UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma.

INTRODUCTION: Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) encodes a master regulator of DNA methylation that has emerged as an epigenetic driver in human cancers. To date, no studies have evaluated UHRF1 expression in malignant pleural mesothelioma (MPM). This study was undertaken to explore the therapeutic potential of targeting UHRF1 in MPM. METHODS: Microarray, real-time quantitative reverse transcription-polymerase chain reaction, immunoblot, and immunohistochemistry techniques were used to evaluate UHRF1 expression in normal mesothelial cells (NMCs) cultured with or without asbestos, MPM lines, normal pleura, and primary MPM specimens. The impact of UHRF1 expression on MPM patient survival was evaluated using two independent databases. RNA-sequencing, proliferation, invasion, and colony formation assays, and murine xenograft experiments were performed to evaluate gene expression and growth of MPM cells after biochemical or pharmacologic inhibition of UHRF1 expression. RESULTS: UHRF1 expression was significantly higher in MPM lines and specimens relative to NMC and normal pleura. Asbestos induced UHRF1 expression in NMC. The overexpression of UHRF1 was associated with decreased overall survival in patients with MPM. UHRF1 knockdown reversed genomewide DNA hypomethylation, and inhibited proliferation, invasion, and clonogenicity of MPM cells, and growth of MPM xenografts. These effects were phenocopied by the repurposed chemotherapeutic agent, mithramycin. Biochemical or pharmacologic up-regulation of p53 significantly reduced UHRF1 expression in MPM cells. RNA-sequencing experiments exhibited the pleiotropic effects of UHRF1 down-regulation and identified novel, clinically relevant biomarkers of UHRF1 expression in MPM. CONCLUSIONS: UHRF1 is an epigenetic driver in MPM. These findings support the efforts to target UHRF1 expression or activity for mesothelioma therapy.

The use of innominate artery cannulation for antegrade cerebral perfusion in aortic dissection.

BACKGROUND: Direct cannulation of the innominate artery for selective antegrade cerebral perfusion has been shown to be safe in elective proximal aortic reconstructions. We sought to evaluate the safety of this technique in acute aortic dissection. METHODS: A multi-institutional retrospective review was undertaken of patients who underwent proximal aortic reconstruction for Stanford type A dissection between 2006 and 2016. Those patients who had direct innominate artery cannulation for selective antegrade cerebral perfusion were selected for analysis. RESULTS: Seventy-five patients underwent innominate artery cannulation for ACP for Stanford Type A Dissections. Isolated replacement of the ascending aorta was performed in 36 patients (48.0%), concomitant aortic root replacement was required in 35 patients (46.7%), of whom 7 had a valve-sparing aortic root replacement, ascending aorta and arch replacement was required in 4 patients (5%). Other procedures included frozen elephant trunk (n = 11 (14.7%)), coronary artery bypass grafting (n = 20 (26.7%)), and peripheral arterial bypass (n = 4 (5.3%)). Mean hypothermic circulatory arrest time was 19 ± 13 min. Thirty-day mortality was 14.7% (n = 11). Perioperative stroke occurred in 7 patients (9.3%). CONCLUSIONS: This study is the first comprehensive review of direct innominate artery cannulation through median sternotomy for selective antegrade cerebral perfusion in aortic dissection. Our experience suggests that this strategy is a safe and effective technique compared to other reported methods of cannulation and cerebral protection for delivering selective antegrade cerebral perfusion in these cases.

Elective proximal aortic surgery in patients with renal insufficiency.

BACKGROUND: To evaluate preoperative risk factors and postoperative outcomes in patients with preoperative renal insufficiency undergoing open surgical repair of the aortic root, ascending aorta, or aortic arch. METHODS: Our institutional database was reviewed for all patients undergoing elective aortic root, ascending aorta, and aortic arch open repairs. Patients were separated into two groups based on renal function. Patients with preoperative renal insufficiency were compared to those with normal renal function. Regression analyses were used to identify independent predictors of short and long term postoperative outcomes. RESULTS: The cohort consisted of 2140 patients, of which 55 had preoperative renal insufficiency (PRI). Patients with PRI were older and had worse cardiovascular risk profiles. On presentation, PRI patients were more likely to have lower ejection fraction. There was no difference in operative mortality between the two groups. The most frequent major postoperative complications among renal insufficiency patients were reoperation for bleeding (9.1%, P = .02). Logistic regression analysis indicated that PRI and left ventricular ejection fraction were independent predictors of major adverse events. Long-term survival was significantly reduced in preoperative renal insufficiency patients in the unmatched cohort. CONCLUSIONS: Aortic patients with preoperative renal insufficiency have a higher risk profile of mortality. Renal insufficiency remains an independent predictor of adverse outcomes following aortic surgery and understanding this patient population can guide physicians to improve outcomes.

ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer.

In this study, we generated induced pluripotent stem cells (iPSC) from normal human small airway epithelial cells (SAEC) to investigate epigenetic mechanisms of stemness and pluripotency in lung cancers. We documented key hallmarks of reprogramming in lung iPSCs (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAECs. Of particular novelty, we identified the PRC2-associated protein, ASXL3, which was markedly upregulated in Lu-iPSCs and small cell lung cancer (SCLC) lines and clinical specimens. ASXL3 overexpression correlated with increased genomic copy number in SCLC lines. ASXL3 silencing inhibited proliferation, clonogenicity, and teratoma formation by Lu-iPSCs, and diminished clonogenicity and malignant growth of SCLC cells in vivo Collectively, our studies validate the utility of the Lu-iPSC model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis and highlight ASXL3 as a novel candidate target for SCLC therapy. Cancer Res; 77(22); 6267-81. ©2017 AACR.

Undersized Stent Grafts for Acute Mesenteric Ischemia in Chronic Type B Dissection.

Acute ischemia in chronic type B dissections carries high rates of morbidity and mortality. A 29-year-old woman with a chronic type B dissection presented with acute abdominal pain. Imaging revealed a worsening dissection with pseudocoarctation causing near complete occlusion of the true lumen by the false lumen. We placed purposefully undersized stent grafts to treat acute mesenteric ischemia by improving true lumen flow. The patient was discharged on postoperative day 4 without adverse events. We suggest that endovascular rescue by placing undersized stent grafts can provide improved flow to the mesenteric vessels with continued false lumen flow to vital organs.

Adrenocortical Cancer: A Molecularly Complex Disease Where Surgery Matters.

The development of new therapies has lagged behind for rare cancers without defined therapeutic targets. Adrenocortical cancer is no exception. Mitotane, an older agent considered "adrenolytic," is used both to control symptoms in advanced disease and as adjuvant therapy after surgical resection. Molecular characterization of adrenocortical cancer has deepened our understanding of this genetically complex disease while identifying subgroups whose importance remains to be determined. Unfortunately, such studies have yet to demonstrate a therapeutic target for drug development, and to date, no targeted therapy has achieved meaningful outcomes. Consequently, first-line therapy for metastatic disease remains a combination regimen of etoposide, doxorubicin, and cisplatinum established in a randomized clinical trial. In addition to evaluating recent studies in adrenocortical cancer, we raise one critical clinical issue-the risk of peritoneal dissemination following laparoscopic resection of adrenocortical cancer. In a retrospective case series of 267 patients referred to the NCI for the treatment of recurrent or advanced adrenocortical cancer, we found extensive peritoneal dissemination in 25 of the 45 patients (55.6%) who had undergone laparoscopic resection, compared with only 7 of the 222 patients (3%) who had undergone an open resection (P < 0.0001). Although this has been debated in the literature, our data argue for an end to laparoscopic resection of adrenocortical cancers to avoid peritoneal dissemination, a complication of laparoscopy that is uniformly fatal. Clin Cancer Res; 22(20); 4989-5000. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "ENDOCRINE CANCERS REVISING PARADIGMS".

Circulating Tumor DNA as an Early Indicator of Response to T-cell Transfer Immunotherapy in Metastatic Melanoma.

PURPOSE: Adoptive transfer of activated autologous tumor-infiltrating lymphocytes (TIL) can mediate complete, durable regressions in patients with metastatic melanoma. Responding patients generally do not have significant changes in noncutaneous RECIST targets before 30 to 60 days following TIL infusion, and complete responses are often not confirmed for 1 to 2 years. There is a critical need for a biomarker that can provide early information regarding the likelihood and duration of a response to enable rational decisions about altering therapy. We wished to evaluate the role of circulating tumor DNA (ctDNA) in separating responding from nonresponding patients. EXPERIMENTAL DESIGN: We studied BRAF V600E ctDNA levels by a sensitive allele-specific PCR assay in 388 serum samples from 48 patients who received TIL immunotherapy at the NCI and correlated differences in the dynamic patterns of their ctDNA measurements with response outcomes. RESULTS: A strong correlation was found between the presence or absence of an early serum peak of V600E ctDNA, and the likelihood of an objective response. Furthermore, patients that developed an early ctDNA peak and cleared their serum of V600E ctDNA were highly likely to achieve a complete response over the next 1 to 2 years. Patients that showed no peak of V600E ctDNA failed to achieve an objective response, with one exception. CONCLUSIONS: We show that the dynamic changes occurring in BRAF V600E ctDNA levels within the first month following T-cell transfer immunotherapy in metastatic melanoma can be used to rapidly identify responding from nonresponding patients, potentially allowing clinicians to make critical treatment-related decisions in a more timely manner. These data also suggest that the majority of tumor killing by TIL occurs very early after the initiation of therapy. Clin Cancer Res; 22(22); 5480-6. ©2016 AACR.

