High-dose methotrexate is beneficial in parenchymal brain masses of uncertain origin suspicious for primary CNS lymphoma

In patients with parenchymal brain masses of uncertain origin responsive to corticosteroids, primary CNS lymphoma (PCNSL) should be considered. PCNSL is a rare but aggressive brain tumor that is highly sensitive to high-dose methotrexate (HDMTX)-based chemotherapy. We report a series of six patients with brain masses without histologic confirmation suspicious for PCNSL based on clinical and radiomorphologic criteria after exclusion of some infectious conditions. All patients were treated with HDMTX. We observed two complete responses, two partial responses, and one stable disease. One patient had progressive disease and received rescue whole-brain irradiation. All patients were alive without disease progression 12-48 months after HDMTX start. No symptoms of late neurotoxicity have occurred so far. The response and survival data in this small series of patients are encouraging and suggest a benefit for patients with suspected PCNSL after initial treatment with HDMTX.     

Ertumaxomab: a trifunctional antibody for breast cancer treatment

Ertumaxomab is an intact bispecific antibody targeting HER2/neu and CD3 with preferential binding to activating Fcgamma type I/III-receptors, resulting in the formation of a tri-cell complex among tumour cell, T cell and accessory cell. Recently, the antibody demonstrated antitumour efficacy against HER2/neu low-expressing tumours resistant to trastuzumab. Data from a completed Phase I study in metastatic breast cancer patients indicates strong immune responses. Owing to efficient tumour cell destruction by humoral and T-cell-dependent mechanisms, differing from conventional HER2/neu directed treatments, and a potential for long-lasting antitumour immunoreactivity, ertumaxomab is at present investigated within Phase II studies enrolling metastatic breast cancer patients even without HER2/neu gene amplification.     

Brain and whole-body FDG-PET in diagnosis,treatment monitoring and long-term follow-up of primary CNS lymphoma

Background

Positron emission tomography (PET) with F-18-labeled fluorodeoxyglucose (FDG) provides remarkable accuracy in detection, treatment monitoring and follow-up of systemic malignant lymphoma. Its value in the management of patients with primary central nervous system lymphoma (PCNSL) is less clear.

Patients and methods

In a prospective trial, 42 FDG-PET examinations were performed in ten immunocompetent patients with newly diagnosed or recurrent PCNSL before and repeatedly during and after the treatment. Brain and whole body FDG-PET were compared to brain MRI and extra-cerebral CT, respectively.

Results

Before the treatment, 6 of 10 patients had congruent findings on FDG-PET and MRI of the brain. Three patients had lesions on brain MRI, not detected by FDG-PET. One patient had additional FDG-PET positive lesions inconspicuous in MRI. The follow-up suggested FDG-PET to be false positive in these lesions. After the treatment, brain PET was in agreement with MRI in 6 of 8 patients. In the remaining 2 patients there were persistent lesions in brain MRI whereas FDG-uptake was reduced to normal values. In the long-term follow-up of 5 patients (63–169 weeks), 3 patients retained normal in both PET and MRI. In 2 patients a new focal pathologic FDG-uptake was detected 69 and 52 weeks after the end of the treatment. In one of these patients, recurrence was confirmed by MRI not until 9 weeks after PET.

Conclusions

Brain FDG-PET may contribute valuable information for the management of PCNSL, particularly in the assessment of the treatment response. Integration of FDG-PET into prospective interventional trials is warranted to investigate prognostic and therapeutic implications.     

