[Primary CNS lymphoma. Progress in the diagnostics and therapy]. / Primäre ZNS-Lymphome : Fortschritte in der Diagnostik und Therapie.

BACKGROUND: Some important knowledge has recently been gained on primary central nervous system lymphomas (PCNSL) despite its rarity. GOAL: This article summarizes the most relevant progress in the diagnostics and therapy of PCNSL and discusses future directions. MATERIAL AND METHODS: Reference articles in the English language literature were studied with respect to future approaches in PCNSL. RESULTS: New diagnostic methods in cerebrospinal fluid have been developed to facilitate lymphoma diagnosis; however, their value still has to be validated. A better immunohistological and molecular characterization of PCNSL will probably result in identification of new therapeutic targets. The only phase III trial for PCNSL completed so far did not demonstrate a survival advantage with whole brain irradiation after high-dose methotrexate (HDMTX)-based chemotherapy as compared to chemotherapy alone. The optimal primary chemotherapy has not yet been established due to a lack of results from randomized trials. Non-comparative studies suggest a superiority of combined polychemotherapy over HDMTX monotherapy. Future therapeutic developments are directed towards consolidation of HDMTX-based induction chemotherapy with noncross-resistant conventional chemotherapy or high-dose chemotherapy with autologous stem cell transplantation. An important goal of all therapies for PCNSL is to avoid delayed neurotoxicity. DISCUSSION: Further improvement of diagnostics and well-designed comparative studies, including new drugs when possible are still needed to define the optimal management of this still frequently prognostically unfavorable disease.

A comprehensive analysis of the cellular and EBV-specific microRNAome in primary CNS PTLD identifies different patterns among EBV-associated tumors.

Primary central nervous system (pCNS) posttransplant lymphoproliferative disorder (PTLD) is a complication of solid organ transplantation characterized by poor outcome. In contrast to systemic PTLD, Epstein-Barr virus (EBV)-association of pCNS PTLD is almost universal, yet viral and cellular data are limited. To identify differences in the pattern of EBV-association of pCNS and systemic PTLD, we analyzed the expression of latent and lytic EBV transcripts and the viral and cellular microRNAome in nine pCNS (eight EBV-associated) and in 16 systemic PTLD samples (eight EBV-associated). Notably although 15/16 EBV-associated samples exhibited a viral type III latency pattern, lytic transcripts were also strongly expressed. Members of the ebv-miR-BHRF1 and ebv-miR-BART clusters were expressed in virtually all EBV-associated PTLD samples. There were 28 cellular microRNAs differentially expressed between systemic and pCNS PTLD. pCNS PTLD expressed lower hsa-miR-199a-5p/3p and hsa-miR-143/145 (implicated in nuclear factor kappa beta and c-myc signaling) as compared to systemic PTLD. Unsupervised nonhierarchical clustering of the viral and cellular microRNAome distinguished non-EBV-associated from EBV-associated samples and identified a separate group of EBV-associated pCNS PTLD that displayed reduced levels of B cell lymphoma associated oncomiRs such as hsa-miR-155, -21, -221 and the hsa-miR-17-92 cluster. EBV has a major impact on viral and cellular microRNA expression in EBV-associated pCNS PTLD.

Prognostic impact of meningeal dissemination in primary CNS lymphoma (PCNSL): experience from the G-PCNSL-SG1 trial.

BACKGROUND: We evaluated the frequency and prognostic impact of meningeal dissemination (MD) in immunocompetent adult patients with primary central nervous system lymphoma treated in a randomized phase III trial. PATIENTS AND METHODS: MD was evaluated at study entry and defined by lymphoma proof in the meningeal compartment detected by at least one of the following methods: cerebrospinal fluid (CSF) cytomorphology, detection of clonal B cells by IgH PCR in CSF or contrast enhancement of the leptomeninges on magnetic resonance imaging (MRI). RESULTS: Data on MD were available in 415 patients, of those, MD was detected in 65 (15.7%): in 44/361 (12.2%) by CSF cytomorphology, in 16/152 (10.5%) by PCR and in 17/415 (4.1%) by MRI. Major patients' characteristics and therapy did not significantly differ between patients with MD (MD+) versus those without MD (MD-). There was a significant correlation of MD with CSF pleocytosis (>5/µl; P < 0.0001), but no correlation with CSF protein elevation (>45 mg/dl). Median progression-free survival was 6.7 months [95% confidence interval (CI) 0-14.5] in MD+ and 8.3 months (5.7-10.8) in MD- patients (P = 0.95); median overall survival was 21.5 months (95% CI 16.8-26.1) and 24.9 months (17.5-32.3), respectively (P = 0.98). CONCLUSION: MD was detected infrequently and had no impact on outcome in this trial.

