How I treat CNS lymphomas.

The pathogenesis of primary and secondary central nervous system (CNS) lymphoma poses a unique set of diagnostic, prognostic, and therapeutic challenges. During the past 10 years, there has been significant progress in the elucidation of the molecular properties of CNS lymphomas and their microenvironment, as well as evolution in the development of novel treatment strategies. Although a CNS lymphoma diagnosis was once assumed to be uniformly associated with a dismal prognosis, it is now reasonable to anticipate long-term survival, and possibly a cure, for a significant fraction of CNS lymphoma patients. The pathogenesis of CNS lymphomas affects multiple compartments within the neuroaxis, and proper treatment of the CNS lymphoma patient requires a multidisciplinary team with expertise not only in hematology/oncology but also in neurology, neuroradiology, neurosurgery, clinical neuropsychology, ophthalmology, pathology, and radiation oncology. Given the evolving principles of management and the evidence for improvements in survival, our goal is to provide an overview of current knowledge regarding the pathogenesis of CNS lymphomas and to highlight promising strategies that we believe to be most effective in establishing diagnosis, staging, and therapeutic management.

CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma.

Establishing the diagnosis of focal brain lesions in patients with unexplained neurologic symptoms represents a challenge. The goal of this study is to provide evidence supporting functional roles for CXC chemokine ligand (CXCL)13 and interleukin (IL)-10 in central nervous system (CNS) lymphomas and to evaluate the utility of each as prognostic and diagnostic biomarkers. We demonstrate for the first time that elevated CXCL13 concentration in cerebrospinal fluid (CSF) is prognostic and that CXCL13 and CXCL12 mediate chemotaxis of lymphoma cells isolated from CNS lymphoma lesions. Expression of the activated form of Janus kinase 1 supported a role for IL-10 in prosurvival signaling. We determined the concentration of CXCL13 and IL-10 in CSF of CNS lymphoma patients and control cohorts including inflammatory and degenerative neurologic disease in a multicenter study involving 220 patients. Bivariate elevated CXCL13 plus IL-10 was 99.3% specific for primary and secondary CNS lymphoma, with sensitivity significantly greater than reference standard CSF tests. These results identify CXCL13 and IL-10 as potentially important biomarkers of CNS lymphoma that merit further evaluation and support incorporation of CXCL13 and IL-10 into diagnostic algorithms for the workup of focal brain lesions in which lymphoma is a consideration.

CNS intravascular large cell lymphoma in a patient with autoimmune hemolytic anemia.

Intravascular large cell lymphoma (IVLCL) is a rare disease characterized by proliferation of malignant lymphocytes within the small blood vessel lumens. The association of IVLCL with autoimmune hemolytic anemia (AIHA) has been described in a single case report, but the true prevalence of this co-occurrence is not known because of declining autopsy rates. Here, we report a case of a 41-year-old woman who carried a diagnosis of AIHA for 2 years, with repeated hemolytic episodes that were initially well controlled with immunomodulatory treatment. At her last presentation, the patient developed rapidly progressive neurologic symptoms and leukoencephalopathy on MRI; she died 4 weeks later with a clinical impression of thrombotic microangiopathy, a known complication of AIHA. At autopsy, the brain showed widespread platelet thrombi and intraparenchymal hemorrhages characteristic of this disorder. In addition, there was evidence of a clinically unsuspected IVLCL, most likely of B-cell lineage. This case illustrates a potential association between IVLCL and AIHA, highlights the need for broad differential diagnosis in cases with atypical disease presentation or progression, and underlines the importance of autopsy in establishing the full cause of morbidity and mortality.

In-transit intramammary sentinel lymph nodes from malignant melanoma of the trunk.

