Emily Z. Keung

Predictors of Outcomes in Patients with Primary Retroperitoneal Dedifferentiated Liposarcoma Undergoing Surgery

BACKGROUND Although sarcoma histology is recognized as a prognostic factor, most studies of retroperitoneal sarcomas report results combining multiple histologies and are inadequately powered to identify prognostic factors specific to a particular histology. We reviewed our experience with retroperitoneal dedifferentiated liposarcoma (RP DDLPS) to identify factors predictive of outcomes. STUDY DESIGN All patients with RP DDLPS treated at our institution between 1998 and 2008 were reviewed. Multivariable Cox regression analyses were performed to identify factors predictive of progression-free survival (PFS), local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), and overall survival (OS). RESULTS We identified 119 patients with primary DDLPS. Median tumor size was 20.5 cm; 21% were multifocal. French Federation of Cancer Centers Sarcoma Group tumor grades were intermediate in 53% of patients and high in 28% (unknown 19%). Resections were complete (R0/R1) in 80% of patients and incomplete (R2) in 11% (unknown 9%). Tumors were removed intact in 72% of patients and fragmented in 16% (unknown 12%). Median follow-up was 74.1 months. One hundred patients (84%) experienced recurrence or progression, with 92% occurring in the retroperitoneum. Median PFS, LRFS, DRFS, and OS were 21.1, 21.5, 45.8, and 59.0 months, respectively, and were significantly worse with R2 resection. On multivariate analysis, tumor integrity (intact vs fragmented) was predictive of PFS, multifocality predicted LRFS, and extent of resection (R0/R1 vs R2), grade, and tumor integrity predicted OS. CONCLUSIONS In this cohort of primary RP DDLPS, factors under surgeon control (tumor integrity, extent of resection) and reflective of tumor biology (grade, multifocality) impact patient outcomes.

Concise review: genetically engineered stem cell therapy targeting angiogenesis and tumor stroma in gastrointestinal malignancy.

Cell‐based gene therapy holds considerable promise for the treatment of human malignancy. Genetically engineered cells if delivered to sites of disease could alleviate symptoms or even cure cancer through expression of therapeutic or suicide transgene products. Mesenchymal stem cells (MSCs), nonhematopoietic multipotent cells found primarily in bone marrow, have garnered particular interest as potential tumor‐targeting vehicles due to their innate tumortropic homing properties. However, recent strategies go further than simply using MSCs as vehicles and use the stem cell‐specific genetic make‐up to restrict transgene expression to tumorigenic environments using tumor‐tissue specific promoters. This addresses one of the concerns with this novel therapy that nonselective stem cell‐based therapy could induce cancer rather than treat it. Even minimal off‐target effects can be deleterious, motivating recent strategies to not only enhance MSC homing but also engineer them to make their antitumor effect selective to sites of malignancy. This review will summarize the advances made in the past decade toward developing novel cell‐based cancer therapies using genetically engineered MSCs with a focus on strategies to achieve and enhance tumor specificity and their application to targeting gastrointestinal malignancies such as hepatocellular carcinoma and pancreatic adenocarcinoma. STEM CELLS2013;31:227–235

Immunocompromised Status in Patients With Necrotizing Soft-Tissue Infection

IMPORTANCE There is a scarcity of research on immunocompromised patients with necrotizing soft-tissue infection (NSTI). OBJECTIVE To evaluate the effect of immunocompromised status in patients with NSTI. DESIGN AND SETTING Single-institution retrospective cohort study at a tertiary academic teaching hospital affiliated with a major cancer center. PARTICIPANTS Patients with NSTI. EXPOSURE Treatment at Brigham and Womens Hospital and Dana-Farber Cancer Institute between November 25, 1995, and April 25, 2011. MAIN OUTCOME AND MEASURE Necrotizing soft-tissue infection-associated in-hospital mortality. RESULTS Two hundred one patients were diagnosed as having NSTI. Forty-six were immunocompromised (as defined by corticosteroid use, active malignancy, receipt of chemotherapy or radiation therapy, diagnosis of human immunodeficiency virus or AIDS, or prior solid organ or bone marrow transplantation with receipt of chronic immunosuppression). At presentation, immunocompromised patients had lower systolic blood pressure (105 vs 112 mm Hg, P = .02), glucose level (124 vs 134 mg/dL, P = .03), and white blood cell count (6600/μL vs 17 200/μL, P < .001) compared with immunocompetent patients. Immunocompromised patients were less likely to have been transferred from another institution (26.1% vs 52.9%, P = .001), admitted to a surgical service (45.7% vs 83.2%, P < .001), or undergone surgical debridement on admission (4.3% vs 61.3%, P = .001). Time to diagnosis and time to first surgical procedure were delayed in immunocompromised patients (P < .001 and P = .001, respectively). Immunocompromised patients had higher NSTI-associated in-hospital mortality (39.1% vs 19.4%, P = .01). CONCLUSIONS AND RELEVANCE Immunocompromised status in patients with NSTI in this study is associated with delays in diagnosis and surgical treatment and with higher NSTI-associated in-hospital mortality. At presentation, immunocompromised patients may fail to exhibit typical clinical and laboratory signs of NSTI. Physicians caring for similar patient populations should maintain a heightened level of suspicion for NSTI and consider early surgical evaluation and treatment.

