CivaSheet® use for soft tissue sarcoma: A single institution experience.

OBJECTIVE: CivaSheet is a palladium-103, implantable, intraoperative radiation therapy device which emits unidirectional radiation that enables boost doses in patients who have otherwise received the maximum radiation dose. Here, we present our initial clinical experience with the first 10 cases using this new technology. METHODS AND MATERIALS: A retrospective chart review of all patients with STS treated with surgical resection and CivaSheet placement at the University of Miami Hospital, a tertiary care center, from January 2018 to December 2019, was performed. Adjuvant radiation was administered by a palladium-103 implant, which delivered an average of 47 Gy (35-55) to a depth of 5 mm. RESULTS: Nine patients underwent CivaSheet placement from January 2018 until December 2019 for a total of 10 CivaSheets placed (1 patient had 2 CivaSheets inserted) and followed for a mean of 27 months (4-45 months). Four tumors were located in the retroperitoneum, two in the chest, two in the groin, and two within the lower extremity. At the time of tumor resection and CivaSheet placement, tumor sizes ranged from 2.5 cm to 13.8 cm with an average of 7.6 cm. Four patients necessitated musculocutaneous tissue flaps for closure and reconstruction. All patients with Grade 4 complications had flap reconstruction and prior radiation. Four patients' tumors recurred locally for a local recurrence rate of 40%. Three patients had modified accordion Grade 4 complications necessitating additional surgery for CivaSheet removal. Extremity tumors unanimously developed modified accordion Grade 4 adverse events. CONCLUSIONS: CivaSheet may be an acceptable alternative treatment modality compared to prior brachytherapy methods.

Long non-coding RNA RAMS11 promotes metastatic colorectal cancer progression.

Colorectal cancer (CRC) is the most common gastrointestinal malignancy in the U.S.A. and approximately 50% of patients develop metastatic disease (mCRC). Despite our understanding of long non-coding RNAs (lncRNAs) in primary colon cancer, their role in mCRC and treatment resistance remains poorly characterized. Therefore, through transcriptome sequencing of normal, primary, and distant mCRC tissues we find 148 differentially expressed RNAs Associated with Metastasis (RAMS). We prioritize RAMS11 due to its association with poor disease-free survival and promotion of aggressive phenotypes in vitro and in vivo. A FDA-approved drug high-throughput viability assay shows that elevated RAMS11 expression increases resistance to topoisomerase inhibitors. Subsequent experiments demonstrate RAMS11-dependent recruitment of Chromobox protein 4 (CBX4) transcriptionally activates Topoisomerase II alpha (TOP2α). Overall, recent clinical trials using topoisomerase inhibitors coupled with our findings of RAMS11-dependent regulation of TOP2α supports the potential use of RAMS11 as a biomarker and therapeutic target for mCRC.

The clonal evolution of metastatic colorectal cancer.

Tumor heterogeneity and evolution drive treatment resistance in metastatic colorectal cancer (mCRC). Patient-derived xenografts (PDXs) can model mCRC biology; however, their ability to accurately mimic human tumor heterogeneity is unclear. Current genomic studies in mCRC have limited scope and lack matched PDXs. Therefore, the landscape of tumor heterogeneity and its impact on the evolution of metastasis and PDXs remain undefined. We performed whole-genome, deep exome, and targeted validation sequencing of multiple primary regions, matched distant metastases, and PDXs from 11 patients with mCRC. We observed intricate clonal heterogeneity and evolution affecting metastasis dissemination and PDX clonal selection. Metastasis formation followed both monoclonal and polyclonal seeding models. In four cases, metastasis-seeding clones were not identified in any primary region, consistent with a metastasis-seeding-metastasis model. PDXs underrepresented the subclonal heterogeneity of parental tumors. These suggest that single sample tumor sequencing and current PDX models may be insufficient to guide precision medicine.

A diagnosis reconsidered: the symptomatic gallbladder remnant.

