Exploring the Utility of Brain Natriuretic Peptide Measurement in Vascular Surgery.

BACKGROUND: The Canadian Cardiovascular Society 2016 guidelines recommend pre-operative measurement of brain natriuretic peptide (BNP) to risk-stratify patients for a 30-day composite outcome of death, myocardial infarction, or asymptomatic myocardial injury after noncardiac surgery (MINS). Whether this practice affects outcomes is unclear. The aim of this study was to examine the clinical utility of brain natriuretic peptide and myocardial injury after noncardiac surgery. METHODS: Analysis of a prospectively maintained database identified all elective open vascular surgery cases at an academic teaching hospital from January 2015 to December 2018. Pre-operative BNP values were available from June 2018 onward after becoming institutionally mandated. Co-morbidities were also collected to stratify patients using the Revised Cardiac Risk Index. The composite outcome of 30-day mortality, myocardial infarction, or MINS was determined. RESULTS: Prior to BNP becoming an institutionally required test, data was available from 1176 open cases. The 30-day mortality was 1.3% (15/1176) and post-operative myocardial infarction rate was 2.3% (27/1176). BNP measurements were collected in 91 consecutive patients. Ten patients (11%) experienced the composite outcome of mortality, myocardial infarction, or MINS. Elevated BNP was associated with increased odds of the composite outcome (P = 0.04), but not with mortality or myocardial infarction. Revised Cardiac Risk Index score was not predictive of outcomes. The majority of patients who qualified for the composite outcome experienced only an asymptomatic troponin rise (80%). Two patients met the universal definition of myocardial infarction, one of whom died. No other deaths occurred within 30 days. Detection of MINS did not result in any significant changes to patient management. CONCLUSIONS: Elevated BNP correlates with increased MINS. An asymptomatic troponin rise is the most commonly observed event, with unclear clinical implications. BNP may over-estimate surgical risk. Further studies on the long-term outcomes of patients with elevated BNP and MINS are required before widely adopting this strategy in vascular surgery patients.

A pilot study of deep learning-based CT volumetry for traumatic hemothorax.

PURPOSE: We employ nnU-Net, a state-of-the-art self-configuring deep learning-based semantic segmentation method for quantitative visualization of hemothorax (HTX) in trauma patients, and assess performance using a combination of overlap and volume-based metrics. The accuracy of hemothorax volumes for predicting a composite of hemorrhage-related outcomes - massive transfusion (MT) and in-hospital mortality (IHM) not related to traumatic brain injury - is assessed and compared to subjective expert consensus grading by an experienced chest and emergency radiologist. MATERIALS AND METHODS: The study included manually labeled admission chest CTs from 77 consecutive adult patients with non-negligible (≥ 50 mL) traumatic HTX between 2016 and 2018 from one trauma center. DL results of ensembled nnU-Net were determined from fivefold cross-validation and compared to individual 2D, 3D, and cascaded 3D nnU-Net results using the Dice similarity coefficient (DSC) and volume similarity index. Pearson's r, intraclass correlation coefficient (ICC), and mean bias were also determined for the best performing model. Manual and automated hemothorax volumes and subjective hemothorax volume grades were analyzed as predictors of MT and IHM using AUC comparison. Volume cut-offs yielding sensitivity or specificity ≥ 90% were determined from ROC analysis. RESULTS: Ensembled nnU-Net achieved a mean DSC of 0.75 (SD: ± 0.12), and mean volume similarity of 0.91 (SD: ± 0.10), Pearson r of 0.93, and ICC of 0.92. Mean overmeasurement bias was only 1.7 mL despite a range of manual HTX volumes from 35 to 1503 mL (median: 178 mL). AUC of automated volumes for the composite outcome was 0.74 (95%CI: 0.58-0.91), compared to 0.76 (95%CI: 0.58-0.93) for manual volumes, and 0.76 (95%CI: 0.62-0.90) for consensus expert grading (p = 0.93). Automated volume cut-offs of 77 mL and 334 mL predicted the outcome with 93% sensitivity and 90% specificity respectively. CONCLUSION: Automated HTX volumetry had high method validity, yielded interpretable visual results, and had similar performance for the hemorrhage-related outcomes assessed compared to manual volumes and expert consensus grading. The results suggest promising avenues for automated HTX volumetry in research and clinical care.

