We report results of a phase 2, randomized, multicenter, open‐label, two‐arm study evaluating the safety and efficacy of eculizumab in preventing acute antibody‐mediated rejection (AMR) in sensitized ...recipients of living‐donor kidney transplants requiring pretransplant desensitization (NCT01399593). In total, 102 patients underwent desensitization. Posttransplant, 51 patients received standard of care (SOC) and 51 received eculizumab. The primary end point was week 9 posttransplant treatment failure rate, a composite of: biopsy‐proven acute AMR (Banff 2007 grade II or III; assessed by blinded central pathology); graft loss; death; or loss to follow‐up. Eculizumab was well tolerated with no new safety concerns. No significant difference in treatment failure rate was observed between eculizumab (9.8%) and SOC (13.7%; P = .760). To determine whether data assessment assumptions affected study outcome, biopsies were reanalyzed by central pathologists using clinical information. The resulting treatment failure rates were 11.8% and 21.6% for the eculizumab and SOC groups, respectively (nominal P = .288). When reassessment included grade I AMR, the treatment failure rates were 11.8% (eculizumab) and 29.4% (SOC; nominal P = .048). This finding suggests a potential benefit for eculizumab compared with SOC in preventing acute AMR in recipients sensitized to their living‐donor kidney transplants (EudraCT 2010‐019630‐28).
In this study of terminal complement inhibition to prevent acute antibody‐mediated rejection in living‐donor kidney transplant recipients with preformed donor‐specific antibodies, prophylactic eculizumab does not significantly reduce the treatment failure rate compared with standard of care, but biopsy reanalysis suggests a benefit for eculizumab in preventing AMR in these patients. See the article by Glotz et al on page 2865.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Gene fusions, like BCR/ABL1 in chronic myelogenous leukemia, have long been recognized in hematologic and mesenchymal malignancies. The recent finding of gene fusions in prostate and lung cancers has ...motivated the search for pathogenic gene fusions in other malignancies. Here, we developed a "breakpoint analysis" pipeline to discover candidate gene fusions by tell-tale transcript level or genomic DNA copy number transitions occurring within genes. Mining data from 974 diverse cancer samples, we identified 198 candidate fusions involving annotated cancer genes. From these, we validated and further characterized novel gene fusions involving ROS1 tyrosine kinase in angiosarcoma (CEP85L/ROS1), SLC1A2 glutamate transporter in colon cancer (APIP/SLC1A2), RAF1 kinase in pancreatic cancer (ATG7/RAF1) and anaplastic astrocytoma (BCL6/RAF1), EWSR1 in melanoma (EWSR1/CREM), CDK6 kinase in T-cell acute lymphoblastic leukemia (FAM133B/CDK6), and CLTC in breast cancer (CLTC/VMP1). Notably, while these fusions involved known cancer genes, all occurred with novel fusion partners and in previously unreported cancer types. Moreover, several constituted druggable targets (including kinases), with therapeutic implications for their respective malignancies. Lastly, breakpoint analysis identified new cell line models for known rearrangements, including EGFRvIII and FIP1L1/PDGFRA. Taken together, we provide a robust approach for gene fusion discovery, and our results highlight a more widespread role of fusion genes in cancer pathogenesis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused ...on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell–mediated rejection (TCMR), borderline, and antibody‐mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor‐specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.