Increased chondroitin sulphate proteoglycan expression (B5 immunoreactivity) in metastases of uveal melanoma

Background: Metastatic uveal melanoma has a poor prognosis andlimited therapeutic options. Proteoglycans are involved in tumorcell invasion and metastatic behavior. The mAbB5 stains a chondroitinsulphate proteoglycan (CSPG) on cutaneous melanoma cells. Here,we compare the B5-staining of CSPG in primaries and metastasesof uveal melanoma. Material and methods: Immunohistopathological staining was performedin 15 cutaneous and 39 uveal melanoma samples. A score for intracellularand surface staining was established. B5 staining was comparedin primaries and metastases of uveal melanoma using Student'st-test. Results: Eight of 11 (73%) uveal melanoma metastases were positivefor B5-staining whereas only 5 of 28 (18%) primary uveal melanomasamples were B5-positive (P < 0.001). Nine of 15 cutaneousmelanoma samples (60%) were B5-positive without significantdifference between primary and metastatic lesions. Surface stainingwas found both on uveal melanoma metastases and cutaneous melanomas. Conclusions: CSPG was expressed significantly more often inmetastases than in primaries of uveal melanoma. It potentiallymay be one factor associated with metastatic spread. Furtherstudies are needed to determine its use as prognostic factor.The mAbB5 may also be a promising tool for immunotherapy dueto its strong staining of CSPG on the surface of cutaneous andmetastatic uveal melanoma cells. Key words: uveal melanoma, ocular melanoma, chondroitin sulphate proteoglycan, immunotherapy, immunohistochemistry     

Reversible ageusia after chemotherapy with pegylated liposomal doxorubicin

OBJECTIVE: To report a case of reversible ageusia in a patient with multiple myeloma receiving pegylated liposomal doxorubicin. CASE SUMMARY: A 67-year-old man with a history of arterial hypertension and persisting left bundle-branch block was diagnosed with multiple myeloma. He was initially treated with cyclophosphamide 200 mg/m(2) (days 1-4), pegylated liposomal doxorubicin 20 mg/m(2) (day 1), and dexamethasone 40 mg (days 1-4) (CLAD). That treatment was followed by high-dose melphalan therapy and autologous peripheral stem-cell transplantation. The disease recurred 18 months later, and renal failure developed. The patient was again treated with the CLAD protocol. After the first cycle, almost complete ageusia occurred, along with weight loss and severe depression. Chemotherapy was continued, but pegylated liposomal doxorubicin was replaced by conventional doxorubicin. Within 12 weeks, the patient's sense of taste returned to normal. DISCUSSION: Pegylated liposomal anthracyclines are increasingly being used as a less cardiotoxic alternative to conventional doxorubicin in first- and second-line therapy of multiple myeloma. Whereas cardiotoxicity and unspecific reactions are seen less frequently, palmar-plantar erythrodysesthesia is a common reaction to pegylated liposomal anthracyclines. No other reasons for ageusia in our patient could be identified. Based on the Naranjo probability scale, ageusia was rated as a probable reaction to pegylated liposomal doxorubicin. CONCLUSIONS: As with all new and innovative drugs, thorough documentation of infrequent adverse events is necessary. We would like to raise awareness for ageusia, which appears to be a rare but severely impairing adverse reaction to a relatively new pharmacologic agent.     

First report on a prospective trial with yttrium-90–labeled ibritumomab tiuxetan (Zevalin) in primary CNS lymphoma

Most patients with primary CNS lymphoma (PCNSL) relapse after primary therapy. Standard salvage treatment has not yet been established in PCNSL. Anti-CD20 immunotherapy has expanded treatment options in systemic B-cell lymphoma; however, its use is limited by reconstitution of the blood–brain barrier after tumor shrinkage. The aim of this phase II trial was to evaluate the therapeutic efficacy, toxicity, and biodistribution of yttrium-90 (⁹⁰Y) ibritumomab tiuxetan in PCNSL. Ten patients with relapsed PCNSL were included in a phase II trial and treated with the ⁹⁰Y-labeled anti-CD20 antibody ibritumomab tiuxetan. Nine patients actually received the planned radioimmunotherapy. In six patients, biodistribution of the antibody was measured by indium-111 (¹¹¹In) ibritumomab tiuxetan whole-body scans and single-photon-emission CT (SPECT) of the brain. All patients were evaluated for toxicity and response at least 4 weeks after therapy. Four patients responded: one patient had a complete response lasting 30+ months, and three patients had short-lived responses of ≤4 weeks. Five patients progressed, and one patient did not receive treatment due to an infection prior to ⁹⁰Y-antibody administration. Target accumulation of the antibody was demonstrated in four of the six patients examined by SPECT imaging with ¹¹¹In ibritumomab tiuxetan. All patients experienced grade 3/4 hematotoxicity but no acute neurotoxicity. Penetration of a therapeutic antibody into PCNSL and significant clinical activity was shown. Because of limited response duration and considerable hematotoxicity, future investigations should focus on a multimodal approach with additional chemotherapy and preferably autologous stem cell support.     

