) per dose. Dose-limiting, cumulative IL-2-related central nervous system (CNS) toxicity was observed at 2.4 MIU per dose. Three responses were confirmed by computed tomography scan during therapy: one complete response (CR) (1 AA), and two partial responses (PR) (2 GBM); as well as a significant increase in GBM survival. One additional CR (GBM) was observed at 17 months. The median survival for immunotherapy patients with GBM was 53 weeks after reoperation (N = 15) (mean, 87.9 +/- 21.4 weeks, standard error for the mean), with 8 of 15 surviving more than 1 year (53%). The median survival for 18 contemporary patients with GBM reoperated and treated with chemotherapy was 25.5 weeks (mean, 27.4 +/- 3.7 weeks), with 1/18 alive at 1 year (> 6%). Six of the 15 patients with GBM had additional surgery or biopsy, and chemotherapy after immunotherapy. The contribution of subsequent chemotherapy to survival cannot be discounted. CONCLUSIONS: Lymphokine-activated killer cells and IL-2 can be administered safely within the CNS resulting in improved long term survival in patients with recurrent glioblastoma. Increased survival was associated with significant biologic changes characterized by a regional eosinophilia, and extensive lymphocytic infiltration. A prospective randomized clinical trial is warranted.