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We report here the physical mapping of recurrent chromosome 12q13-q15 breakpoints in cell lines derived from primary myxoid liposarcoma, lipoma, uterine leiomyoma, and pleomorphic adenoma of the salivary glands. In fluorescence in situhybridization (FISH) experiments, we first mapped the position of the chromosome 12 translocation breakpoint in uterine leiomyoma cell line LM-30.1/SV40 relative to loci COL2A1, D12S4, D12S17, D12S6, D12S19, D12S8, and D12S7. It mapped between linkage probes CRIC86 (D12S19) and p7G11 (D12S8). We then isolated YAC clones using CRI-C86- and p7G11-derived sequence-tagged sites, constructed corresponding YAC contigs of 310 and 800 kb, respectively, and established long-range physical maps of these. Cosmid clones LLNL12NCO1-98C10 and LLNL12NCO1-113D12 were isolated using STSs within the CRI-C86- and the p7G11-derived YAC contigs, respectively, and a mixture of them was used to routinely study the various tumor cell lines by FISH analysis. The chromosome 12 breakpoints of all tumor cell lines tested mapped between cosmids LLNL12NCO1-98CI0 and LLNL12NCO1-113D12. None of the breakpoints appeared to map within any of the isolated YAC clones. Furthermore, FISH analysis using cosmid LLNL12-NCO1-144G3, which maps at the CHOPlocus, revealed that the chromosome 12 breakpoints in all cell lines of the three benign solid tumors that were tested were located distal to the chromosome 12 translocation breakpoint with the CHOPgene in myxoid liposarcoma cells with t(12;16). In conclusion, our studies seem to indicate that the chromosome 12 breakpoints of myxoid liposarcoma, lipoma, uterine leiomyoma, and pleomorphic adenoma of the salivary glands are all clustered within the 7-cM interval between D12S19 and D12S8, with those of the benign solid tumors distal to CHOP. Finally, the MYF5gene mapped telomeric to LLNL12NCO1-113D12, and the MIPgene mapped centromeric to the chromosome 12 translocation breakpoint in myxoid liposarcoma cells.

• A cytogenetic study was performed on short-term cultures from fresh surgical specimens obtained from 41 patients with soft-tissue sarcomas of various histologic origins. The results demonstrated that myxoid liposarcomas (five tumors) were associated with a specific translocation between chromosomes 12 and 16 and that synovial sarcomas (six tumors) were associated with a specific translocation between the X chromosome and chromosome 18. These chromosomal data have been used to differentiate myxoid liposarcoma from other myxoid tumors exhibiting a noncharacteristic histologic picture, as well as to ascertain the diagnosis of synovial sarcoma in undifferentiated soft-tissue sarcomas. The results to date indicate that identification of specific chromosomal changes in sarcomas may provide a new diagnostic criterion for these tumors and possibly improve prognostication with regard to survival and response to treatment.(Arch Surg 1987;122:1257-1260)

A translocation that involves chromosome X (band p11.2) and chromosome 18 (band q11.2) was observed in short-term in vitro cultures of cells from five synovial sarcomas and one malignant fibrous histiocytoma. In four of these tumors, the translocation t(X;18)(p11.2;q11.2) was reciprocal. The two other tumors had complex translocations: t(X;18;21)(p11.2;q11.2;p13) and t(X;15;18)(p11.2;q23;q11.2). A translocation between chromosomes X and 18 was not detected in other histological types of soft tissue sarcoma. The X;18 rearrangement appears to characterize the synovial sarcoma and is the first description of a primary, nonrandom change in the sex chromosome of a human solid tumor.

PURPOSE To evaluate the role of surgery in patients diagnosed with primary cutaneous B-cell lymphoma (PCBCL) – a rare disease entity. The authors offer a rationale for the use of primary surgical excision in the treatment of isolated cutaneous lymphomas.METHODS A literature review examining the use of primary surgical excision in the treatment of PCBCL was conducted. The lymphoma database at the Juravinski Cancer Centre (Hamilton, Ontario) was searched from January 1995 to July 2008, generating a list of 4924 patients. A simulated computer program was subsequently designed to search for all possible PCBCLs. A retrospective chart review was then conducted on the new list of 1325 patients, identifying 25 patients diagnosed with PCBCL.RESULTS The mean age of the 25 patients with PCBCL was 59.9 years; nine (36%) were treated with surgery, and sixteen (64%) with radiation. The average follow-up period for patients was 3.6 years. Twenty-four of the 25 patients were completely cured, with only one patient recurring in the radiation subgroup. There were no complications in the surgery subgroup. There were two local complications in the radiation subgroup consisting of chronic ulcerations.CONCLUSIONS Primary surgical excision is an effective management option in the treatment of PCBCL, particularly the marginal zone and follicle centre subtypes.