Phase I study of the novel, fully synthetic epothilone sagopilone (ZK-EPO) in patients with solid tumors.

BACKGROUND: Sagopilone (ZK-EPO) is a fully synthetic microtubule-stabilizing agent that has demonstrated high antitumor activity in preclinical models. This first-in-human phase I study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxic effects (DLTs) of 3-weekly sagopilone treatment. PATIENTS AND METHODS: A total of 52 patients with advanced solid tumors received a 30-min infusion of escalating doses of sagopilone (0.6-29.4 mg/m(2)) every 3 weeks. Nine additional patients were recruited to a 3-h infusion arm (16.53- or 22.0-mg/m(2) dose) to assess the incidence of neuropathy with prolonged infusion. RESULTS: The MTD was established as 22.0 mg/m(2). DLTs comprised peripheral sensory neuropathy (PNP), infection, hyponatremia, diarrhea, and central ataxia. PNP was the most common grade 3 event, with a similar incidence in the 30-min and 3-h arms. Hematologic adverse events were rare and of low intensity. One confirmed partial response (PR) and one unconfirmed PR were reported in the 30-min arm, and a further unconfirmed PR was observed in the 3-h arm. Eleven patients achieved disease stabilization. Sagopilone showed high levels of tissue binding and no obvious serum accumulation in both arms. CONCLUSIONS: These data demonstrate that sagopilone therapy is feasible and well tolerated. The recommended dose for phase II studies is 16.53 mg/m(2), once every 3 weeks.

High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma: a prospective multicentre trial by the German Cooperative PCNSL study group.

To investigate safety and efficacy of high-dose chemotherapy followed by autologous stem cell transplantation (HCT-ASCT) in relapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL), we conducted a single-arm multicentre study for immunocompetent patients (<66 years) with PCNSL failing high-dose methotrexate)-based chemotherapy. Induction consisted of two courses of rituximab (375 mg/m2), high-dose cytarabine (2 × 3 g/m2) and thiotepa (40 mg/m2) with collection of stem cells in between. Conditioning for HCT-ASCT consisted of rituximab 375 mg/m2, carmustine 400 mg/m2 and thiotepa (4 × 5 mg/kg). Patients commenced HCT-ASCT irrespective of response after induction. Patients not achieving complete remission (CR) after HCT-ASCT received whole-brain radiotherapy. Primary end point was CR after HCT-ASCT. We enrolled 39 patients; median age and Karnofsky performance score are 57 years and 90%, respectively. About 28 patients had relapsed and 8 refractory disease. About 22 patients responded to induction and 32 patients commenced HCT-ASCT. About 22 patients (56.4%) achieved CR after HCT-ASCT. Respective 2-year progression-free survival (PFS) and overall survival (OS) rates were 46.0% (median PFS 12.4 months) and 56.4%; median OS not reached. We recorded four treatment-related deaths. Thiotepa-based HCT-ASCT is an effective treatment option in eligible patients with r/r PCNSL. Comparative studies are needed to further scrutinise the role of HCT-ASCT in the salvage setting.

A 19-year-old male with generalized seizures, unconsciousness and a deviation of gaze.