Vascular Access Complications and Clinical Outcomes of Vascular Surgical Repairs Following Transcatheter Aortic Valve Implantation (TAVI).

BACKGROUND: Transcatheter aortic valve implantation (TAVI) procedures have revolutionized the treatment of aortic stenosis. However, due to large sheaths, improperly deployed closure devices, and the comorbidities and challenges innate to this population, vascular access complications can be devastating. The objective of this study is to evaluate vascular access complications in one of the largest TAVI sites in North America. METHODS: This was a retrospective single center review between January 2014 and December 2018 of vascular access complications necessitating operative intervention by vascular surgery. Patient demographics and preoperative comorbidities were collected. Type of vascular access complication, types of repair, closure device used, and postoperative outcomes were analyzed. RESULTS: A total of 37 cases out of a total of 985 TAVI procedures were identified. TAVI was carried out in the operating suite (70%) or the catheterization lab (30%). Consults to vascular surgery were requested intraoperatively (60%), immediately postoperative (14%), later in the day of the TAVI (20%), and on postoperative day 1 (6%). The location of injury included common femoral artery (49%), superficial femoral artery (11%) and external iliac artery (41%), with some cases injuring multiple vessels. Closure devices were found in the subcutaneous tissue (26%), anterior wall (37%), posterior wall (11%), intra-arterial (11%), closing the anterior to the posterior wall (16%), and in the inguinal ligament (5%). Injuries included tears (11%), dissections (38%), and vessel rupture (19%). The majority of repairs were done primarily (64%), with patch (28%) and bypass (8%) less frequently. Four patients died perioperatively (11%), 2 from hemorrhage, 1 from cardiac arrest, and 1 from progressive respiratory disease. CONCLUSIONS: Access complications during TAVI procedures predispose complex patients to increased risk of morbidity and mortality. Careful patient selection, proper access techniques, and performing high risk patients in the operating suite with vascular surgery are fundamental in minimizing complications.

Cost-minimization study of the percutaneous approach to endovascular aortic aneurysm repair.

OBJECTIVE: Percutaneous access for endovascular aortic aneurysm repair (P-EVAR) is less invasive compared with surgical access for endovascular aortic aneurysm repair (S-EVAR). P-EVAR has been associated with shorter recovery and fewer wound complications. However, vascular closure devices (VCDs) are costly, and the economic effects of P-EVAR have important implications for resource allocation. The objective of our study was to estimate the differences in the costs between P-EVAR and S-EVAR. METHODS: We used a decision tree to analyze the costs from a payer perspective throughout the course of the index hospitalization. The probabilities, relative risks, and mean difference summary measures were obtained from a systematic review and meta-analysis. We modelled differences in surgical site infection, lymphocele, and the length of hospitalization. Cost parameters were derived from the 2014 National Inpatient Sample using "International Classification of Diseases, 9th Revision, Clinical Modification" codes. Attributable costs were estimated using generalized linear models adjusted by age, sex, and comorbidities. A sensitivity analysis was performed to determine the robustness of the results. RESULTS: A total of 6876 abdominal and thoracic EVARs were identified. P-EVAR resulted in a mean cost savings of $751 per procedure. The mean costs for P-EVAR were $1287 (95% confidence interval [CI], $884-$1835) and for S-EVAR were $2038 (95% CI, $757-$4280). P-EVAR procedures were converted to open procedures in 4.3% of the cases. The P-EVAR patients had a difference of -1.4 days (95% CI, -0.12 to -2.68) in the length of hospitalization at a cost of $1190/d (standard error, $298). The cost savings of P-EVAR was primarily driven by the cost differences in the length of hospitalization. In the base case, four VCDs were used per P-EVAR at $200/device. In the two-way sensitivity analysis, P-EVAR resulted in cost savings, even when 1.5 times more VCDs had been used per procedure and the cost of each VCD was 1.5 times greater. In our probabilistic sensitivity analysis, P-EVAR was the cost savings strategy for 82.6% of 10,000 Monte Carlo simulations when simultaneously varying parameters across their uncertainty ranges. CONCLUSIONS: P-EVAR had lower costs compared with S-EVAR and could result in dramatic cost savings if extrapolated to the number of aortic aneurysms repaired. Our analysis was a conservative estimate that did not account for the improved quality of life after P-EVAR.