Cytogenetic analysis on a 7-day-old culture of a fibrothecoma showed only numerical chromosome abnormalities: 57, XX, +4, +5, +6, +10, + 12, +12, +14, +17, +18, +19, +20. The finding of an extra copy of chromosome 12 in mesenchymal tumors, mostly benign and originating from the female genital tract, may possibly point towards their common embryonic origin.

Brunner: Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Chen:Magenta: Consultancy; Takeda: Consultancy; Kiadis: Consultancy; Incyte: Consultancy; Abbvie: Consultancy. Fathi:Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria; Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy. Narayan:Genentech: Other: Equity ownership (spouse); Merck: Other: Equity ownership (spouse); Takeda: Other: Employment (spouse). Benhadji:Taiho Oncology: Employment. Hobbs:Incyte: Consultancy, Research Funding; Merck: Research Funding; Jazz pharmaceuticals: Consultancy; Celgene: Consultancy; Bayer: Research Funding; Agios: Consultancy.

Introduction

Herrera: Adaptive Biotechnologies: Research Funding; Genentech: Research Funding; Immune Design: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding. Song:Seattle Genetics: Consultancy. Chen:Genentech: Consultancy, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Koreth:LLS: Research Funding; amgen inc: Consultancy; takeda pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; kadmon corp: Membership on an entity's Board of Directors or advisory committees; prometheus labs inc: Research Funding; millennium pharmaceuticals: Research Funding. Pillai:Trillium Therapeutics: Research Funding. Siddiqi:Janssen Biotech: Research Funding, Speakers Bureau; Seattle Genetics: Speakers Bureau; Juno Therapeutics: Research Funding; Kite Pharma: Research Funding; Acerta Pharma: Research Funding; MedImmune: Research Funding; Genentech: Research Funding; TG Therapeutics: Research Funding. Zain:Seattle Genetics: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Kwak:XEME BioPharma: Consultancy, Equity Ownership; Antigenics: Equity Ownership; Celltrion: Consultancy; Sella Life Sciences: Consultancy. Nademanee:Celgene: Consultancy; Seattle Genetics: Consultancy, Research Funding. Weinstock:Novartis: Consultancy, Research Funding. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Rodig:Bristol-Myers Squibb: Honoraria, Research Funding; Perkin Elmer: Membership on an entity's Board of Directors or advisory committees. Armand:Roche: Research Funding; Pfizer: Research Funding; Sequenta Inc: Research Funding; Merck: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding.

The present report describes a recent case of recurrent infection in a breast reconstruction patient with a history of psoriasis. Following surgery, the patient developed psoriatic plaques along the incision scars. This phenomenon is known as Koebnerization, and has been found to affect surgical incisions. Cases of psoriatic patients being denied surgical procedures because of their inherent risk to Koebnerize have been previously reported. Similarly, such patients have been denied surgical procedures because of their increased risk of infection. The present case and literature review on this subject is described.

