PurposeWe investigated the combination of lymphodepleting chemotherapy followed by the adoptive transfer of autologous tumor reactive lymphocytes for the treatment of patients with refractory metastatic melanoma. Patients and MethodsThirty-five patients with metastatic melanoma, all but one with disease refractory to treatment with high-dose interleukin (IL)-2 and many with progressive disease after chemotherapy, underwent lymphodepleting conditioning with two days of cyclophosphamide (60 mg/kg) followed by five days of fludarabine (25 mg/m 2 ). On the day following the final dose of fludarabine, all patients received cell infusion with autologous tumor-reactive, rapidly expanded tumor infiltrating lymphocyte cultures and high-dose IL-2 therapy. ResultsEighteen (51%) of 35 treated patients experienced objective clinical responses including three ongoing complete responses and 15 partial responses with a mean duration of 11.5 ± 2.2 months. Sites of regression included metastases to lung, liver, lymph nodes, brain, and cutaneous and subcutaneous tissues. Toxicities of treatment included the expected hematologic toxicities of chemotherapy including neutropenia, thrombocytopenia, and lymphopenia, the transient toxicities of high-dose IL-2 therapy, two patients who developed Pneumocystis pneumonia and one patient who developed an Epstein-Barr virus-related lymphoproliferation. ConclusionLymphodepleting chemotherapy followed by the transfer of highly avid antitumor lymphocytes can mediate significant tumor regression in heavily pretreated patients with IL-2 refractory metastatic melanoma.Address reprint requests to
We assessed the cerebrospinal fluid (CSF) by flow cytometry and cytology in 51 newly diagnosed and 9 treated aggressive B-cell lymphomas at risk for central nervous system (CNS) involvement to examine the utility of flow cytometry, incidence of CSF disease, and clinical surrogates of CNS spread. Multicolor flow cytometry using multiple antibody panels for light chains and B-and T-cell antigens identified neoplastic clones that constituted as little as 0.2% of total CSF lymphocytes. Among 51 newly diagnosed patients, 11 (22%) had occult CSF involvement. All 11 were detected by flow cytometry but only 1 by cytology (P ؍ .002). Among 9 treated patients, CSF involvement was detected by flow cytometry alone in 2 and also by cytology in 1 case. CSF chemistry and cell counts were similar in patients with and without CSF lymphoma. Only the number of extranodal sites was associated with occult CSF lymphoma in newly diagnosed patients by univariate
A mutational analysis of the matrix metalloproteinase (MMP) gene family in human melanoma identified somatic mutations in 23% of melanomas. Five mutations in one of the most commonly mutated genes, MMP8, reduced MMP enzyme activity. Expression of wild-type but not mutant MMP8 in human melanoma cells inhibited growth on soft agar in vitro and tumor formation in vivo, suggesting that wild-type MMP-8 has the ability to inhibit melanoma progression.MMPs are proteolytic enzymes that degrade components of extracellular matrix and basement membranes 1 . MMPs have been associated with cancer metastasis 2,3 , and small molecule inhibitors of MMPs were tested as potential anticancer agents. However, clinical trials using these inhibitors showed no effect and, occasionally, accelerated tumor growth 4,5 . In contrast to the idea that MMP activity promotes melanoma progression, mouse models suggested that MMPs can have an antitumor role 6-8 . In particular, an increase in skin tumor incidence was seen in MMP-8-deficient mice 6 . These findings suggest that an in-depth analysis of the specific role of individual MMPs in particular cancer types is warranted. We systematically addressed © 2009 Nature America, Inc. All rights reserved.Correspondence should be addressed to Y.S. (samuelsy@mail.nih.gov).. AUTHOR CONTRIBUTIONS L.H.P. and Y.S. designed the study; J.R.W., P.F., A.C.F. and S.A.R. collected and analyzed the melanoma samples, A.S.B., J.C.C., N.S.A., P.B., P.P.-G., S.D., C.W., C.E.B., J. Table 2 online) and sequenced with dye terminator chemistry. To determine whether a given mutation was somatic, we sequenced the gene in genomic DNA from matched normal tissue. From the ∼5.5 Mb of sequence information obtained, we identified eight MMP genes containing somatic mutations (Table 1). Genes found to have one or more nonsynonymous mutations were then screened for mutations in an additional 47 melanomas. Through this approach, we identified 28 somatic mutations in eight genes, affecting 23% of the melanoma tumors analyzed (Table 1 and Supplementary Fig. 1 online).In seven tumors, both alleles of the MMP gene were affected, a characteristic associated with tumor suppressor genes. In addition, 6 of the 28 mutations were nonsense or splice-site alterations, which were predicted to result in aberrant or truncated proteins. Most tumors with MMP gene mutations also contained mutations in NRAS or BRAF. The clinical information associated with melanoma tumors containing MMP mutations is described in Supplementary Table 3 online.The observed somatic mutations could be either 'driver' mutations that have a functional role underlying neoplasia or nonfunctional 'passenger' changes. In the eight genes found to be mutated, 28 nonsynonymous (N) and 5 synonymous (S) somatic mutations were identified, yielding a N:S ratio of 28:5, significantly higher than the N:S ratio of 2:1 predicted for nonselected passenger mutations 9 (P < 0.026), suggesting that these are driver mutations. The ratio of C>T mutations compared to other nucleotide s...
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