Light chain deposition disease (LCDD) is a form of monoclonal immunoglobulin deposition diseases (MIDD) which in contrast to light-chain derived (AL) amyloidosis is characterized by non-congophilic, non-fibrillary monoclonal protein deposits. Systemic organ deposits are common with the kidney being a major target organ. A clonal lymphoplasmocytic proliferation, e.g. plasmacytoma, is present in the majority of cases. Here we report on a 19-year-old male who presented with generalized seizures and an enhancing white matter lesion on MRI scans. A stereotactic brain biopsy revealed a low-grade B cell lymphoma with plasmacellular differentiation as well as lambda light chain deposits without birefringence under polarized microscopy. No systemic lymphoma manifestations or systemic light chain deposits were found, nor was a monoclonal gammopathy detectable in serum and urine. After systemic chemotherapy with three courses high-dose methotrexate the size of the lesion and the condition of the patient have remained stable for 24 months now. This is the first description of cerebral LCDD developing without systemic disease in conjunction with the diagnosis of a cerebral low-grade B cell lymphoma. We present the clinical, laboratory and radiological findings and discuss the pathogenesis of this unusual LCDD manifestation.

Phase I clinical and pharmacokinetic study of titanocene dichloride in adults with advanced solid tumors.

This Phase I dose-escalation clinical trial of a lyophilized formulation of titanocene dichloride (MKT4) was conducted to determine the maximum tolerated dose, the dose-limiting toxicity (DLT), and pharmacokinetics of titanium (Ti) after a single i.v. infusion of MKT4. Forty patients with refractory solid malignancies were treated with a total of 78 courses. Using a modified Fibonacci scheme, 15 mg/m2 initial doses of titanocene dichloride were increased in cohorts of three patients up to level 11 (560 mg/m2) if DLT was not observed. The maximum tolerated dose was 315 mg/m2, and nephrotoxicity was DLT. Two minor responses (bladder carcinoma and non-small cell lung cancer) were observed. The pharmacokinetics of plasma Ti were assessed in 14 treatment courses by atomic absorption spectroscopy. The ratio for the area under the curve(0-infinity) in plasma and whole blood was 1.2. The following pharmacokinetic parameters were determined for plasma, as calculated in a two-compartment model: biological half-life t1/2beta in plasma was 22.8+/-11.2 h (xh +/- pseudo-SD), peak plasma concentration cmax approximately 30 microg/ml at a dose of 420 mg/m2, distribution volume Vss= 5.34+/-2.1 L (xa +/- SD), and a total clearance CItotal = 2.58+/-1.23 ml/min (xa +/- SD). There was a linear correlation between the area under the curve(0-infinity) of Ti in plasma and the titanocene dichloride dose administered with a correlation coefficient r2 of 0.8856. Plasma protein binding of Ti was in the 70-80% range. Between 3% and 16% of the total amount of Ti administered were renally excreted during the first 36 h. The recommended dose for Phase II evaluation is 240 mg/m2 given every 3 weeks with i.v. hydration to reduce renal toxicity.

[Special hematological diagnostics and therapy options for ocular lymphoma taking CNS involvement into account]. / Hämatologische Spezialdiagnostik und Therapieoptionen bei okulären Lymphomen unter Berücksichtigung einer ZNS-Beteiligung.

BACKGROUND: Intraocular lymphomas are very rare and occur as either vitreoretinal or uveal tumors. Management in the clinical routine is highly variable and controversial. OBJECTIVES: To present the most important aspects of the diagnostics and therapy from the perspective of hematological oncologists and formulate management recommendations. METHODS: The English language literature was reviewed and the most important data were analyzed for presentation. RESULTS: In patients with vitreoretinal lymphoma evaluation for central nervous system (CNS) involvement should be performed due to its strong association with primary CNS lymphoma (PCNSL). The prognosis is relatively poor, particularly when the CNS is involved. Optimal therapy has not yet been established. For isolated vitreoretinal manifestations local therapy, such as intraocular methotrexate (MTX) or rituximab or radiation is recommended; however, there is a very high frequency of CNS relapse. Systemic high-dose MTX-based chemotherapy analogous to PCNSL treatment is an alternative option and is the treatment of choice in patients with simultaneous CNS and vitreoretinal lymphoma. Primary uveal lymphoma is usually an indolent lymphoma and treated by local therapy, whereas secondary uveal lymphoma predominantly occurs in aggressive systemic (non-CNS) lymphoma and is treated by systemic chemotherapy. DISCUSSION: Data on intraocular lymphoma are derived from small, usually retrospective and very heterogeneous studies with a relatively short follow-up. To gain more knowledge on this rare disease, inclusion of patients in the prospective registry, currently in progress in Germany, is desirable.