Diffuse large B-cell lymphomas (DLBCLs) arise from normal germinal center (GC) or post GC B cells. Negative selection of low-affinity or self-reactive normal GC B cells requires CD95 (FAS)-mediated apoptosis. Mutations of the FAS receptor that result in deletion of the cytoplastic death domain (DD) destabilize the trimeric structure and inhibit FAS-mediated apoptosis. This apoptotic pathway is also inhibited when the NFκB target, c-FLIP, interacts with the death-inducing signaling complex, assembled around the cytoplasmic FAS DD. We analyzed FAS receptor mutations and NFκB-mediated overexpression of c-FLIP as potential mechanisms for deregulating the extrinsic apoptotic pathway in DLBCL subtypes defined by gene expression profiling (GEP) -- OxPhos, BCR/proliferation and Host Response (HR) tumors (Monti et al, Blood2005; 105:1851). Study specimens included 117 newly diagnosed DLBCLs that were previously characterized for BCL2 and BCL6 translocations and assigned to the recently described consensus clusters by transcriptional profiling (40 OxPhos, 55 BCR and 22 HR tumors). The FAS coding region from each tumor was amplified by RT-PCR and sequenced. Mutations resulting in deletions of the cytoplasmic DD occurred in 8 DLBCLs. In all tumors, the resulting frameshifts or amino acid substitutions created STOP codons upstream of or at the beginning of the FAS DD. There was a significantly increased incidence of FAS DD deletions in OxPhos tumors (6 tumors, p = .05); these OxPhos tumors also had more frequent t(14;18) (p = .05), indicating that structural abnormalities of extrinsic and intrinsic apoptotic pathway components were more common in this DLBCL subtype. We previously found that HR tumors were significantly less likely to have either BCL2 or BCL6 translocations (1/22 tumors with t(14;18), no tumors with t(3;V)); these DLBCLs also had no mutations of the FAS DD. Given the brisk host inflammatory/immune cell infiltrate in HR tumors, we performed additional mixing studies and confirmed that the PCR-based assay was sufficiently sensitive to detect FAS DD mutations in HR tumor cells. HR tumors have increased expression of a large series of NFκB target genes suggesting that these tumors may be dependent upon NFκB activation (Feuerhake et al, Blood2005; 106:1392). The NFκB target gene, c-FLIPlong, inhibits FAS-induced apoptosis in normal GC B-cells and Hodgkin’s lymphomas. For these reasons, we identified c-FLIP probe sets from the long-form specific C-terminal domain and assessed c-FLIPlong transcript abundance in the DLBCL consensus clusters. The expression of c-FLIPlong was highest in HR tumors and lowest in OxPhos DLBCLs (p < .0001, Kruskal-Wallis test); HR tumors also expressed significantly more abundant c-FLIPlong transcripts than normal GC B-cells (P = .03, Wilcoxon rank sum test). Therefore, NFκB-mediated upregulation of c-FLIPlong likely represents an alternative method of inhibiting FAS-mediated apoptosis in HR DLBCLs which lack structural abnormalities of the FAS receptor. These data further support the notion that GEP-defined subtypes of DLBCL differ with respect to underlying genetic lesions and suggest that these molecular signatures have therapeutic relevance.

Philadelphia chromosome positive acute myeloid leukemia (Ph+ AML) is a rare entity reported to comprise 1% of tumors bearing the Philadelphia chromosome. Controversy exists over whether this represents a distinct entity or is merely presentation of patients in the blastic phase of chronic myeloid leukemia (CML). Our study sought to determine the clinicopathologic characteristics of Ph+ AML in comparison to CML in blast crisis. We searched the archival files of Massachusetts General Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, and MD Anderson Cancer Center from 1995 to 2005 for cases of apparent de novo Ph+ AML. After excluding biphenotypic leukemias and cases with any evidence of prior CML or other myeloid neoplasia, we retrieved 18 Ph+ AML cases. 20 cases of documented CML in myeloid blast crisis (CML-MBC) who had not received prior imatinib mesylate therapy or bone marrow transplant were used as a control group. The clinical and laboratory features, bone marrow morphology, immunophenotype, cytogenetics, and type of BCR/ABL transcript were analyzed. The Ph+ AML patients included 13 males and 5 females with a median age of 55 years, which was not significantly different from CML-MBC patients. The median WBC at presentation was 15.7 x 109/L. Compared to CML-MBC patients, the Ph+ AML patients were less likely to have splenomegaly (22% vs. 68%, p=0.008) or peripheral basophilia (median absolute basophil count 0.16 vs. 1.24 x 109/L, p=0.003). The bone marrow in Ph+ AML patients was less cellular (median cellularity 80% vs. 98%, p=0.002) with a lower myeloid:erythroid ratio (1.3 vs. 4.8, p=0.01), but more prominent erythroid and myeloid lineage dysplasia (p=0.04) than that of CML-MBC patients. While cytogenetic abnormalities in addition to t(9;22) occurred in 67% of Ph+ AML cases, the typical additional cytogenetic changes of CML-MBC (+8, +19, iso17q, and +Ph+) were uncommon (22% vs. 87% for CML-MBC, p=0.0004). In 5/6 Ph+ AML cases with multiple clones, the Ph+ was present in all clones, suggesting that this represents an early event in the evolution of these leukemias. RT-PCR revealed a predicted BCR/ABL product of p210 (10/13 cases), p190 (2/13 cases) or p230 (1/13 cases). 6/7 Ph+ AML patients treated with imatinib showed at least a partial hematologic response, but this was of a short duration (median 2.5 months, range 1–6 months) in comparison to the reported median response duration of 10 months in imatinib-responsive CML-MBC. The median survival of the Ph+ AML patients was 10.5 months, similar to that of CML-MBC and AML with adverse cytogenetics. In summary, Ph+ AML is a rare entity distinct from CML-MBC, with an aggressive clinical course and only transient response to imatinib.