OBJECTIVE: Our goal was to determine the incidence and outcomes of intramammary in-transit sentinel lymph nodes (IMSLN) from primary malignant melanoma (MM) of the trunk. We hypothesize that regional metastasis to the breast from anterior trunk MM also occurs via the lymphatic system to these intramammary in-transit sentinel lymph nodes. BACKGROUND: MM is the most common solid tumor metastasis to the breast. The mechanism of intramammary (IM) metastasis is generally attributed to hematogenous rather than lymphatic spread. METHODS: We retrospectively reviewed medical records from all patients who underwent selective sentinel lymph node dissection at the UCSF Melanoma Center from 1993 to 2008 after the approval of UCSF Committee on Human Research. Of the 1911 cases, we found 614 patients with primary MM located on the trunk, and queried their medical records for in-transit SLN and SLNs in the breast. Data from preoperative lymphoscintigraphy, intraoperative lymphatic mapping, operative notes, and pathology and clinic notes were gathered. RESULTS: Of the 1911 patients with MM, 169 (8.9%) and 420 (22.0%) had anterior and posterior trunk lesions, respectively, and 25 patients (1.3%) with flank lesions (lateral abdominal wall below the rib cage, above the iliac crest). Of the anterior trunk population, 18 patients had in-transit SLNs. The vast majority of these patients (14 of 18, 77.8%) had in-transit IMSLN. Of patients with posterior trunk melanoma, 27 patients had in-transit nodes with 1 patient having IMSLNs. Of patients with flank melanomas, 3 patients had in-transit nodes with 1 patient having IMSLNs. Interestingly, all patients with IMSLNs had primary lesions located inferior to the breasts. Two of the 16 patients with IMSLNs had micrometastasis to IMSLN; 1 patient died and the other currently is disease free 4 years after initial SLND. Four of the 32 patients with non-IM in-transit nodes had micrometastases to these in-transit nodes. Of all patients with trunk melanomas, 4 patients had micrometastases to axillary SLNs (AxSLNs). Three of the 4 patients with positive AxSLNs also had positive in-transit nodes whereas only half of the patients with positive in-transit SLNs had positive AxSLNs. CONCLUSIONS: IMSLNs exist in the breast. Our results establish an anatomic basis for lymphatic metastasis to the breast from primary cutaneous melanoma mainly from the anterior trunk inferior to the breasts. For anterior trunk melanomas, IMSLNs should not be overlooked during SLND as they may harbor micrometastasis.

Use of an expanded immunohistochemical panel to distinguish cutaneous Hodgkin lymphoma from histopathologic imitators.

In lymph nodes, classical Hodgkin lymphoma can typically be distinguished from non-Hodgkin lymphoma (NHL) by the presence of Hodgkin and Reed-Sternberg cells that co-express CD30 and CD15. However, anaplastic large cell lymphoma (ALCL) and diffuse large B-cell lymphoma (DLBCL) can show identical features, and some cases of classical Hodgkin lymphoma lack CD15 expression, rendering them difficult to differentiate from CD30-positive NHL. The differential diagnosis of cutaneous Hodgkin lymphoma similarly includes ALCL and DLBCL, and, additionally, tumors of mycosis fungoides. Recent studies have shown that classical Hodgkin lymphoma is of B-cell origin in virtually all cases, and shows at least focal weak expression of the B-cell marker PAX5 and often focal weak expression and no expression of the B-cell markers Oct-2 and BOB.1, respectively. All three of these markers are almost invariably absent in T-cell lymphomas and are strongly expressed in B-cell lymphomas. We report a 40-year-old man with classical Hodgkin lymphoma who developed cutaneous nodules. A biopsy from one revealed Hodgkin/Reed-Sternberg cells with a similar immunophenotype to the diagnostic lymph node biopsy, namely CD30+/CD15+, diffusely but weakly PAX5+, focally weakly Oct-2+ and lacking BOB.1 expression, thereby confirming a diagnosis of cutaneous Hodgkin lymphoma. To our knowledge, this is the first report of the expression pattern of the combination of PAX5, Oct-2 and BOB.1 in the context of cutaneous involvement by Hodgkin lymphoma.

Selective sentinel lymph node dissection for melanoma: importance of harvesting nodes with lower radioactive counts without the need for blue dye.

BACKGROUND: Determining how many sentinel lymph nodes (SLNs) should be removed for melanoma is important. The purpose of this study is to determine the frequency at which nodes that are less radioactive than the "hottest" node (which is negative) are positive for melanoma, how low of a radioactivity should warrant harvest, and if isosulfan blue is necessary. METHODS: We reviewed 1,152 melanoma patients who underwent lymphoscintigraphy with technetium, with or without blue dye, and SLN dissection from 1996 to 2008. SLNs with radioactivity ≥10% of the "hottest" SLN, all blue nodes, and all suspicious nodes were removed and analyzed. The miss rate was calculated as the proportion of node positive cases in which the "hottest" SLN was negative. RESULTS: SLNs were identified in 1,520 nodal basins in 1,152 patients. SLN micrometastases were detected in 218 basins (14%) in 204 patients (18%). In 16% of SLN-positive patients (33/204 patients), the positive SLN was found to have a lower radioactive count than the "hottest" SLN, which was negative. In 21 of these cases, the positive SLNs had radioactivity ≤50% of the "hottest" SLN. The 10% rule significantly reduced the miss rate to 2.5% compared with removal of only the "hottest" SLN (miss rate = 16%). Also, blue dye did not significantly decrease the miss rate compared with radiocolloid alone using the 10% rule. CONCLUSIONS: To decrease the miss rate, all SLNs with ≥10% of the ex vivo radioactivity of the "hottest" SLN should be removed and blue dye is not essential.

