Delayed but Complete Response following Oral Temozolomide Treatment in Melanoma Leptomeningeal Carcinomatosis

Isolated leptomeningeal recurrence of melanoma is rare, occurring in 2% of patients with central nervous system involvement secondary to melanoma. The optimal treatment of leptomeningeal carcinomatosis (LMC) in melanoma has not yet been determined and remains a major challenge. We report a melanoma patient who presented with isolated LMC in the form of a new-onset weakness of the lower limbs, paresthesia of the left hand and foot, lumbago and headache. A lumbar puncture and spinal MRI confirmed LMC. The patient was treated with temozolomide 75 mg/m2/day on a 4 weeks on/2 weeks off schedule. After an initial transient clinical deterioration, the patient showed a complete radiological response as well as a dramatic improvement in quality of life. The encouraging clinical response reported here suggests that dose-intensified temozolomide might have significant activity in the treatment of leptomeningeal dissemination of melanoma and may be a valid treatment option for patients who have not been previously exposed to this agent. Moreover, this treatment regimen is extremely well tolerated and obviates the need for repeated intrathecal administrations of chemotherapeutic agents, which are often not well tolerated by patients who have significant co-morbidities due to their disease. As illustrated in this case, response to temozolomide may occur in a delayed manner, highlighting the importance of following temozolomide treatment long enough before determining that it is inefficient in a given patient

Survivin in brain tumors: an attractive target for immunotherapy

Summary: Survivin, a member of the inhibitor of apoptosis proteins gene family, was recently shown to be expressed by tumors originating from different cell lineages. There are also cumulative evidences that spontaneous immune response against survivin derived epitopes may occur. Here, using RT-PCR, Western-blot analysis and immunohistochemistry, we show that survivin is widely expressed by gliomas, meningiomas and schwannomas, bothin vitro andin vivo. These data indicate that survivin may serve as an attractive target for immunotherapies designed for brain tumor

Gastrointestinal relapse of multiple myeloma and sustained response to lenalidomide: a case report

<p>Abstract</p> <p>Introduction</p> <p>Gastrointestinal relapse in patients with multiple myeloma is very rare and, when reported, always associated with a poor prognosis.</p> <p>Case presentation</p> <p>We describe the case of a 71-year-old Caucasian man who presented with life-threatening hematemesis and melena due to a digestive relapse of his multiple myeloma. Despite the active hemorrhage, we initiated a third-line treatment with lenalidomide. The response was spectacular and long-lasting.</p> <p>Conclusions</p> <p>Clinicians must consider digestive tract involvement in myeloma patients presenting with a gastrointestinal hemorrhage. Furthermore, myeloma patients do benefit from novel oral drugs, even when they are critically ill.</p

Percutaneous cementoplasty in multiple myeloma: a valuable adjunct for pain control and ambulation maintenance

Goals of work: Bone pain and functional impairment are major concerns for multiple myeloma (MM) patients. The goal of this study was to better define the role of percutaneous cementoplasty (PC) in improving their quality of life. Materials and methods: This retrospective analysis included 28 consecutive heavily pretreated MM patients managed at our institution between 1996 and 2002. They underwent a total of 34 PC procedures for the treatment of 117 vertebrae and 2 iliac sites and were evaluated at 1month. Main results: Significant pain reduction of >50% was obtained after 83% of the procedures, with a mean visual analogous score decreasing from 7.48/10 to 2.1/10 (p < 0.001). It resulted in a complete interruption of opiate analgesic consumption after 59.3% of the procedures, with a mean decrease of 70.4% in the opiate dose. Functional impairment was evaluated with the Eastern Cooperative Oncology Group (ECOG) performance status scale, with mean scores improving from 1.9 to 0.86 after the procedures (p = 0.001). There was no major complication. Conclusion: PC is a safe, feasible, and efficient approach for the treatment of bone pain and disability in MM patient

MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status

The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic glioma suggest a prognostic value for MGMT methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate MGMT classification to assess high throughput molecular databases. Promoter methylation-mediated gene silencing is strongly dependent on the location of the methylated CpGs, complicating classification. Using the HumanMethylation450 (HM-450K) BeadChip interrogating 176 CpGs annotated for the MGMT gene, with 14 located in the promoter, two distinct regions in the CpG island of the promoter were identified with high importance for gene silencing and outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg1243587 and cg12981137 provided good classification properties and prognostic value (kappa=0.85; log-rank p<0.001) using a training-set of 63 glioblastomas from homogenously treated patients, for whom MGMT methylation was previously shown to be predictive for outcome based on classification by methylation-specific PCR. MGMT-STP27 was successfully validated in an independent cohort of chemo-radiotherapy-treated glioblastoma patients (n=50; kappa=0.88; outcome, log-rank p<0.001). Lower prevalence of MGMT methylation among CpG island methylator phenotype (CIMP) positive tumors was found in glioblastomas from The Cancer Genome Atlas than in low grade and anaplastic glioma cohorts, while in CIMP-negative gliomas MGMT was classified as methylated in approximately 50% regardless of tumor grade. The proposed MGMT-STP27 prediction model allows mining of datasets derived on the HM-450K or HM-27K BeadChip to explore effects of distinct epigenetic context of MGMT methylation suspected to modulate treatment resistance in different tumor type

Degeneracy of Antigen Recognition as the Molecular Basis for the High Frequency of Naive A2/Melan-A Peptide Multimer+ CD8+ T Cells in Humans

In contrast with the low frequency of most single epitope reactive T cells in the preimmune repertoire, up to 1 of 1,000 naive CD8+ T cells from A2+ individuals specifically bind fluorescent A2/peptide multimers incorporating the A27L analogue of the immunodominant 26–35 peptide from the melanocyte differentiation and melanoma associated antigen Melan-A. This represents the only naive antigen-specific T cell repertoire accessible to direct analysis in humans up to date. To get insight into the molecular basis for the selection and maintenance of such an abundant repertoire, we analyzed the functional diversity of T cells composing this repertoire ex vivo at the clonal level. Surprisingly, we found a significant proportion of multimer+ clonotypes that failed to recognize both Melan-A analogue and parental peptides in a functional assay but efficiently recognized peptides from proteins of self- or pathogen origin selected for their potential functional cross-reactivity with Melan-A. Consistent with these data, multimers incorporating some of the most frequently recognized peptides specifically stained a proportion of naive CD8+ T cells similar to that observed with Melan-A multimers. Altogether these results indicate that the high frequency of Melan-A multimer+ T cells can be explained by the existence of largely cross-reactive subsets of naive CD8+ T cells displaying multiple specificities