CSF evaluation in primary CNS lymphoma patients by PCR of the CDR III IgH genes.

BACKGROUND: Cytologic evaluation of CSF does not consistently detect malignant cells in patients with primary CNS lymphoma (PCNSL). The potentially more sensitive molecular assessment of monoclonality has not been shown in CSF samples. METHODS: The authors studied nested PCR of the complementary determining region III (CDR III) on 76 CSF specimens of patients with PCNSL. Patients with systemic disseminated B-cell non-Hodgkin's lymphoma (n = 17) and 17 patients with no history of lymphoma were compared. PCR products were evaluated by automated fluorescent fragment analysis (ALF). RESULTS: In 68 patients with PCNSL, the authors analyzed the first obtained CSF sample. Nevertheless, 60 patients were taking corticosteroids. In 16 PCNSL samples, amplifiable DNA was not yielded. Taking into account that at least two independent assays have to be performed, CDR III PCR consistently revealed monoclonal products in eight PCNSL and polyclonal results in 52 PCNSL specimens. CDR III PCR detected no monoclonal PCR products in patients without history of lymphoma. In 10 patients with PCNSL, the PCR result and the CSF cytology were discordant. Concerning therapeutic impact, leptomeningeal tumor spread did not predict tumor response in this group of patients with PCNSL. CONCLUSIONS: This study performed CDR III PCR as a routine diagnostic technique applicable even on CSF samples with low cell counts. These data present low incidence of leptomeningeal involvement in this subset of pretreated PCNSL patients. Because the CSF evaluation did not predict outcome in our patients, further analysis in patients with PCNSL should focus on CSF samples that are obtained very early after diagnosis.

Response to topotecan of symptomatic brain metastases of small-cell lung cancer also after whole-brain irradiation. a multicentre phase II study.

The purpose of this multicentre phase II study was to evaluate the efficacy and toxicity of topotecan in pretreated patients with small-cell lung cancer (SCLC) who relapsed with symptomatic brain metastases. 30 patients with a median age of 62 years were entered into the study. 22 patients received the initially planned dose of 1.5 mg/m(2) topotecan as a 30-min intravenous (i.v.) infusion for 5 consecutive days every 3 weeks. Due to the observed thrombocytopenia, the dose was reduced to 1.25 mg/m(2) in the last 8 patients. All 30 patients were pretreated with chemotherapy: 14 with one and 16 with at least two protocols. 8 patients had prior whole-brain iradiation (WBI): 7 in the prophylactic and 1 in the palliative setting. Concomitant systemic metastases were recorded in 24 patients at the time of brain relapse. Cerebral metastases responded in 33% of patients (10/30; three complete responses (CR) and seven partial responses (PR)). Noteworthy is the fact that response was achieved in 4 of 8 patients pretreated by WBI (3 in prophylactic and 1 in palliative setting). The systemic response rate was 29% (7/24). Median time to progression was 3.1 months (range 0.25-14.2+ months), median survival from the beginning of this study was 3.6 months (range 0.25-14.2+ months). Therapy was generally well tolerated, with myelotoxicity being the most common adverse event. Grade 3 leucocytopenia according to the Common Toxicity Criteria (CTC) occurred in 28% (23/83) of the courses and grade 4 in 22% (18/83). Grade 3 thrombocytopenia was observed in 17% of the courses (14/83) and grade 4 in 11% (9/83). 17% of patients (5/30) had a documented grade 3 infection. These results using topotecan are promising in heavily pretreated patients with SCLC brain metastases and merit further evaluation.

Macrophage inflammatory protein (mip)-1-alpha stem-cell inhibitor (sci) does not affect clonal growth of human solid tumor-cell lines in-vitro.