This report focuses on the clarification of the criteria for chronic active T cell–mediated rejection and antibody‐mediated rejection and the optimization of the inflammation threshold for the diagnosis of borderline for acute T cell–mediated rejection, and discusses the potential to use machine learning in diagnostics and personalized therapeutics in solid organ transplantation.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A retrospective analysis of 25 patients with a history of prostate cancer (PC) who subsequently underwent allogeneic hematopoietic cell transplantation (HCT) for treatment of a hematologic malignancy ...was performed. Median patient age was 66.7 years. Median duration from the diagnosis of PC to HCT was 4.2 years. Twenty-three patients had Gleason group 1 or 2 disease. Therapy included prostatectomy (
n
= 13) and external beam or brachytherapy (
n
= 9). Hematologic diagnoses included both myeloid (
n
= 15) and lymphoid neoplasms (
n
= 10). Twenty-four patients received either a nonmyeloablative or reduced intensity conditioning regimen. GVHD prophylaxis included a calcineurin inhibitor and mycophenolate mofetil ± sirolimus. Twenty patients had HLA-matched sibling or HLA-matched unrelated donors; five patients had HLA-mismatched donors. Eleven patients are alive, and 14 have died. Median survival was 2.5 years (range, .02–12.6 years). The major cause of death was hematologic relapse. Only one patient had evidence of recurrent PC, occurring 1.5 years posttransplant. In carefully selected patients with a prior history of PC, there was no evidence of rapid recurrence of the solid tumor (ST) after HCT. PC patients who are in remission from their ST or have control of their disease on therapy should be considered eligible for HCT.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A major function of long non-coding RNAs (lncRNAs) is regulating gene expression through changes in chromatin state. Experimental evidence suggests that in cancer, they can influence Polycomb ...Repressive Complexes (PRC) to retarget to an occupancy pattern resembling that of the embryonic state. We have previously demonstrated that the expression level of lncRNA in the HOX locus, including HOTAIR, is a predictor of breast cancer metastasis. In this current project, RNA in situ hybridization of probes to three different lncRNAs (HOTAIR, ncHoxA1, and ncHoxD4), as well a immunohistochemical staining of EZH2, is undertaken in formalin-fixed paraffin-embedded breast cancer tissues in a high throughput tissue microarray format to correlate expression with clinicopathologic features. Though overall EZH2 and HOTAIR expression levels were highly correlated, the subset of cases with strong HOTAIR expression correlated with ER and PR positivity, while the subset of cases with strong EZH2 expression correlated with an increased proliferation rate, ER and PR negativity, HER2 underexpression, and triple negativity. Co-expression of HOTAIR and EZH2 trended with a worse outcome. In matched primary and metastatic cancers, both HOTAIR and EZH2 had increased expression in the metastatic carcinomas. This is the first study to show that RNA in situ hybridization of formalin fixed paraffin-embedded clinical material can be used to measure levels of long non-coding RNAs. This approach offers a method to make observations on lncRNAs that may influence the cancer epigenome in a tissue-based technique.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We evaluated TLR function in primary human dendritic cells (DCs) from 104 young (age 21-30 y) and older (> or =65 y) individuals. We used multicolor flow cytometry and intracellular cytokine staining ...of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) and found substantial decreases in older compared with young individuals in TNF-alpha, IL-6, and/or IL-12 (p40) production in mDCs and in TNF-alpha and IFN-alpha production in pDCs in response to TLR1/2, TLR2/6, TLR3, TLR5, and TLR8 engagement in mDCs and TLR7 and TLR9 in pDCs. These differences were highly significant after adjustment for heterogeneity between young and older groups (e.g., gender, race, body mass index, number of comorbid medical conditions) using mixed-effect statistical modeling. Studies of surface and intracellular expression of TLR proteins and of TLR gene expression in purified mDCs and pDCs revealed potential contributions for both transcriptional and posttranscriptional mechanisms in these age-associated effects. Moreover, intracellular cytokine production in the absence of TLR ligand stimulation was elevated in cells from older compared with young individuals, suggesting a dysregulation of cytokine production that may limit further activation by TLR engagement. Our results provide evidence for immunosenescence in DCs; notably, defects in cytokine production were strongly associated with poor Ab response to influenza immunization, a functional consequence of impaired TLR function in the aging innate immune response.
The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can ...activate certain mutant androgen receptors (AR) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone-activated mutant ARs.
AR was examined by targeted sequencing in metastatic tumor biopsies from 18 patients with CRPC who were progressing on a CYP17A1 inhibitor (17 on abiraterone, 1 on ketoconazole), alone or in combination with dutasteride, and by whole-exome sequencing in residual tumor in one patient treated with neoadjuvant leuprolide plus abiraterone.
The progesterone-activated T878A-mutant AR was present at high allele frequency in 3 of the 18 CRPC cases. It was also present in one focus of resistant tumor in the neoadjuvant-treated patient, but not in a second clonally related resistant focus that instead had lost one copy of PTEN and both copies of CHD1. The T878A mutation appeared to be less common in the subset of patients with CRPC treated with abiraterone plus dutasteride, and transfection studies showed that dutasteride was a more potent direct antagonist of the T878A versus the wild-type AR.
These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition.