Outcomes of a Spinal Drain and Intraoperative Neurophysiologic Monitoring Protocol in Thoracic Endovascular Aortic Repair.

BACKGROUND: Adjuncts for early detection and treatment of spinal cord ischemia (SCI) in thoracic aortic surgery are supported by robust clinical experience in open repair. The utility of cerebrospinal fluid (CSF) drainage and neurophysiologic monitoring (NPM) in thoracic endovascular aortic repair (TEVAR) is less clear. The purpose of this investigation is to determine the influence of a selective institutional spinal cord protection protocol using prophylactic NPM and CSF on outcomes for standard TEVAR. METHODS: Patients undergoing standard TEVAR entered into a prospectively maintained database from a single institution from 2007 to 2016 were retrospectively reviewed. Preoperative characteristics, aneurysm extent, and etiology were reviewed. Utilization of CSF drains including volume of fluid removed, duration of drainage, and catheter-related complications were collected. NPM data were reviewed to determine the influence on intraoperative management. Exact logistic regression was used to identify independent predictors of SCI. RESULTS: Of 223 patients undergoing TEVAR, 130 met inclusion criteria for the study. CSF drains were used in 71 patients (54.6%), and 56 of 130 (43%) had NPM. SCI occurred in 7 patients (5.4%), of whom 5 had partial or complete recovery. Median time to symptoms of SCI was delayed in all cases (median 52 hr, range 8-312), and none of the 4 of 7 patients with adjunct NPM demonstrated intraoperative changes. Intraoperative changes in NPM occurred in 26 (46%), and represented unilateral leg ischemia in all but 2 cases. In both patients, changes consistent with SCI were associated with intraoperative hypotension and resolved with blood pressure augmentation. Neither patient developed postoperative SCI. Median length of stay (22 vs. 9 days, P = 0.012), operative room time (262 vs. 209, P = 0.040), and perioperative mortality (28.6% vs. 4.1%, P = 0.046) were significantly higher for patients with SCI versus those without. Length of aortic coverage was found to be the sole independent predictor of SCI (odds ratio 8.2, P = 0.026). Complications related to CSF drainage occurred in 4 patients (5.6%) with major complications occurring in 2 patients (2.8%), including 1 with an intrathecal hematoma and permanent bilateral paraparesis. CONCLUSIONS: Selective use of prophylactic CSF drainage in TEVAR was associated with moderate risk and questionable benefit. The use of neurophysiological monitoring allowed for early detection and treatment of spinal ischemia, but its utility is limited by logistical factors and to the minority of patients with intraoperative spinal ischemic events.

Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus.