Pathologic correlates of primary central nervous system lymphoma defined in an orthotopic xenograft model.

PURPOSE: The prospect for advances in the treatment of patients with primary central nervous system lymphoma (PCNSL) is likely dependent on the systematic evaluation of its pathobiology. Animal models of PCNSL are needed to facilitate the analysis of its molecular pathogenesis and for the efficient evaluation of novel therapeutics. EXPERIMENTAL DESIGN: We characterized the molecular pathology of CNS lymphoma tumors generated by the intracerebral implantation of Raji B lymphoma cells in athymic mice. Lymphoma cells were modified for bioluminescence imaging to facilitate monitoring of tumor growth and response to therapy. In parallel, we identified molecular features of lymphoma xenograft histopathology that are evident in human PCNSL specimens. RESULTS: Intracerebral Raji tumors were determined to faithfully reflect the molecular pathogenesis of PCNSL, including the predominant immunophenotypic state of differentiation of lymphoma cells and their reactive microenvironment. We show the expression of interleukin-4 by Raji and other B lymphoma cell lines in vitro and by Raji tumors in vivo and provide evidence for a role of this cytokine in the M2 polarization of lymphoma macrophages both in the murine model and in diagnostic specimens of human PCNSL. CONCLUSION: Intracerebral implantation of Raji cells results in a reproducible and invasive xenograft model, which recapitulates the histopathology and molecular features of PCNSL, and is suitable for preclinical testing of novel agents. We also show for the first time the feasibility and accuracy of tumor bioluminescence in the monitoring of a highly infiltrative brain tumor.

Prognostic implications of positive nonsentinel lymph nodes removed during selective sentinel lymphadenectomy for breast cancer.

Nonsentinel lymph nodes (SLNs) are commonly removed at the time of selective sentinel lymphadenectomy (SSL). Their predictive value for the rest of the nodal basin is unknown. A retrospective review of 436 breast cancer patients who underwent SSL between 12/97 and 04/03 at a single institution. One-hundred nineteen patients had non-SLNs removed at SSL; eight were positive (6.7%). Positive non-SLNs predicted that SLNs would also be positive (p = 0.008). There was no difference in rates of additional positive nodes found on completion axillary node dissection between the non-SLN and SLN positive patients (p = 0.62). After adjustment for covariates, the presence of positive non-SLNs was not associated with poorer disease free survival (p = 0.24), time to systemic recurrence (p = 0.57), or overall survival (p = 0.70). Positive non-SLNs removed during SSL are not a significant risk factor for additional positive nodes on completion axillary nodal dissection (CALND) or for worse survival than positive SLNs.

Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma.

There is an unmet need for effective biological therapies for relapsed central nervous system (CNS) lymphoma. Lenalidomide is active in activated B-cell type diffuse large B-cell lymphoma and rituximab is effective in CNS lymphoma. These observations are the basis for this first trial of an immunomodulatory drug as monotherapy in CNS lymphoma, and, in patients with inadequate responses to lenalidomide, with rituximab. In an independent cohort, we evaluated lenalidomide maintenance after salvage with high-dose methotrexate or focal irradiation in relapsed primary CNS lymphoma (PCNSL). We determined safety, efficacy, and cerebrospinal fluid (CSF) penetration of lenalidomide at 10-, 15-, and 20-mg dose levels in 14 patients with refractory CD20+ CNS lymphoma. Nine subjects with relapsed, refractory CNS lymphoma achieved better than partial response with lenalidomide monotherapy, 6 maintained response ≥9 months, and 4 maintained response ≥18 months. Median progression-free survival for lenalidomide/rituximab was 6 months. In the independent cohort, response duration with lenalidomide maintenance after complete responses 2 through 5 were significantly longer than response durations after standard therapy. The CSF/plasma partition coefficient of lenalidomide was ≥20% at 15- and 20-mg dose levels. Change in CSF interleukin-10 at 1 month correlated with clinical response and response duration to lenalidomide. Metabolomic profiling of CSF identified novel biomarkers, including lactate, and implicated indoleamine-2,3 dioxygenase activity with CNS lymphoma progression on lenalidomide. We conclude that lenalidomide penetrates ventricular CSF and is active as monotherapy in relapsed CNS lymphomas. We provide evidence that maintenance lenalidomide potentiates response duration after salvage in relapsed PCNSL and delays whole brain radiotherapy (WBRT). This trial was registered at www.clinicaltrials.gov as #NCT01542918.