Platelets are uniquely positioned as mediators of not only hemostasis but also innate immunity. However, how age and geriatric conditions such as frailty influence platelet function during an immune ...response remains unclear. We assessed the platelet transcriptome at baseline and following influenza vaccination in Younger (age 21–35) and Older (age ≥65) adults (including community‐dwelling individuals who were largely non‐frail and skilled nursing facility (SNF)‐resident adults who nearly all met criteria for frailty). Prior to vaccination, we observed an age‐associated increase in the expression of platelet activation and mitochondrial RNAs and decrease in RNAs encoding proteins mediating translation. Age‐associated differences were also identified in post‐vaccination response trajectories over 28 days. Using tensor decomposition analysis, we found increasing RNA expression of genes in platelet activation pathways in young participants, but decreasing levels in (SNF)‐resident adults. Translation RNA trajectories were inversely correlated with these activation pathways. Enhanced platelet activation was found in community‐dwelling older adults at the protein level, compared to young individuals both prior to and post‐vaccination; whereas SNF residents showed decreased platelet activation compared to community‐dwelling older adults that could reflect the influence of decreased translation RNA expression. Our results reveal alterations in the platelet transcriptome and activation responses that may contribute to age‐associated chronic inflammation and the increased incidence of thrombotic and pro‐inflammatory diseases in older adults.
Platelets mediate innate immune responses as well as thrombosis. We found an age‐associated increase in platelet activation RNAs, further increased in skilled nursing facility (enriched for frailty) vs. community‐dwelling (largely non‐frail) older adults. Tensor decomposition analysis revealed distinct trajectories of platelet activation following high‐dose influenza vaccine. Our results implicate platelets, which are anucleate and lack nuclear transcription, in age‐related chronic inflammation.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Adenoid cystic carcinoma is a locally aggressive salivary gland neoplasm, which has a poor long-term prognosis. A chromosomal translocation involving the genes encoding the transcription factors, MYB ...and NFIB, has been recently discovered in these tumors.
MYB translocation and protein expression were studied in 37 adenoid cystic carcinomas, 112 other salivary gland neoplasms, and 409 nonsalivary gland neoplasms by fluorescence in situ hybridization and immunohistochemistry. MYB translocation and expression status in adenoid cystic carcinoma was correlated with clinicopathologic features including outcome, with a median follow-up of 77.1 months (range, 23.2 to 217.5 mo) for living patients.
A balanced translocation between MYB and NFIB is present in 49% of adenoid cystic carcinomas but is not identified in other salivary gland tumors or nonsalivary gland neoplasms. There is no apparent translocation of MYB in 35% of the cases. Strong Myb immunostaining is very specific for adenoid cystic carcinomas but is only present in 65% of all cases. It is interesting to note that Myb immunostaining is confined to the basal cell component although the translocation is present in all the cells. Neoplasms with MYB translocation show a trend toward higher local relapse rates, but the results are not statistically significant with the current number of cases.
MYB translocation and expression are useful diagnostic markers for a subset of adenoid cystic carcinomas. The presence of the translocation may be indicative of local aggressive behavior, but a larger cohort may be required to show statistical significance.
Purpose: Macrophages play an important role in breast carcinogenesis. The pathways that mediate the macrophage contribution to breast
cancer and the heterogeneity that exists within macrophages are ...incompletely understood. Macrophage colony-stimulating factor
1 (CSF1) is the primary regulator of tissue macrophages. The purpose of this study was to define a novel CSF1 response signature
and to evaluate its clinical and biological significance in breast cancer.
Experimental Design: We defined the CSF1 response signature by identifying genes overexpressed in tenosynovial giant cell tumor and pigmented
villonodular synovitis (tumors composed predominantly of macrophages recruited in response to the overexpression of CSF1)
compared with desmoid-type fibromatosis and solitary fibrous tumor. To characterize the CSF1 response signature in breast
cancer, we analyzed the expression of CSF1 response signature genes in eight published breast cancer gene expression data
sets ( n = 982) and did immunohistochemistry and in situ hybridization for CSF1 response genes on a breast cancer tissue microarray ( n = 283).
Results: In both the gene microarray and tissue microarray analyses, a consistent subset (17-25%) of breast cancers shows the CSF1
response signature. The signature is associated with higher tumor grade, decreased expression of estrogen receptor, decreased
expression of progesterone receptor, and increased TP53 mutations ( P < 0.001).
Conclusions: Our data show that the CSF1 response signature is consistently seen in a subset of breast carcinomas and correlates with
biological features of the tumor. Our findings provide insight into macrophage biology and may facilitate the development
of personalized therapy for patients most likely to benefit from CSF1-targeted treatments.
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