Surgical resection of high-grade nonfunctional pancreatic neuroendocrine carcinoma is associated with improved survival.

BACKGROUND AND OBJECTIVES: The role of surgery in the treatment of nonfunctional pancreatic neuroendocrine carcinomas (PNEC) is not well defined. This study investigated the effect of surgical resection on cause-specific survival compared with nonoperative management. METHODS: The Surveillance, Epidemiology, and End Results Program (SEER) database was utilized to identify patients with nonfunctional pancreatic neuroendocrine carcinoma diagnosed between January 1, 2004 and December 31, 2015. Survival was modeled using Kaplan-Meier analysis and multivariable Cox proportional hazards models. RESULTS: Of the 488 patients identified, 137 (29%) underwent surgical resection of the primary site. Patients who underwent surgery had a median CSS of 31 months compared with 5 months in those who did not (p < 0.01). A survival benefit was observed when the cohort was stratified into local, nodal, and metastatic disease. CONCLUSION: Resection of the primary site in the cohort of PNEC patients compiled by SEER is associated with improved survival. Further consideration be placed on primary surgical resection for PNEC while additional studies that can select specifically for high-grade, poorly differentiated carcinomas need to be undertaken.

Transarterial Chemoembolization of Hepatocellular Carcinoma with Oncozene Microspheres: An Initial, Short-Term Clinical Experience-A Retrospective, Matched, Comparison Study.

Background: The purpose of this study is to describe a single institution's experience using Oncozene (OZ) microspheres for transarterial chemoembolization (OZ-TACE) of hepatocellular carcinoma (HCC), and to compare tolerability, safety, short-term radiographic tumor response, progression-free survival (PFS), and overall survival (OS) of these procedures to TACE (LC-TACE) performed with LC beads (LC). Methods: A retrospective, matched cohort study of patients undergoing DEB-TACE (drug-eluting bead transarterial chemoembolization) with OZ or LC was performed. The cohort comprised 23 patients undergoing 29 TACE with 75 or 100 µm OZ and 24 patients undergoing 29 TACE with 100-300 µm LC. Outcome measures were changes in liver function tests, complications, treatment tolerability, short-term radiographic tumor response according to modified RECIST criteria for HCC, PFS, and 1-year OS. The Mann-Whitney U test, Fisher exact test, and log rank test were used to compare the groups. Results: The BCLC or Child-Pugh scores were similar between the OZ and LC group. However, the two groups differed with respect to the etiology of background cirrhosis (p = 0.02). All other initial demographic and tumor characteristics were similar between the two groups. OZ-TACE used less doxorubicin per treatment compared to LC-TACE (median 50 vs. 75 mg; p = 0.0005). Rates of pain, nausea, and postembolization syndrome were similar, irrespective of the embolic agent used. OZ-TACE resulted in an overall complication rate comparable to LC-TACE (20.7% vs. 10.3%; p = 0.47). LC-TACE resulted in a higher percent increase in total bilirubin on post-procedure day 1 (median 18.8 vs. 0%; p = 0.05), but this difference resolved at 1 month. Both OZ-TACE and LC-TACE resulted in similar complete (31% vs. 24%) and objective (66% vs. 79%) target lesion response rates on 1-month post-TACE imaging. Both OZ-TACE and LC-TACE had similar median progression-free survival (283 vs. 209 days; p = 0.14) and 1-year overall survival rates (85% vs. 76%; p = 0.30). Conclusion: With a significantly reduced dose of doxorubicin, TACE performed with Oncozene microspheres in a heterogeneous patient population is well-tolerated, safe, and produces a similar radiological response and survival rate when compared to LC Bead TACE.

Synthesis and Biological Evaluation of a Carbamate-Containing Tubulysin Antibody-Drug Conjugate.

Antibody-drug conjugates (ADCs) use antibodies to deliver cytotoxic payloads directly into tumor cells via specifically binding to the target cell surface antigens. ADCs can enhance the anti-tumor effects of antibodies, and increase the delivery of cytotoxic payloads to cancer cells with a better therapeutic index. An ADC was prepared with a potent carbamate-containing tubulysin analogue attached to an anti-mesothelin antibody via a Cit-Val dipeptide linker. An aniline functionality in the tubulysin analogue was created to provide a site of linker attachment via an amide bond that would be stable in systemic circulation. Upon ADC internalization into antigen-positive cancer cells, the Cit-Val dipeptide linker was cleaved by lysosomal proteases, and the drug was released inside the tumor cells. The naturally occurring acetate of tubulysin was modified to a carbamate to reduce acetate hydrolysis of the ADC in circulation and to increase the hydrophilicity of the drug. The ADC bearing the monoclonal anti-mesothelin antibody and the carbamate-containing tubulysin was highly potent and immunologically specific to H226 human lung carcinoma cells in vitro, and efficacious at well-tolerated doses in a mesothelin-positive OVCAR3 ovarian cancer xenograft mouse model.