Long-term survival in AIDS-related primary central nervous system lymphoma.

BACKGROUND: The optimal therapeutic approach for patients with AIDS-related primary central nervous system lymphoma (AR-PCNSL) remains undefined. While its incidence declined substantially with combination antiretroviral therapy (cART), AR-PCNSL remains a highly aggressive neoplasm for which whole brain radiotherapy (WBRT) is considered a standard first-line intervention. METHODS: To identify therapy-related factors associated with favorable survival, we first retrospectively analyzed outcomes of AR-PCNSL patients treated at San Francisco General Hospital, a public hospital with a long history of dedicated care for patients with HIV and AIDS-related malignancies. Results were validated in a retrospective, multicenter analysis that evaluated all newly diagnosed patients with AR-PCNSL treated with cART plus high-dose methotrexate (HD-MTX). RESULTS: We provide evidence that CD4+ reconstitution with cART administered during HD-MTX correlates with long-term survival among patients with CD4 <100. This was confirmed in a multicenter analysis which demonstrated that integration of cART regimens with HD-MTX was generally well tolerated and resulted in longer progression-free survival than other treatments. No profound differences in immunophenotype were identified in an analysis of AR-PCNSL tumors that arose in the pre- versus post-cART eras. However, we detected evidence for a demographic shift, as the proportion of minority patients with AR-PCNSL increased since advent of cART. CONCLUSION: Long-term disease-free survival can be achieved in AR-PCNSL, even among those with histories of opportunistic infections, limited access to health care, and medical non-adherence. Given this, as well as the long-term toxicities of WBRT, we recommend that integration of cART plus first-line HD-MTX be considered for all patients with AR-PCNSL.

A phase II trial of rosiglitazone in patients with thyroglobulin-positive and radioiodine-negative differentiated thyroid cancer.

BACKGROUND: Rosiglitazone is a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist that has been shown to induce differentiation, cell cycle arrest, and apoptosis in a variety of human cancers including thyroid cancer. METHODS: Ten patients with differentiated thyroid cancer were enrolled in an open-label, phase II trial of oral rosiglitazone treatment (4 mg daily for 1 week, then 8 mg daily for 7 weeks). The levels of PPARgamma receptor mRNA and protein expression were determined in the patient's neoplasm. RESULTS: Of 10 patients, 4 had positive radioiodine scans after rosiglitazone therapy with uptake in the neck in 3 patients and in the pelvis in 1 patient. After treatment, the serum thyroglobulin level decreased in 2 patients, increased in 5 patients, and was stable in 3 patients. No patient developed clinically important toxicity associated with rosiglitazone treatment. We found no relationship in the level of PPARgamma mRNA and protein expression in patients who had radioiodine uptake compared with those who did not. CONCLUSIONS: Our findings suggest that rosiglitazone treatment may induce radioiodine uptake in some patients with thyroglobulin-positive and radioiodine-negative differentiated thyroid cancer. We found no relationship between the expression level of the PPARgamma mRNA and protein in the neoplasm and radioiodine uptake status after rosiglitazone therapy, questioning the potential pathway of effect.

Molecular pathogenesis of primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is an aggressive form of non-Hodgkin lymphoma (NHL) typically associated with a worse prognosis than other localized extranodal lymphomas with similar histological characteristics. The defining feature of PCNSL is its confinement to the central nervous system (CNS), with proclivity for growth within the leptomeningeal as well as intraocular compartments. Primary CNS lymphoma rarely disseminates outside the CNS and accounts for less than 5% of all primary brain neoplasms. At least 95% of PCNSLs are of large B-cell histology, the most common subtype of NHL. Consistent with the trend seen in systemic NHLs, the incidence of PCNSL has markedly increased over the past three decades, both in immunocompromised and immunocompetent patients. Because PCNSL is relatively rare, the identification of molecular prognostic biomarkers and the definition of a standard therapeutic strategy have been challenging. The authors discuss the current knowledge of the molecular pathogenesis of CNS lymphomas and review the recent advances in gene expression profile analysis and identification of novel prognostic biomarkers.