MIP-1alpha is a member of a family of proinflammatory cytokines produced by activated macrophages which has been shown to be a negative regulator of early hematopoietic stem cell progenitors. We report on results testing recombinant human (rh) MIP-1alpha on the clonal growth of different human nonhematopoietic tumor cell lines in vitro. Cell lines tested included the following histologies: 7 glioblastomas, 1 neuroblastoma, 2 head and neck carcinomas, 4 lung carcinomas, 3 colorectal carcinomas, 1 gastric carcinoma, 1 pancreatic carcinoma, 1 breast carcinoma, 1 prostate carcinoma, 1 choriocarcinoma, 1 ovary carcinoma, 1 osteosarcoma, and 3 melanomas. MIP-1alpha (0, 2, 20, 200 ng/ml) was tested in human tumor cloning assays (HTCA) in agar-containing capillaries (HTCAcap) and in mixtures of methylcellulose and agar (HTCAmix), representing assay systems with different plating efficiencies (PE). Tumor cells were continuously exposed to the cytokine for the complete assay period. Clonal growth of none of the cell lines was significantly and reproducibly stimulated or inhibited by MIP-1alpha.

Phase-I tolerability study of 5-methyltetrahydrofolate in combination with a 4-hour infusion of 5-Fluorouracil in cancer-patients.

5-methyltetrahydrofolate (MTHF) is a main serum metabolite of 5-formyltetrahydrofolate (folinic acid, FA), a standard agent for potentiation of the cytotoxic activity of 5-fluorouracil (5-FU). The clinical application of MTHF instead of FA as a precursor of the biologically active metabolite 5,10-methyltetrahydrofolate (mTHF) is based on favorable pharmacologic characteristics of MTHF described so far. In this phase I study 18 patients with advanced solid malignancies were treated with MTHF for 5 days at doses ranging from 100 to 500 mg/m(2)/day in combination with a fixed dose of 500 mg/m2/day 5-FU given as a 4-hour infusion. The treatment was repeated after 21 days. The toxicity observed was mainly gastrointestinal with loss of appetite, nausea and vomiting (up to WHO grade III), and less frequently stomatitis, decline of hemoglobin and hematuria (up to WHO grade II). The frequency and severity of side effects seen were not related to the dose of MTHF. Cumulative toxicity was not observed. The MTD was not reached up to an MTHF dose of 500 mg/m(2)/day. Objective remissions were not seen. The study was terminated on the basis of results showing comparable 5,10-methylenetetrahydrofolate (mTHF) tumor- and tissue levels after administration of MTHF or FA.

Testicular germ cell tumor with rhabdomyosarcoma successfully treated by disease-adapted chemotherapy including high-dose chemotherapy: case report and review of the literature.

Treatment and prognosis have not been well characterized in germ cell tumors (GCT) with a malignant nongerm cell component. Patients with a mediastinal tumor, neural or rhabdomyosarcomatous differentiation and distant metastases have the poorest prognosis. We report a rare case of mixed GCT composed of seminoma, teratoma and rhabdomyosarcoma with the rhabdomyosarcomatous component metastasized into the liver and bone marrow (BM) causing hypercalcemia. The patient was treated with differentiation-tailored chemotherapy (CHT) including a disease-adapted high-dose (HD) CHT regimen with purified autologous PBSCT (APBSCT) and pamidronate. To date, remission has lasted for 4 years. Tumor-adapted CHT including HD-CHT with APBSCT can induce long term remissions in high-risk patients with transformed GCT. A review of the literature is given.

Successful treatment of non-Hodgkin's lymphoma of the central nervous system with BMPD chemotherapy followed by radiotherapy.

The treatment of patients with primary non-Hodgkin's lymphoma of the central nervous system (PCNSL) is still of limited success, as compared with other extranodal sites. The poor results obtained with radiotherapy alone can be improved by adding chemotherapy reaching a median survival up to over 30 months and 5-years-survival rate up to 35%. The optimal management for patients with CNS relapse of systemic lymphoma remains uncertain and their prognosis is even worse. Here, we describe our preliminary data on the treatment of patients with CNS lymphoma with a new regimen composed of CNS-penetrating drugs, namely: carmustine (BCNU) 80 mg/m2 i.v. dl, methotrexate 1500 mg/m2 over 24h i.v. d2, procarbacine 100 mg/m2 p.o. d1-8, and dexamethasone 3 x 8 mg p.o. d1-14. An average of 3 treatment courses were given under response control seen using CT-scan or NMR. Patients with positive CSF cytology received additionally intrathecal therapy with methotrexate. Until now between March 1994 and September 1997, 7 patients with PCNSL and 4 patients with CNS relapse of systemic lymphoma have been treated. The median age of the patients was 56 (range, 39-74); 5 patients were > or =60 years old. Three patients had multifocal disease. Whole brain radiotherapy with 4000 to 5000 cGy was given in 7 patients (cerebrospinal in 1 patient). Complete response at the end of chemotherapy was achieved in 6 patients, and a partial response in two. Most remarkably, 2 elderly patients (70 and 57 years), 1 patient with multifocal disease and 1 with simultaneous CNS and systemic relapse after chemotherapy had a complete remission lasting for 40 months, and a partial remission lasting for 37 months, respectively.