Epidural Analgesia Improves Postoperative Pain Control but Impedes Early Discharge in Patients Undergoing Pancreatic Surgery.

OBJECTIVES: The aim of this study was to evaluate the impact of epidural analgesia (EA) on postoperative length of stay (LOS), expeditious discharge, and pain relief after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP). METHODS: Retrospective reviews of 2014-2015 American College of Surgeons National Surgical Quality Improvement Program databases and our institutional pancreatic surgery database were conducted. RESULTS: On univariate analysis, EA was associated with statistically significant longer lengths of stay for both PD and DP. On comparative analysis at mode LOS, discharged before versus after 7 days for PD and 6 days for DP, EA was a significant predictor for the longer groups for both procedures on multivariable analysis (PD, odds ratio of 1.465, P < 0.001; DP, odds ratio of 1.471, P = 0.004). On review of our institution's pancreatic surgery database, patient-reported pain scores were significantly lower in the EA groups than intravenous narcotics groups on the day of surgery only for both PD and DP. CONCLUSIONS: Epidural analgesia was associated with longer LOS with a most pronounced effect on early discharge after surgery for patients undergoing open PD and DP. It only resulted in superior pain control on the day of surgery.

Optical Coherence Tomography of the Retinal Ganglion Cell Complex in Leber's Hereditary Optic Neuropathy and Dominant Optic Atrophy.

Background: Mitochondrial optic neuropathies such as Leber's Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA) have been shown to produce an optic neuropathy secondary to retinal ganglion cell loss with thinning of the retinal ganglion cell complex (RGCC). Methods: We performed a retrospective analysis assessing the thicknesses of the peripapillary retinal nerve fiber layer (pRNFL) along with the macular retinal ganglion cell-inner plexiform layer (RGC-IPL) using optical coherence tomography (OCT). We compared these changes among acute and chronic LHON, DOA, and normal healthy control patients. Results: Patients with chronic LHON exhibited statistically significant thinning of the RNFL in the superior, nasal, and inferior quadrants of the retina. In acute LHON, the RNFL was relatively thicker in all but the temporal quadrant when compared with respective quadrants in normal eyes; however, statistical significance was not achieved. In DOA, the RNFL was thinnest in the superior and inferior quadrants of the retina, measuring between acute and chronic LHON thickness values. In chronic LHON and DOA, both the pRNFL and RGC-IPL were significantly thinner in all four retinal quadrants relative to controls. Conclusions: This article represents the first comparative study of the RGCC between LHON and DOA. Our findings demonstrated significant thickness reductions in pRNFL and macular RGC-IPL in patients with LHON and DOA, with different specific patterns consistent with the general patterns of thinning classically observed. This study suggests the usefulness of the RGCC as a potential in vivo biomarker for assessing disease in patients with LHON and DOA.

Highly multiplexed targeted DNA sequencing from single nuclei.

Single-cell DNA sequencing methods are challenged by poor physical coverage, high technical error rates and low throughput. To address these issues, we developed a single-cell DNA sequencing protocol that combines flow-sorting of single nuclei, time-limited multiple-displacement amplification (MDA), low-input library preparation, DNA barcoding, targeted capture and next-generation sequencing (NGS). This approach represents a major improvement over our previous single nucleus sequencing (SNS) Nature Protocols paper in terms of generating higher-coverage data (>90%), thereby enabling the detection of genome-wide variants in single mammalian cells at base-pair resolution. Furthermore, by pooling 48-96 single-cell libraries together for targeted capture, this approach can be used to sequence many single-cell libraries in parallel in a single reaction. This protocol greatly reduces the cost of single-cell DNA sequencing, and it can be completed in 5-6 d by advanced users. This single-cell DNA sequencing protocol has broad applications for studying rare cells and complex populations in diverse fields of biological research and medicine.