External Validation of a Prognostic Nomogram for Overall Survival in Women With Uterine Leiomyosarcoma

There is no validated system to identify prognostically distinct cohorts of women with uterine leiomyosarcoma (ULMS). By using an independent, pooled, multi‐institutional, international patient cohort, the authors validated a recently proposed ULMS nomogram.

Systematic Epigenomic Analysis Reveals Chromatin States Associated with Melanoma Progression

The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. Through systematic epigenomic profiling of 35 epigenetic modifications and transcriptomic analysis, we define chromatin state changes associated with melanomagenesis by using a cell phenotypic model of non-tumorigenic and tumorigenic states. Computation of specific chromatin state transitions showed loss of histone acetylations and H3K4me2/3 on regulatory regions proximal to specific cancer-regulatory genes in important melanoma-driving cell signaling pathways. Importantly, such acetylation changes were also observed between benign nevi and malignant melanoma human tissues. Intriguingly, only a small fraction of chromatin state transitions correlated with expected changes in gene expression patterns. Restoration of acetylation levels on deacetylated loci by histone deacetylase (HDAC) inhibitors selectively blocked excessive proliferation in tumorigenic cells and human melanoma cells, suggesting functional roles of observed chromatin state transitions in driving hyperproliferative phenotype. Through these results, we define functionally relevant chromatin states associated with melanoma progression.

Increased H3K9me3 drives dedifferentiated phenotype via KLF6 repression in liposarcoma

Liposarcoma (LPS) can be divided into 4 different subtypes, of which well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) are the most common. WDLPS is typically low grade, whereas DDLPS is high grade, aggressive, and carries a worse prognosis. WDLPS and DDLPS frequently co-occur in patients. However, it is not clear whether DDLPS arises independently from WDLPS, or whether epigenomic alterations underly the histopathological differences of these subtypes. Here, we profiled 9 epigenetic marks in tumor samples from 151 patients with LPS and showed elevated trimethylation of histone H3 at Lys9 (H3K9me3) levels in DDLPS tumors. Integrated ChIP-seq and gene expression analyses of patient-derived cell lines revealed that H3K9me3 mediates differential regulation of genes involved in cellular differentiation and migration. Among these, Kruppel-like factor 6 (KLF6) was reduced in DDLPS, with increased H3K9me3 at associated regulatory regions. Pharmacologic inhibition of H3K9me3 with chaetocin decreased DDLPS proliferation and increased expression of the adipogenesis-associated factors PPARγ, CEBPα, and CEBPβ, suggesting that increased H3K9me3 may mediate DDLPS-associated aggressiveness and dedifferentiation properties. KLF6 overexpression partially phenocopied chaetocin treatment in DDLPS cells and induced phenotypic changes that were consistent with adipocytic differentiation, suggesting that the effects of increased H3K9me3 may be mediated through KLF6. In conclusion, we provide evidence of an epigenetic basis for the transition between WDLPS and DDLPS.