Plasma uric acid (PUA) is associated with metabolic, cardiovascular, and renal abnormalities in patients with type 2 diabetes but is less well understood in type 1 diabetes (T1D). Our aim was to compare PUA levels and fractional uric acid excretion (FEUA) in patients with T1D vs. healthy controls (HC) during euglycemia and hyperglycemia. PUA, FEUA, blood pressure (BP), glomerular filtration rate (GFR-inulin), and effective renal plasma flow (ERPF-paraaminohippurate) were evaluated in patients with T1D (n = 66) during clamped euglycemia (glucose 4-6 mmol/l) and hyperglycemia (9-11 mmol/l), and in HC (n = 41) during euglycemia. To separate the effects of hyperglycemia vs. increased glycosuria, parameters were evaluated during clamped euglycemia in a subset of T1D patients before and after sodium glucose cotransporter 2 (SGLT2) inhibition for 8 wk. PUA was lower in T1D vs. HC (228 ± 62 vs. 305 ± 75 µmol/l, P < 0.0001). In T1D, hyperglycemia further decreased PUA (228 ± 62 to 199 ± 65 µmol/l, P < 0.0001), which was accompanied by an increase in FEUA (7.3 ± 3.8 to 11.6 ± 6.7, P < 0.0001). In T1D, PUA levels correlated positively with SBP (P = 0.029) and negatively with ERPF (P = 0.031) and GFR (P = 0.028). After induction of glycosuria with SGLT2 inhibition while maintaining clamped euglycemia, PUA decreased (P < 0.0001) and FEUA increased (P < 0.0001). PUA is lower in T1D vs. HC and positively correlates with SBP and negatively with GFR and ERPF in T1D. Glycosuria rather than hyperglycemia increases uricosuria in T1D. Future studies examining the effect of uric acid-lowering therapies should account for the impact of ambient glycemia, which causes an important uricosuric effect.

Erlotinib and radiation therapy for elderly patients with esophageal cancer - clinical and correlative results from a prospective multicenter phase 2 trial.

PURPOSE: Elderly patients with esophageal cancer who are not candidates for chemoradiation may benefit from targeted agents; hence erlotinib combined with radiotherapy was evaluated in this trial. MATERIALS AND METHODS: Patients >65 years with carcinoma of the thoracic esophagus or gastroesophageal junction who were not eligible for platinum-based treatment received erlotinib daily for 1 year starting on day 1 of radiotherapy [50.4 Gy days 1-28 (Mon-Fri) at 1.8 Gy per fraction]. Response was assessed by endoscopy and computed tomography. The primary endpoint was overall survival (OS), and secondary endpoints were complete response, progression-free survival (PFS) and toxicity. RESULTS: The ECOG performance status in the 17 study patients was 0,1 and 2 in 2, 12 and 3 patients, respectively; 1, 5, 7 and 4 patients were in stage I, II, III and IV, respectively; adenocarcinoma was noted in 16 patients and squamous cell carcinoma in 1; there were 3 current, 12 past and 2 never smokers. Median OS was 7.3 months (95% confidence interval, CI: 3.8-22.3) with 14 deaths. There were 2 mucosal complete responses, 1 residual carcinoma in situ and 3 partial endoscopic responses in 9 patients who had endoscopy after radiotherapy. Estimated PFS was 4.5 months (95% CI: 2.4-7.3). Progression was distant (n = 3), locoregional (n = 6), unknown (n = 5) and too early (n = 3). Estimated 1-year survival was 29% (95% CI: 11-51%), 5 patients lived >12 months. Treatment-related toxicities of grade 3-4 occurred in 5 patients. Patients with epidermal growth factor receptor amplification and never smokers had the longest OS (22.3 and 16.6 months, respectively). CONCLUSIONS: Erlotinib with radiotherapy is tolerable and warrants further biomarker-driven evaluation in this population.

Progress in Programmable DNA-Aided Self-Assembly of the Master Frame of a Drug Delivery System.