Carboxypeptidase G2 rescue in a 79 year-old patient with cranial lymphoma after high-dose methotrexate induced acute renal failure.

A 79 year-old female patient presented with immunoblastic B-cell lymphoma of the ethmoidal sinuses and destruction of the anterior cranial fossa. After 3 cycles of high-dose methorexate (HD-MTX) MTX serum level remained elevated and creatinine serum levels raised. The patient received Carboxypeptidase G2 (CPG2) intravenously. Within one hour the MTX serum level decreased to <1 micromol/l as determined by high pressure liquid chromatography (HPLC). The patient recovered without significant toxicity and attained a long lasting ongoing (>14 months) complete remission. In this case we were able to demonstrate that rescue from HD-MT nephrotoxicity by CPG2 is also safe and effective in patients with advanced age with impaired renal function. With the help of CPG2, sufficient and potentially curative therapy with HD-MTX may also be provided to patients with a high risk of renal failure.

Modern concepts in the biology, diagnosis, differential diagnosis and treatment of primary central nervous system lymphoma.

Recent studies addressing the molecular characteristics of PCNSL, which is defined as malignant B-cell lymphoma with morphological features of DLBCL, have significantly improved our understanding of the pathogenesis of this lymphoma entity, which is associated with an inferior prognosis as compared with DLBCL outside the CNS. This unfavorable prognosis stimulated intense efforts to improve therapy and induced recent series of clinical studies, which addressed the role of radiotherapy and various chemotherapeutic regimens. This review combines the discussion of diagnosis, differential diagnosis and recent progress in studies addressing the molecular pathogenesis as well as therapeutic options in PCNSL.

Meningeal dissemination in primary CNS lymphoma: prospective evaluation of 282 patients.

BACKGROUND: The impact of meningeal dissemination in primary CNS lymphoma (PCNSL) is debated, and the reported frequency varies. We prospectively evaluated the diagnostic value of PCR in comparison with CSF cytomorphology and MRI for diagnosing meningeal dissemination in PCNSL. METHODS: We evaluated 282 patients from a multicenter therapy study for PCNSL for the presence of meningeal dissemination: 205 with CSF cytomorphology, 171 with PCR of the rearranged immunoglobulin heavy-chain genes in CSF, and 217 with cranial MRI. RESULTS: Meningeal dissemination was found in 33 of 205 patients (16%) by cytomorphology, in 19 of 171 (11%) patients evaluated by PCR, and in 8 of 217 patients (4%) by MRI. Considering either of these methods, the relative frequency of meningeal dissemination was 17.4% (49 of 282 patients). PCR was monoclonal in 6 of 19 (32%) samples with positive cytomorphology, 1 of 13 samples (8%) with suspicious cytology, and in 10 of 105 (10%) cytologically negative samples. In 11 samples with positive and 12 with suspicious cytology, PCR showed only a polyclonal pattern. The probability of meningeal dissemination detection was higher in cases with CSF pleocytosis (>5/microL) with an OR of 2.48 (95% CI 1.15-5.34, p = 0.018). CSF protein had no predictive value for meningeal dissemination detection. CONCLUSIONS: We found a low rate of meningeal dissemination in primary CNS lymphoma in this large prospective study. The rate of discordant PCR and cytomorphologic results was high. Thus, the methods should be regarded as complementary. CSF pleocytosis had predictive value for meningeal dissemination detection.