Genomic copy number analysis of non-small cell lung cancer using array comparative genomic hybridization: implications of the phosphatidylinositol 3-kinase pathway.

Genomic abnormalities at 348 loci encoding genes that may contribute to lung cancer transformation and progression were assessed using array comparative genomic hybridization in 21 squamous carcinomas (SqCas) and 16 adenocarcinomas (AdCas). Hierarchical clustering showed a clear pattern of gains and losses for the SqCas, whereas the pattern for AdCas was less distinct. Cross-validated classification using a K-nearest-neighbor assigned, on average, 32 of 37 samples to their proper histological subtype. The most noticeable differences between SqCas and AdCas were gain of chromosome 3q22-q26 and loss of chromosome 3p. These occurred almost exclusively in SqCas. The region of recurrent increase is approximately 30 Mb in extent, ranging from EVI1 to TFRC. PIK3CA, the alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is in this region. The PIK3CA copy number increase was validated using fluorescence in situ hybridization to lung cancer tissue microarrays. Activity of the downstream PI3K effector protein kinase B (PKB) was higher in SqCas than in AdCas and was correlated with PIK3CA copy number (r = 0.75), suggesting that these copy number increases contribute to activation of PI3K signaling in SqCas of the lung.

Pathology and genetics of primary central nervous system and intraocular lymphoma.

Ongoing studies based on gene expression profile analysis using microarrays have provided preliminary evidence for significant molecular distinctions between primary central nervous system lymphoma (PCNSL) and nodal lymphomas of the large B-cell type. The application of array-based comparative genomic hybridization techniques attempts to identify genomic distinctions between PCNSL and nodal lymphomas and to identify the molecular markers that relate to prognosis. It is possible that insights gained from these studies will facilitate the development of targeted therapies, which address the fundamental genetic mutations that drive PCNSL and intraocular lymphoma growth.

Id1 gene expression is up-regulated in hyperplastic and neoplastic thyroid tissue and regulates growth and differentiation in thyroid cancer cells.

The Id (inhibitor of DNA binding) proteins are a family of helix-loop-helix (HLH) proteins (Id1, Id2, Id3, and Id4) that lack the basic domain necessary for DNA binding. The Id1 protein enhances cell proliferation and inhibits cellular differentiation in a variety of cell types. We have previously demonstrated that the Id1 gene is up-regulated in papillary and medullary thyroid cancers. In this study we characterized the expression and distribution of the Id1 protein in normal, hyperplastic, and neoplastic human thyroid tissue. We also evaluated the effect of the Id1 gene on thyroid cancer cell growth and markers of thyroid cell differentiation. We used semiquantitative immunohistochemistry to characterize Id1 protein expression in normal, hyperplastic (multinodular goiter and Graves' disease), and neoplastic thyroid tissue from 103 patients. Normal thyroid tissue had the lowest level of Id1 protein expression (P < 0.0001). Anaplastic thyroid cancer had the highest level (vs. benign and malignant thyroid tissues, P < 0.01). Id1 protein expression was higher in malignant thyroid tissue than in hyperplastic thyroid tissue (P < 0.02). We found no significant association between the level of Id1 protein expression and patient age, sex, tumor-node-metastasis stage, tumor size, primary tumor vs. lymph node metastasis, primary tumor vs. recurrent tumors, and extent of tumor differentiation. Inhibiting Id1 mRNA expression in thyroid cancer cell lines using Id1 antisense oligonucleotides resulted in growth inhibition (P < 0.03) and decreased thyroglobulin and sodium-iodine symporter mRNA expression (P < 0.02). In conclusion, Id1 is overexpressed in hyperplastic and neoplastic thyroid tissue and directly regulates the growth of thyroid cancer cells of follicular cell origin, but is not a marker of aggressive phenotype in differentiated thyroid cancer.

The helix-loop-helix protein, Id-1, is overexpressed and regulates growth in papillary thyroid cancer.