Every year cancer causes approximately 10 million deaths globally. Researchers have developed numerous targeted drug delivery systems (DDSs) with nanoparticles, polymers, and liposomes, but these synthetic materials have poor degradability and low biocompatibility. Because DNA nanostructures have good degradability and high biocompatibility, extensive studies have been performed to construct DDSs with DNA nanostructures as the molecular-layer master frame (MF) assembled via programmable DNA-aided self-assembly for targeted drug release. To learn the progressing trend of self-assembly techniques and keep pace with their recent rapid advancements, it is crucial to provide an overview of their past and recent progress. In this review article, we first present the techniques to assemble the MF of a DDS with solely DNA strands; to assemble MFs with one or more additional type of construction materials, e.g., polymers (including RNA and protein), inorganic nanoparticle, or metal ions, in addition to DNA strands; and to assemble the more complex DNA nanocomplexes. It is observed that both the techniques used and the MFs constructed have become increasingly complex and that the DDS constructed has an increasing number of advanced functions. From our focused review, we anticipate that DDSs with the MF of multiple building materials and DNA nanocomplexes will attract an increasing number of researchers' interests. On the basis of knowledge about materials and functional components (e.g., targeting aptamers/peptides/antibodies and stimuli for drug release) obtained from previously performed studies, researchers can combine more materials with DNA strands to assemble more powerful MFs and incorporate more components to endow DDSs with improved or additional properties/functions, thereby subsequently contributing to cancer prevention.

Harnessing the abscopal effect for gastrointestinal malignancies in the era of immunotherapy.

Gastrointestinal (GI) cancers are among the leading causes of cancer-related mortality and have traditionally been treated using a combination of surgical resection and chemoradiotherapy (CRT). While the introduction of immunotherapies over the last decade have dramatically changed the treatment landscape for some GI malignancies, including esophageal, gastric, and colorectal cancer, treatment resistance remains a major unaddressed obstacle for many patients. There has thus been emerging interest in determining the optimal treatment strategy for the delivery of immunotherapy in combination with traditional therapies. In this regard, a growing number of preclinical and clinical studies have suggested that combining radiation therapy (RT) with immunotherapy may work synergistically to improve treatment response through amplification of the abscopal effect. In this review, we discuss the rationale for RT in combination with immunotherapy. We further discuss how this knowledge may lead to a paradigm shift in the application of RT and highlight remaining issues pertaining to the delivery of combination therapy.

Image-Guided Proton Therapy: A Comprehensive Review.

Image guidance for radiation therapy can improve the accuracy of the delivery of radiation, leading to an improved therapeutic ratio. Proton radiation is able to deliver a highly conformal dose to a target due to its advantageous dosimetric properties, including the Bragg peak. Proton therapy established the standard for daily image guidance as a means of minimizing uncertainties associated with proton treatment. With the increasing adoption of the use of proton therapy over time, image guidance systems for this modality have been changing. The unique properties of proton radiation present a number of differences in image guidance from photon therapy. This paper describes CT and MRI-based simulation and methods of daily image guidance. Developments in dose-guided radiation, upright treatment, and FLASH RT are discussed as well.

Perianal basosquamous carcinoma treated with radiation therapy, a case report.

Background: Perianal basal cell carcinoma (BCC) is very rare and estimated to account for 0.08% of all BCC and 0.02% of all anorectal neoplasms. Perianal lesions are more likely to be squamous cell carcinoma (SCC) as BCC usually develops on areas of skin exposed to ultraviolet (UV) light such as the face and arms. Proper diagnosis with the assistance of immunohistochemistry (IHC) stains to distinguish the two entities can help inform the suitable course of treatment. Case Description: Our case is an 82-year-old male with a history of cutaneous BCC on the arms and trunk presenting with a symptomatic perianal lesion. Initial biopsy demonstrated BCC with subsequent IHC studies differentiating from basaloid SCC. Standard treatment includes wide local excision (WLE) but given his poor performance status, radiation only was recommended. He was successfully treated and tolerated 30 Gy in 5 daily fractions. Conclusions: Radiation only is a unique and feasible non-surgical treatment for basosquamous carcinoma of the anus.

Evaluation of hydrophilic polymer embolization from endovascular sheath devices in an in vitro perfusion system.