HLA-A2 expression, stage, and survival in colorectal cancer

INTRODUCTION: Most cancer vaccination trials have been performed in human leukocyte antigen (HLA)-A2 positive populations. Some studies have used HLA-A2 negative patients as control group. However, HLA-type and HLA-expression can interact with tumor biology and possibly affect prognosis. HLA-A2 negative patients might constitute an inadequate control group. MATERIALS AND METHODS: Patients with colorectal cancer were serologically analyzed for HLA-A2 expression. Patients were evaluated for tumor stage, grading, tumor location. Overall survival (OAS) of HLA-A2 positive and HLA-A2 negative patients was compared. RESULTS: One hundred forty-four patients were evaluable (50% HLA-A2+). Median age was 62 years. UICC stage III or IV: 45.8%. Gender, location, and UICC stage were equally distributed between HLA-A2 subgroups. HLA-A2 positive patients more frequently had grade 3 histology (27.8% vs 13.9%) and chemotherapy (62.9% vs 45.6%). At a median follow-up of 75.8 months, median OAS for the entire study population was 123.3 months, 5-year OAS was 77.5%. No statistically significant difference in OAS was observed between HLA-A2 positive and negative patients (116.5 vs 157 months, 5-year-OAS 74.1 +/- 11.6% vs 81 +/- 11.6%, p = 0.46). Expectedly, patients with UICC stage I and II disease lived significantly longer than patients with stage III and IV (5-year OAS 94.3% vs 53.4%; p < 0.001). A significantly superior OAS was also found for women, independent of stage or HLA status. CONCLUSION: HLA-A2 positive patients exhibit poorer tumor differentiation. This might account for a non-significant difference in OAS. The use of HLA-A2 negative patients as control cohort in CRC vaccinations would rather underestimate potential treatment-related survival effects. Therefore, we suggest they constitute a valid auxiliary control group.     

Topotecan and ifosfamide systemic chemotherapy for CNS involvement of solid tumors

The prognosis of patients with CNS involvement of solid tumors is poor. In these patients, systemic chemotherapy has a theoretical advantage of concurrent treatment of systemic disease and reduced risk of neurotoxicity. Here, we report on the efficacy and toxicity of topotecan/ifosfamide (TOPO/IFO) combination chemotherapy in patients treated for CNS involvement of different solid malignancies. Fourteen patients with CNS manifestations (seven with brain metastases, two meningeal carcinomatosis, and five both) of solid tumors (seven with breast cancer, six lung cancer, and one unknown primary cancer) received TOPO/IFO treatment. Eleven patients each were pretreated with 1–6 systemic therapy regimens and whole-brain irradiation. Patients received a total of 34 (median 2) TOPO/IFO cycles. TOPO dosage was 3.6 mg/m² (1.2 mg/m², days 1–3) and IFO dosage 3,000 mg/m² (1,500 mg/m², days 1–2) per cycle. Of 12 patients with brain metastases, one patient had partial remission, three stable disease, two progressed, and six had no radiologic CNS response evaluation. Response of meningeal carcinomatosis was found in two and progressive disease in two (three patients not evaluated). Neurologic improvement or stabilization was observed in six of twelve evaluable patients. No systemic tumor response was seen in seven evaluated patients. Grade 3/4 toxicities in eleven evaluable patients were leukopenia (n = 9), infection (n = 6), and thrombopenia (n = 5). Median time to treatment failure was 43 days and median overall survival 107 days. Symptom control was frequently achieved with TOPO/IFO systemic chemotherapy despite a low objective response rate. The feasibility of this treatment is impaired by severe hematotoxicity.