BACKGROUND: Members of the Id helix-loop-helix proteins are key regulators of cell growth and differentiation in a variety of cell types. They are also required for cell cycle progression and regulate tumor angiogenesis. Furthermore, deregulated expression of Id proteins has been observed in some human malignancies. Therefore we hypothesized that the Id-1 gene may play a role in papillary thyroid carcinogenesis. METHODS: Id-1 gene expression was characterized by Northern blot analysis and Id-1 immunohistochemistry in human thyroid tissue. Id-1 gene expression and regulation was evaluated in a human papillary thyroid cancer cell line, TPC-1, by Northern blot analysis. RESULTS: The Id-1 gene was significantly overexpressed in papillary thyroid cancer compared with normal thyroid tissue from the same patients (n = 18) by both Northern blot analysis and semiquantitative Id-1 immunohistochemistry (P <.001). Id-1 immunoreactivity was primarily localized to the cytoplasm of the thyroid follicular cells. In the TPC-1 cell line, stimulation by TSH and serum up-regulated Id-1 mRNA expression 1.5- and 4.0-fold, respectively. Activation of the mitogen intracellular protein kinase A and protein kinase C signaling pathways also up-regulated Id-1 mRNA expression. Inhibition of Id-1 mRNA expression with Id-1 antisense oligonucleotide inhibited growth compared with control Id-1 sense and random oligonucleotides (P <.05). CONCLUSIONS: The Id-1 gene is overexpressed in papillary thyroid cancer. Id-1 may play a role in the regulation of growth in papillary thyroid cancer.

Genomic alterations in human mesothelioma including high resolution mapping of common regions of DNA loss in chromosome arm 6q.

BACKGROUND: Molecular genetic analysis of 14 freshly resected human mesotheliomas was used to identify regions in the tumor genomes that display DNA copy number alterations, especially the regions that may harbor tumor suppressor genes. MATERIALS AND METHODS: Three methods for molecular analysis were used, comparative genomic hybridization (CGH), loss of heterozygosity (LOH) and a new method, quantitative microsatellite analysis (QuMA). RESULTS: The most frequent alteration detected by CGH and LOH was deletion in chromosome 6q, for which QuMA was performed at 30 different loci so as to define the region(s) of common deletion(s). Our data indicates that there are three independent regions of common deletion, one of size 8.4 Mb located at 6q14, a second of size 15.9 Mb at 6q22 and a third of size 12.0 Mb at 6q24. CONCLUSION: This suggests that at least 3 tumor suppressor genes mapped to chromosome 6q are commonly involved in the pathogenesis of mesothelioma.

Vasal injury during inguinal herniorrhaphy: a case report and review of the literature.

An injury to the vas deferens during inguinal herniorrhaphy from possible tethering of the vas has not, to our knowledge, previously been described in the surgical literature. We report a case of iatrogenic injury of the vas deferens that occurred during elective hernia repair in a 28-year-old man who had previously sustained blunt trauma to the abdomen and pelvis.

Immunochemotherapy with intensive consolidation for primary CNS lymphoma: a pilot study and prognostic assessment by diffusion-weighted MRI.

PURPOSE: We evaluated a novel therapy for primary central nervous system lymphoma (PCNSL) with induction immunochemotherapy with high-dose methotrexate, temozolomide, and rituximab (MT-R) followed by intensive consolidation with infusional etoposide and high-dose cytarabine (EA). In addition, we evaluated the prognostic value of the minimum apparent diffusion coefficient (ADC(min)) derived from diffusion-weighted MRI (DW-MRI) in patients treated with this regimen. EXPERIMENTAL DESIGN: Thirty-one patients (median age, 61 years; median Karnofsky performance score, 60) received induction with methotrexate every 14 days for 8 planned cycles. Rituximab was administered the first 6 cycles and temozolomide administered on odd-numbered cycles. Patients with responsive or stable central nervous system (CNS) disease received EA consolidation. Pretreatment DW-MRI was used to calculate the ADC(min) of contrast-enhancing lesions. RESULTS: The complete response rate for MT-R induction was 52%. At a median follow-up of 79 months, the 2-year progression-free and overall survival were 45% and 58%, respectively. For patients receiving EA consolidation, the 2-year progression-free and overall survival were 78% and 93%, respectively. EA consolidation was also effective in an additional 3 patients who presented with synchronous CNS and systemic lymphoma. Tumor ADC(min) less than 384 × 10(-6) mm(2)/s was significantly associated with shorter progression-free and overall survival. CONCLUSIONS: MT-R induction was effective and well tolerated. MT-R followed by EA consolidation yielded progression-free and overall survival outcomes comparable to regimens with chemotherapy followed by whole-brain radiotherapy consolidation but without evidence of neurotoxicity. Tumor ADC(min) derived from DW-MRI provided better prognostic information for PCNSL patients treated with the MTR-EA regimen than established clinical risk scores.