Objective: Case reports, tissue pathology, and autopsies have suggested that the hydrophilic polymer coating designed to improve endovascular deliverability and minimize vessel trauma can embolize and be associated with adverse outcomes such as ischemia, infarction, and death. This study sought to determine whether hydrophilic polymers shed off commercially available sheaths in a controlled in vitro environment, with the hypothesis that significant differences between coated and uncoated (control) sheaths would be found. Methods: Six sheaths from each manufacturer, including Zenith Alpha abdominal endovascular stent grafts (Cook Medical), DrySeal sheaths (W.L. Gore & Associates), and Sentrant Introducer sheaths (Medtronic), were tested in an in vitro environment. Noncoated Check-Flo performer introducer sheaths (Cook Medical) were used as controls. Each test circuit ran for 150 minutes at an output of 3 L/min, the circuit was then drained and the fluid collected. Quantitative analysis included weighing the dried filter paper and using particle size light scattering to quantify the particle size and count. Attenuated total reflectance spectroscopy was also used. Results: Each of the three coated sheaths had significantly greater shedding compared with the control sheaths. The Cook Zenith alpha sheath had significantly more residue weight (2.87 ± 0.52 mg/L) than the Gore DrySeal (1.07 ± 0.06 mg/L) and Medtronic Sentrant introducer (0.98 ± 0.14 mg/L) sheaths. The average particle size was not significantly different between the coated and uncoated (control) sheaths. Attenuated total reflectance spectroscopy identified sheath particulate in the Cook Zenith Alpha and Medtronic Sentrant samples. Conclusions: Polymer embolization was present and significantly greater in all three commercially available hydrophilic sheaths compared with the control group. Further investigation is needed into the clinical significance of these findings.

Improved blood glucose disposal and altered insulin secretion patterns in adenosine A(1) receptor knockout mice.

Type 2 diabetes mellitus (T2DM) is characterized by the inability of the pancreatic ß-cells to secrete enough insulin to meet the demands of the body. Therefore, research of potential therapeutic approaches to treat T2DM has focused on increasing insulin output from ß-cells or improving systemic sensitivity to circulating insulin. In this study, we examined the role of the A(1) receptor in glucose homeostasis with the use of A(1) receptor knockout mice (A(1)R(-/-)). A(1)R(-/-) mice exhibited superior glucose tolerance compared with wild-type controls. However, glucose-stimulated insulin release, insulin sensitivity, weight gain, and food intake were comparable between the two genotypes. Following a glucose challenge, plasma glucagon levels in wild-type controls decreased, but this was not observed in A(1)R(-/-) mice. In addition, pancreas perfusion with oscillatory glucose levels of 10-min intervals produced a regular pattern of pulsatile insulin release with a 10-min cycling period in wild-type controls and 5 min in A(1)R(-/-) mice. When the mice were fed a high-fat diet (HFD), both genotypes exhibited impaired glucose tolerance and insulin resistance. Increased insulin release was observed in HFD-fed mice in both genotypes, but increased glucagon release was observed only in HFD-fed A(1)R(-/-) mice. In addition, the regular patterns of insulin release following oscillatory glucose perfusion were abolished in HFD-fed mice in both genotypes. In conclusion, A(1) receptors in the pancreas are involved in regulating the temporal patterns of insulin release, which could have implications in the development of glucose intolerance seen in T2DM.

Proton therapy for hepatocellular carcinoma.

Proton radiotherapy has seen an increasing role in the treatment of hepatocellular carcinoma (HCC). Historically, external beam radiotherapy has played a very limited role in HCC due to a high incidence of toxicity to surrounding normal structures. The ability to deliver a high dose of radiation to the tumor is a key factor in improving outcomes in HCC. Advances in photon radiotherapy have improved dose conformity and allowed dose escalation to the tumor. However, despite these advances there is still a large volume of normal liver that receives a considerable radiation dose during treatment. Proton beams do not have an exit dose along the beam path once they enter the body. The inherent physical attributes of proton radiotherapy offer a way to maximize tumor control via dose escalation while avoiding excessive radiation to the remaining liver, thus increasing biological effectiveness. In this review we discuss the physical attributes and rationale for proton radiotherapy in HCC. We also review recent literature regarding clinical outcomes of using proton radiotherapy for the treatment of HCC.

