4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis.

Metastases are the cause of the vast majority of cancer deaths. In the metastatic process, cells migrate to the vasculature, intravasate, extravasate, and establish metastatic colonies. This pattern of spread requires the cancer cells to change shape and to navigate tissue barriers. Approaches that block this mechanical program represent new therapeutic avenues. We show that 4-hydroxyacetophenone (4-HAP) inhibits colon cancer cell adhesion, invasion, and migration in vitro and reduces the metastatic burden in an in vivo model of colon cancer metastasis to the liver. Treatment with 4-HAP activates nonmuscle myosin-2C (NM2C) (MYH14) to alter actin organization, inhibiting the mechanical program of metastasis. We identify NM2C as a specific therapeutic target. Pharmacological control of myosin isoforms is a promising approach to address metastatic disease, one that may be readily combined with other therapeutic strategies.

In Vivo Delivery and Therapeutic Effects of a MicroRNA on Colorectal Liver Metastases.

Multiple therapeutic agents are typically used in concert to effectively control metastatic tumors. Recently, we described microRNAs that are associated with the oligometastatic state, in which a limited number of metastatic tumors progress to more favorable outcomes. Here, we report the effective delivery of an oligometastatic microRNA (miR-655-3p) to colorectal liver metastases using nanoscale coordination polymers (NCPs). The NCPs demonstrated a targeted and prolonged distribution of microRNAs to metastatic liver tumors. Tumor-targeted microRNA miR-655-3p suppressed tumor growth when co-delivered with oxaliplatin, suggesting additive or synergistic interactions between microRNAs and platinum drugs. This is the first known example of systemically administered nanoparticles delivering an oligometastatic microRNA to advanced metastatic liver tumors and demonstrating tumor-suppressive effects. Our results suggest a potential therapeutic strategy for metastatic liver disease by the co-delivery of microRNAs and conventional cytotoxic agents using tumor-specific NCPs.

Clinical and molecular markers of long-term survival after oligometastasis-directed stereotactic body radiotherapy (SBRT).

BACKGROUND: The selection of patients for oligometastasis-directed ablative therapy remains a challenge. The authors report on clinical and molecular predictors of survival from a stereotactic body radiotherapy (SBRT) dose-escalation trial for oligometastases. METHODS: Patients who had from 1 to 5 metastases, a life expectancy of >3 months, and a Karnofsky performance status of >60 received escalating SBRT doses to all known cancer sites. Time to progression, progression-free survival, and overall survival (OS) were calculated at the completion of SBRT, and clinical predictors of OS were modeled. Primary tumor microRNA expression was analyzed to identify molecular predictors of OS. RESULTS: Sixty-one evaluable patients were enrolled from 2004 to 2009. The median follow-up was 2.3 years for all patients (range, 0.2-9.3 years) and 6.8 years for survivors (range, 2.0-9.3 years). The median, 2-year, and 5-year estimated OS were 2.4 years, 57%, and 32%, respectively. The rate of progression after SBRT was associated with an increased risk of death (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.24-1.82). The time from initial cancer diagnosis to metastasis (HR, 0.98; 95% CI, 0.98-0.99), the time from metastasis to SBRT (HR, 0.98; 95% CI, 0.98-0.99), and breast cancer histology (HR, 0.12; 95% CI, 0.07-0.37) were significant predictors of OS. In an exploratory analysis, a candidate classifier using expression levels of 3 microRNAs (miR-23b, miR-449a, and miR-449b) predicted survival among 17 patients who had primary tumor microRNA expression data available. CONCLUSIONS: A subset of oligometastatic patients achieves long-term survival after metastasis-directed SBRT. Clinical features and primary tumor microRNA expression profiling, if validated in an independent dataset, may help select oligometastatic patients most likely to benefit from metastasis-directed therapy. Cancer 2016;122:2242-50. © 2016 American Cancer Society.

JAK2 Inhibitor SAR302503 Abrogates PD-L1 Expression and Targets Therapy-Resistant Non-small Cell Lung Cancers.

Lung cancer is the leading cause of cancer-related deaths worldwide. Approximately 85% of all lung cancers are non-small cell histology [non-small cell lung cancer (NSCLC)]. Modern treatment strategies for NSCLC target driver oncogenes and immune checkpoints. However, less than 15% of patients survive beyond 5 years. Here, we investigated the effects of SAR302503 (SAR), a selective JAK2 inhibitor, on NSCLC cell lines and tumors. We show that SAR is cytotoxic to NSCLC cells, which exhibit resistance to genotoxic therapies, such as ionizing radiation, cisplatin, and etoposide. We demonstrate that constitutive IFN-stimulated gene expression, including an IFN-related DNA damage resistance signature, predicts for sensitivity to SAR. Importantly, tumor cell-intrinsic expression of PD-L1 is IFN-inducible and abrogated by SAR. Taken together, these findings suggest potential dual roles for JAK2 inhibitors, both as a novel monotherapy in NSCLCs resistant to genotoxic therapies, and in tandem with immune checkpoint inhibition. Mol Cancer Ther; 17(4); 732-9. ©2018 AACR.