Dual Roles of RNF2 in Melanoma Progression

UNLABELLED Epigenetic regulators have emerged as critical factors governing the biology of cancer. Here, in the context of melanoma, we show that RNF2 is prognostic, exhibiting progression-correlated expression in human melanocytic neoplasms. Through a series of complementary gain-of-function and loss-of-function studies in mouse and human systems, we establish that RNF2 is oncogenic and prometastatic. Mechanistically, RNF2-mediated invasive behavior is dependent on its ability to monoubiquitinate H2AK119 at the promoter of LTBP2, resulting in silencing of this negative regulator of TGFβ signaling. In contrast, RNF2s oncogenic activity does not require its catalytic activity nor does it derive from its canonical gene repression function. Instead, RNF2 drives proliferation through direct transcriptional upregulation of the cell-cycle regulator CCND2. We further show that MEK1-mediated phosphorylation of RNF2 promotes recruitment of activating histone modifiers UTX and p300 to a subset of poised promoters, which activates gene expression. In summary, RNF2 regulates distinct biologic processes in the genesis and progression of melanoma via different molecular mechanisms. SIGNIFICANCE The role of epigenetic regulators in cancer progression is being increasingly appreciated. We show novel roles for RNF2 in melanoma tumorigenesis and metastasis, albeit via different mechanisms. Our findings support the notion that epigenetic regulators, such as RNF2, directly and functionally control powerful gene networks that are vital in multiple cancer processes.

Management of Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract. The stomach is the most common site of origin. Management of GISTs changed after the introduction of molecularly targeted therapies. Although the only potentially curative treatment of resectable primary GISTs is surgery, recurrence is common. Patients with primary GISTs at intermediate or high risk of recurrence should receive imatinib postoperatively. Imatinib is also first-line therapy for advanced disease. Cytoreductive surgery might be considered in advanced GIST for patients with stable/responding disease or limited focal progression on tyrosine kinase inhibitor therapy. GIST requires multidisciplinary management.

Suicide Gene Therapy against Cancer

A major limitation of conventional chemotherapies used in cancer treatments today are low therapeutic indices and side effects that result from drug effects on normal tissues (off target). One of the most innovative approaches to developing antineoplastic agents with increased tumor selectivity is the use of suicide gene therapy. Suicide gene therapy involves delivering a gene product in proximity to the targeted cancer tissue through various targeted delivery methods followed by tissue/tumor-specific expression of the gene product which then converts a systemically available pro-drug into an active drug within the tumor locale. Here we summarize the concept of gene therapy for cancer and introduce the most frequently used suicide gene therapy systems. In addition we discuss viral, molecular and cellular vectors and their advantages and disadvantages. Finally, we describe the clinical applications, limitations and potential side effects of suicide gene therapy to date.

Analysis of the immune infiltrate in undifferentiated pleomorphic sarcoma of the extremity and trunk in response to radiotherapy: Rationale for combination neoadjuvant immune checkpoint inhibition and radiotherapy

ABSTRACT Background: Undifferentiated pleomorphic sarcoma of the extremity and trunk (ET-UPS) presents a unique therapeutic challenge. Although immunotherapy has recently been employed in advanced soft tissue sarcoma, there is limited data characterizing the immune infiltrate in ET-UPS. Radiotherapy (RT) has been shown in other tumor types to promote tumor antigen release and enhance tumor-specific targeting by the adaptive immune system. The aim of this study was to 1) characterize the baseline immune infiltrate and 2) evaluate the effect of preoperative RT on the histologic appearance of and the immune infiltrate in ET-UPS. Methods: We identified 17 matched ET-UPS samples before and after RT. Immunohistochemistry was performed with CD8, CD4, PD-L1, PD1, CD3, CD163 and FoxP3 positive cells identified in all samples. Changes in the immune infiltrate following RT were examined. Results: There was a trend towards increased density of tumor infiltrating immune cells in ET-UPS following RT, with increases in median number of CD3 (158 vs 219 cells/mm2, p = 0.06), CD4 (3 vs 13 cells/mm2, p = 0.01), CD8 (55 vs 111 cells/mm2, p = 0.17), and FOXP3 (14 vs 25 cells/mm2, p = 0.23) positive cells. Interestingly, although PD-L1 was not expressed in any ET-UPS tumor at baseline, positive PD-L1 expression was observed in 21% (3/14) of tumors after RT (p = 0.07). Conclusion: An immune infiltrate is present in ET-UPS at the time of diagnosis, with a trend towards increased density of immune infiltrate and PD-L1 expression after RT. These data support prospectively evaluating immune checkpoint inhibitors with standard of care RT in the treatment of ET-UPS.