Cryopreserved venous allograft in the treatment of a mycotic abdominal aortic aneurysm caused by group B Streptococcus.

We report a case of a mycotic abdominal aortic aneurysm caused by invasive group B streptococcus. Given the anatomical suitability with healthy segments of aortoiliac vessels, in situ repair was performed. A cryopreserved femoral vein graft was chosen because of risks of graft reinfection and negated the need for bilateral femoral vein harvest. The patient remained clinically well and the graft patent with no concerns at 6 months of follow-up. A review of literature on group B Streptococcus aortitis was performed.

A phase II trial of gemcitabine and erlotinib followed by ChemoProton therapy plus capecitabine and oxaliplatin for locally advanced pancreatic cancer.

Background: Epidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer. EGFR expression plays a potentially important role in modulation of tumor sensitivity to either chemotherapy or radiotherapy. Erlotinib is a receptor tyrosine kinase inhibitor with specificity for EGFR/HER1. A phase II trial was conducted to explore the efficacy of a regimen utilizing erlotinib and proton therapy. Methods: Patients with unresectable or borderline resectable non-metastatic adenocarcinoma of the pancreas were included. Patients received 8-week systemic treatment with gemcitabine 1,000 mg/m2 and erlotinib 100 mg (GE). If there was no evidence of metastatic disease after GE, then patients preceded with proton therapy to 50.4 Gy in 28 fractions with concurrent capecitabine 825 mg/m2 (CPT). This was followed with oxaliplatin 130 mg/m2 and capecitabine 1,000 mg/m2 (CapOx) for 4 cycles. The primary study objective was 1-year overall survival (OS). The benchmark was 43% 1-year survival as demonstrated in RTOG/NRG 98-12. The Kaplan-Meier method was used to estimate the one-year OS and the median OS and progression-free survival (PFS). Results: The study enrolled 9 patients ages 47-81 years old (median 62) between January 2013 and March 2016, when the trial was closed due to low patient accrual. The 1-year OS rate was 55.6% (95% CI: 31% to 99%). The median OS was 14.1 months (95% CI: 11.4-NE) and the median PFS was 10.8 months (95% CI: 7.44-NE). A majority of patients completed CPT and GE, but only 33.3% completed the four cycles of CapOx. A third of patients experienced grade 3 toxicities, which were all hepatic along with one patient who also had grade 3 diarrhea. There were no grade 4 or 5 toxicities. Four patients were enrolled with borderline resectable disease, three of which were eligible for pancreaticoduodenectomy after GE and CPT treatment. One of two patients who underwent resection had a negative margin. Conclusions: This regimen for locally advanced pancreatic cancer (LAPC) exceeded the pre-specified benchmark and was safe and well tolerated. Additional investigations utilizing more current systemic treatment regimens with proton therapy are warranted. Trial Registration: ClinicalTrials.gov identifier (NCTNCT01683422).

The American Brachytherapy Society consensus statement for permanent implant brachytherapy using Yttrium-90 microsphere radioembolization for liver tumors.

PURPOSE: To develop a multidisciplinary consensus for high quality multidisciplinary implementation of brachytherapy using Yttrium-90 (90Y) microspheres transarterial radioembolization (90Y TARE) for primary and metastatic cancers in the liver. METHODS AND MATERIALS: Members of the American Brachytherapy Society (ABS) and colleagues with multidisciplinary expertise in liver tumor therapy formulated guidelines for 90Y TARE for unresectable primary liver malignancies and unresectable metastatic cancer to the liver. The consensus is provided on the most recent literature and clinical experience. RESULTS: The ABS strongly recommends the use of 90Y microsphere brachytherapy for the definitive/palliative treatment of unresectable liver cancer when recommended by the multidisciplinary team. A quality management program must be implemented at the start of 90Y TARE program development and follow-up data should be tracked for efficacy and toxicity. Patient-specific dosimetry optimized for treatment intent is recommended when conducting 90Y TARE. Implementation in patients on systemic therapy should account for factors that may enhance treatment related toxicity without delaying treatment inappropriately. Further management and salvage therapy options including retreatment with 90Y TARE should be carefully considered. CONCLUSIONS: ABS consensus for implementing a safe 90Y TARE program for liver cancer in the multidisciplinary setting is presented. It builds on previous guidelines to include recommendations for appropriate implementation based on current literature and practices in experienced centers. Practitioners and cooperative groups are encouraged to use this document as a guide to formulate their clinical practices and to adopt the most recent dose reporting policies that are critical for a unified outcome analysis of future effectiveness studies.