Diffuse large B-cell lymphomas (DLBCLs) arise from normal germinal center (GC) or post GC B cells. Negative selection of low-affinity or self-reactive normal GC B cells requires CD95 (FAS)-mediated apoptosis. Mutations of the FASreceptor that result in deletion of the cytoplastic death domain (DD) destabilize the trimeric structure and inhibit FAS-mediated apoptosis. This apoptotic pathway is also inhibited when the NFκB target, c-FLIP, interacts with the death-inducing signaling complex, assembled around the cytoplasmic FAS DD. We analyzed FASreceptor mutations and NFκB-mediated overexpression of c-FLIP as potential mechanisms for deregulating the extrinsic apoptotic pathway in DLBCL subtypes defined by gene expression profiling (GEP) -- OxPhos, BCR/proliferation and Host Response (HR) tumors (Monti et al, Blood 2005; 105:1851). Study specimens included 117 newly diagnosed DLBCLs that were previously characterized for BCL2and BCL6translocations and assigned to the recently described consensus clusters by transcriptional profiling (40 OxPhos, 55 BCR and 22 HR tumors). The FAS coding region from each tumor was amplified by RT-PCR and sequenced. Mutations resulting in deletions of the cytoplasmic DD occurred in 8 DLBCLs. In all tumors, the resulting frameshifts or amino acid substitutions created STOP codons upstream of or at the beginning of the FASDD. There was a significantly increased incidence of FASDD deletions in OxPhos tumors (6 tumors, p = .05); these OxPhos tumors also had more frequent t(14;18) (p = .05), indicating that structural abnormalities of extrinsic and intrinsic apoptotic pathway components were more common in this DLBCL subtype. We previously found that HR tumors were significantly less likely to have either BCL2or BCL6translocations (1/22 tumors with t(14;18), no tumors with t(3;V)); these DLBCLs also had no mutations of the FASDD. Given the brisk host inflammatory/immune cell infiltrate in HR tumors, we performed additional mixing studies and confirmed that the PCR-based assay was sufficiently sensitive to detect FASDD mutations in HR tumor cells. HR tumors have increased expression of a large series of NFκB target genes suggesting that these tumors may be dependent upon NFκB activation (Feuerhake et al, Blood 2005; 106:1392). The NFκB target gene, c-FLIPlong, inhibits FAS-induced apoptosis in normal GC B-cells and Hodgkin's lymphomas. For these reasons, we identified c-FLIPprobe sets from the long-form specific C-terminal domain and assessed c-FLIPlongtranscript abundance in the DLBCL consensus clusters. The expression of c-FLIPlongwas highest in HR tumors and lowest in OxPhos DLBCLs (p < .0001, Kruskal-Wallis test); HR tumors also expressed significantly more abundant c-FLIPlongtranscripts than normal GC B-cells (P= .03, Wilcoxon rank sum test). Therefore, NFκB-mediated upregulation of c-FLIPlonglikely represents an alternative method of inhibiting FAS-mediated apoptosis in HR DLBCLs which lack structural abnormalities of the FASreceptor. These data further support the notion that GEP-defined subtypes of DLBCL differ with respect to underlying genetic lesions and suggest that these molecular signatures have therapeutic relevance.

For Abstract see ChemInform Abstract in Full Text.