Author Correction: Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis.

In the originally published version of this Article, the affiliation details for Kevin P. White inadvertently omitted 'Tempus Labs, Chicago, IL, 60654, USA'. This has now been corrected in both the PDF and HTML versions of the Article.

Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis.

The oligometastasis hypothesis suggests a spectrum of metastatic virulence where some metastases are limited in extent and curable with focal therapies. A subset of patients with metastatic colorectal cancer achieves prolonged survival after resection of liver metastases consistent with oligometastasis. Here we define three robust subtypes of de novo colorectal liver metastasis through integrative molecular analysis. Patients with metastases exhibiting MSI-independent immune activation experience the most favorable survival. Subtypes with adverse outcomes demonstrate VEGFA amplification in concert with (i) stromal, mesenchymal, and angiogenic signatures, or (ii) exclusive NOTCH1 and PIK3C2B mutations with E2F/MYC activation. Molecular subtypes complement clinical risk stratification to distinguish low-risk, intermediate-risk, and high-risk patients with 10-year overall survivals of 94%, 45%, and 19%, respectively. Our findings provide a framework for integrated classification and treatment of metastasis and support the biological basis of curable oligometastatic colorectal cancer. These concepts may be applicable to many patients with metastatic cancer.

Robotic-Assisted Transanal Repair of a Rectovaginal Fistula.

BACKGROUND: Various methods exist for the treatment of rectovaginal fistulas, with the choice of repair largely dependent on the fistula location. Options include local repair with mucosal advancement flaps, the use of agents like fibrin glue, and an abdominal approach with resection and colo-anal reconstruction. Traditionally, local repair with mucosal advancement flaps is reserved for simple, low rectovaginal fistulas, while high rectal fistulas require a transabdominal approach.1,2 METHODS: Here, we demonstrate an innovative approach for the treatment of a complex, high rectovaginal fistula in a patient with a hostile pelvis via a transanal approach with robotic assistance. The video demonstrates the basic steps of a repair of a rectovaginal fistula: debridement of the fistula tract, mobilization of the mucosal advancement flap, primary closure of the fistula tract, suturing of the mucosal advancement flap, and flexible sigmoidoscopy to confirm lumen patency and visualization of the closure. RESULTS: By utilizing robotic assistance, we were provided with improved dexterity, precision, and scalability to accomplish the complex task of dissection, suturing, and knot tying in the confines of the rectum. CONCLUSIONS: We suggest that this approach can be used on selected patients with high rectovaginal fistula or other rectal pathology who are otherwise not candidates for a transanal approach.

Advanced Animal Model of Colorectal Metastasis in Liver: Imaging Techniques and Properties of Metastatic Clones.

Patients with a limited number of hepatic metastases and slow rates of progression can be successfully treated with local treatment approaches1,2. However, little is known about the heterogeneity of liver metastases, and animal models capable of evaluating the development of individual metastatic colonies are needed. Here, we present an advanced model of hepatic metastases that provides the ability to quantitatively visualize the development of individual tumor clones in the liver and estimate their growth kinetics and colonization efficiency. We generated a panel of monoclonal derivatives of HCT116 human colorectal cancer cells stably labeled with luciferase and tdTomato and possessing different growth properties. With a splenic injection followed by a splenectomy, the majority of these clones are able to generate hepatic metastases, but with different frequencies of colonization and varying growth rates. Using the In Vivo Imaging System (IVIS), it is possible to visualize and quantify metastasis development with in vivo luminescent and ex vivo fluorescent imaging. In addition, Diffuse Luminescent Imaging Tomography (DLIT) provides a 3D distribution of liver metastases in vivo. Ex vivo fluorescent imaging of harvested livers provides quantitative measurements of individual hepatic metastatic colonies, allowing for the evaluation of the frequency of liver colonization and the growth kinetics of metastases. Since the model is similar to clinically observed liver metastases, it can serve as a modality for detecting genes associated with liver metastasis and for testing potential ablative or adjuvant treatments for liver metastatic disease.

Successful Primary Repair of a Colopericardial Fistula: A Late Complication of Esophageal Replacement.

Colopericardial fistula after colonic interposition is a rare complication, with few prior reported cases. Management of such cases has usually consisted of resection of the colonic segment with cervical diversion. Here we present a case of successful primary repair of a colopericardial fistula in a 73-year-old woman who had initially undergone a colonic interposition graft 30 years before presentation.

Imaging of tumor clones with differential liver colonization.

We present a model of hepatic colorectal metastases which represents monoclonal cell lines double-labeled by luciferase and tdTomato. These cells form liver metastasis in varying numbers and patterns similar to those observed in patients. Using in vivo and ex vivo luminescent and fluorescent imaging we determine the growth kinetics and clonogenic frequency of tumor cells colonizing liver. Molecular profiling detected stable expressional differences between clones consistent with their phenotypes. The data indicate that clinically relevant phenotypes of liver metastases can be modeled in vivo.