Glucose-dependent insulinotropic polypeptide is expressed in pancreatic islet alpha-cells and promotes insulin secretion.

BACKGROUND & AIMS: Glucose-dependent insulinotropic polypeptide (GIP) and the proglucagon product glucagon-like peptide-1 (GLP-1) are gastrointestinal hormones that are released in response to nutrient intake and promote insulin secretion. Interestingly, a subset of enteroendocrine cells express both GIP and GLP-1. We sought to determine whether GIP also might be co-expressed with proglucagon in pancreatic alpha-cells. METHODS: We assessed GIP expression via reverse-transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry. We developed a novel bioassay to measure GIP release from isolated islets, compared the biological activities of full-length and truncated GIP, and assessed the impact of immunoneutralization of islet GIP on glucose-stimulated insulin secretion in isolated islets. RESULTS: GIP messenger RNA was present in mouse islets; GIP protein localized to islet alpha-cells of mouse, human, and snake pancreas, based on immunohistochemical analyses. However, using a C-terminal GIP antibody, immunoreactivity was detected in islets from prohormone convertase (PC) 2 knockout but not wild-type mice. Bioactive GIP was secreted from mouse and human islets after arginine stimulation. In the perfused mouse pancreas, GIP(1-42) and amidated GIP(1-30) had equipotent insulinotropic actions. Finally, immunoneutralization of GIP secreted by isolated islets decreased glucose-stimulated insulin secretion. CONCLUSIONS: GIP is expressed in and secreted from pancreatic islets; in alpha-cells, PC2 processes proGIP to yield a truncated but bioactive form of GIP that differs from the PC1/3-derived form from K-cells. Islet-derived GIP promotes islet glucose competence and also could support islet development and/or survival.

Involvement of adenosine signaling in controlling the release of ghrelin from the mouse stomach.

Ghrelin, a potent orexigenic hormone released from the stomach, is important in regulating energy metabolism. Abnormal ghrelin levels are associated with eating disorders and metabolic diseases. However, factors involved in the regulation of ghrelin release remain unclear. Here, we examined the involvement of adenosine signaling in the control of ghrelin release from the perfused mouse stomach. Adenosine stimulated ghrelin release concentration-dependently, and the A(2A) receptor-selective antagonists 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) and 2-(2-furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine (SCH 58261) abolished the increased release. The A(2A) receptor-selective agonist 2-p-(2-carboxyethyl)phenethylamino-5-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) augmented ghrelin release concentration-dependently, whereas the A(1) receptor-selective agonist 2-chloro-N(6)-cyclopentyladenosine inhibited ghrelin release. In A(2A) receptor knockout mice, adenosine inhibited ghrelin release, and the A(1) receptor-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked this inhibition. The adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride increased ghrelin release in wild-type and A(1) receptor knockout mice but not in A(2A) receptor knockout mice. Colocalization of ghrelin immunoreactivity with A(1) and A(2A) receptor immunoreactivities in the gastric nerve fibers were observed. Colocalization was also detected for ghrelin and A(1) receptor immunoreactivities in the gastric mucosa. Blockade of neural activities with tetrodotoxin abolished the stimulatory effect of adenosine on ghrelin release. In conclusion, adenosine exerts predominantly a tonic A(2A) receptor-mediated stimulatory action on gastric ghrelin release, whereas an A(1) receptor-mediated inhibitory action is also apparent when the tonic excitatory effect was removed.