BACKGROUND: Patients can present with symptomatic gallbladder disease after cholecystectomy due to a remnant gallbladder. This is a rare problem and challenging diagnosis with limited prior characterization; thus, we present a large series of patients with a gallbladder remnant. METHODS: A retrospective review was performed of all patients presenting with symptomatic gallbladder remnant at a tertiary care center from 2002 to 2016. Data on presenting symptoms, diagnostic tests, treatments, and follow-up were collected. RESULTS: Thirty-one patients diagnosed and treated for a symptomatic gallbladder remnant were identified. The most common presenting symptoms included right upper quadrant pain (87%) and nausea (55%). The median time from symptom presentation to definitive diagnosis was 60 days. Diagnostic modalities utilized in the evaluation of these patients demonstrated that endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography were effective with sensitivities of 85% and 90%, respectively. Twenty-three (76.2%) patients underwent completion cholecystectomy, which proved to be definitive treatment. Additionally, eight (25.8%) patients were non-operative candidates and underwent endoscopic retrograde cholangiopancreatography and sphincterotomy, three of whom developed recurrent symptoms. CONCLUSION: A symptomatic gallbladder remnant after cholecystectomy is infrequently seen; however, the diagnosis should be considered in patients with recurrent biliary symptoms after cholecystectomy. Completion cholecystectomy can be challenging but is highly effective for definitive treatment.

Recruitment of CCR2+ tumor associated macrophage to sites of liver metastasis confers a poor prognosis in human colorectal cancer.

The tumor microenvironment (TME) represents a significant barrier to creating effective therapies for metastatic colorectal cancer (mCRC). In several malignancies, bone marrow derived CCR2+ inflammatory monocytes (IM) are recruited to the TME by neoplastic cells, where they become immunosuppressive tumor associated macrophages (TAM). Here we report that mCRC expression of the chemokine CCL2 facilitates recruitment of CCR2+ IM from the bone marrow to the peripheral blood. Immune monitoring of circulating monocytes in patients with mCRC found this influx was a prognostic biomarker and correlated with worse clinical outcomes. At the metastatic site, mCRC liver tumors were heavily infiltrated by TAM, which displayed a robust ability to dampen endogenous anti-tumor lymphocyte activity. Using a murine model of mCRC that recapitulates these findings from human disease, we show that targeting CCR2 reduces TAM accumulation in liver metastasis and restores anti-tumor immunity. Additional quantitative analysis of hepatic metastatic tumor burden and treatment efficacy found that administration of a small molecule CCR2 inhibitor (CCR2i) improves chemotherapeutic responses and increases overall survival in mice with mCRC liver tumors. Our study suggests that targeting the CCL2/CCR2 chemokine axis decreases TAM at the metastatic site, disrupting the immunosuppressive TME and rendering mCRC susceptible to anti-tumor T-cell responses.

Single institution results of radical antegrade modular pancreatosplenectomy for adenocarcinoma of the body and tail of pancreas in 78 patients.

BACKGROUND: The purpose of this report is to present results of the radical antegrade modular pancreatosplenectomy (RAMPS) procedure in 78 patients from a single center. METHODS: Seventy-eight patients had RAMPS procedure over 13 years. A database dealing with RAMPS for adenocarcinoma of the pancreas was constructed so that it could be converted into a set of tables. Each table covered one element of the subject. The database was populated from clinical records of patients who had a RAMPS procedure from 1999 to 2013. RESULTS: Fifty-six patients had anterior RAMPS and 22 had posterior RAMPS. Negative tangential margins were obtained in 94% of specimens. Overall the R0 rate was 85%. Mean lymph node count was 20. There were no 30-day or in-hospital mortalities but two patients died within 90 days. Pancreatic fistula and need for postoperative transfusion were the most common complications. Median survival was 24.6 months and 5-year overall actuarial survival was 25.1%. CONCLUSIONS: The RAMPS technique resulted in high negative tangential margin rates and good lymph node retrieval. The long-term survival result in 78 patients is probably an accurate reflection of what is possible with this tumor using this technique at this time.