Randomized, Prospective Evaluation Comparing Intensity of Lymphodepletion Before Adoptive Transfer of Tumor-Infiltrating Lymphocytes for Patients With Metastatic Melanoma.

PURPOSE: Adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, can mediate objective tumor regression in a majority of patients with metastatic melanoma (52 of 93; 56%). Addition and intensification of total body irradiation (TBI) to the preparative lymphodepleting chemotherapy regimen in sequential trials improved objective partial and complete response (CR) rates. Here, we evaluated the importance of adding TBI to the adoptive transfer of tumor-infiltrating lymphocytes (TIL) in a randomized fashion. PATIENTS AND METHODS: A total of 101 patients with metastatic melanoma, including 76 patients with M1c disease, were randomly assigned to receive nonmyeloablative chemotherapy with or without 1,200 cGy TBI before transfer of tumor-infiltrating lymphcytes. Primary end points were CR rate (as defined by Response Evaluation Criteria in Solid Tumors v1.0) and overall survival (OS). Clinical and laboratory data were analyzed for correlates of response. RESULTS: CR rates were 24% in both groups (12 of 50 v 12 of 51), and OS was also similar (median OS, 38.2 v 36.6 months; hazard ratio, 1.11; 95% CI, 0.65 to 1.91; P = .71). Thrombotic microangiopathy was an adverse event unique to the TBI arm and occurred in 13 of 48 treated patients. With a median potential follow-up of 40.9 months, only one of 24 patients who achieved a CR recurred. CONCLUSION: Adoptive cell transfer can mediate durable complete regressions in 24% of patients with metastatic melanoma, with median survival > 3 years. Results were similar using chemotherapy preparative regimens with or without addition of TBI.

Insulin-like growth factor-1 receptor expression in thymic malignancies.

INTRODUCTION: Thymic epithelial tumors are rare mediastinal malignancies that can be invasive and difficult to treat. Insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane receptor implicated in the regulation of cell metabolism, growth, and survival. As higher levels of IGF-1R protein expression may be associated with relative sensitivity to anti-IGF-1R antibody treatment, we investigated IGF-1R expression in thymic malignancies. METHODS: Sixty-three thymic tumors (56 thymomas and seven thymic carcinomas) were analyzed for total IGF-1R expression using immunohistochemistry with a specific antibody (clone G11, Roche-Ventana, Tucson, AZ). Expression levels were correlated with relevant clinical and pathologic variables, including epidermal growth factor receptor and KIT expression, and patient outcome. RESULTS: IGF-1R staining was negative in 13 (21%) cases, low (1+) in 20 (32%) cases, moderate (2+) in 20 (32%) cases, and high (3+) in 10 (16%) cases. Moderate to high IGF-1R staining was observed in 6 of 7 (86%) thymic carcinomas and in 24 of 56 (43%) thymomas (p = 0.039). Moderate to high IGF-1R staining was associated with high epidermal growth factor receptor staining (p = 0.015). By multivariate analysis, only tumor stage and histologic type were significant prognostic factors on time to progression (hazard ratio [HR] = 4.12, 95% confidence interval [CI]: 1.98-14.23; p = 0.010 and HR = 2.79, 95% CI: 1.62-12.50; p = 0.018, respectively). There was no association between IGF-1R expression and time to progression (HR = 3.07, 95% CI: 0.38-24.59; p = 0.291). CONCLUSION: A majority of thymic malignancies display moderate to high expression of IGF-1R. The lack of preclinical models prevented us to further study the functional consequences of anti-IGF-1R therapy in this setting. However, given correlations in other cancers, these data support the evaluation of anti-IGF-1R inhibitors in thymic tumors.