Citations

PurposeTo assess risks of RF‐heating of a vagus nerve stimulator (VNS) during 1.5 T prostate MRI using body coil transmit and to compare these risks with those associated with MRI head exams using a transmit/receive head coil.MethodsSpatial distributions of radio‐frequency (RF) B1 fields generated by transmit/receive (T/R) body and head coils were empirically assessed along the long axis of a 1.5 T MRI scanner bore. Measurements were obtained along the center axis of the scanner and laterally offset by 15 cm (body coil) and 7 cm (head coil). RF‐field measurements were supplemented with direct measurements of RF‐heating of 15 cm long copper wires affixed to and submerged in the “neck” region of the gelled saline‐filled (sodium chloride and polyacrylic acid) “head‐and‐torso” phantom. Temperature elevations at the lead tips were measured using fiber‐optic thermometers with the phantom positioned at systematically increased distances from the scanner isocenter.ResultsB1 field measurements demonstrated greater than 10 dB reduction in RF power at distances beyond 28 cm and 24 cm from isocenter for body and head coil, respectively. Moreover, RF power from body coil transmit at distances greater than 32 cm from isocenter was found to be lower than from the RF power from head coil transmit measured at locations adjacent to the coil array at its opening. Correspondingly, maximum temperature elevations at the tips of the copper wires decreased with increasing distance from isocenter — from 7.4°C at 0 cm to no appreciable heating at locations beyond 40 cm.ConclusionsFor the particular scanner model evaluated in this study, positioning an implanted VNS farther than 32 cm from isocenter (configuration achievable for prostate exams) can reduce risks of RF‐heating resulting from the body coil transmit to those associated with using a T/R head coil.

Investigators have dedicated considerable effort to understanding the molecular basis underlying Fanconi Anemia (FA), a rare human genetic disease featuring an extremely high incidence of cancer and many congenital defects. Among those studies, FA group D2 protein (FANCD2) has emerged as the focal point of FA signaling and plays crucial roles in multiple aspects of cellular life, especially in the cellular responses to DNA damage. Here, we discuss the recent and relevant studies to provide an updated review on the roles of FANCD2 in the DNA damage response.

Abstract Aims: Androgen-targeted therapies (ATTs) are the mainstay treatment for metastatic prostate cancer (PCa). However, ATTs promote adaptation of tumour cells and lead to castration resistant disease (CRPC). We have recently identified the cell surface receptor, Neuropilin-1 (NRP1) as increased during EMT and in CRPC. However, the role of NRP1 in the prostate epithelium is poorly understood. This study aims to determine whether the inhibition of NRP1 will be a feasible therapeutic strategy for blocking PCa metastasis and therapy resistance. Methods: qPCR and western blotting were used to assess NRP1 expression in PCa cell lines. NRP1 expression in CRPC was assessed using a murine LNCaP xenograft model of castration. NRP1 was knocked down with shRNA sequences from the pLKO.1 lentiviral construct. For metastasis assays, PC3 cells were microinjected into the zebrafish yolk sac and metastatic dissemination imaged 5 days later. NRP1 expression in radical prostatectomy (RP) samples from Mayo Clinic (545 patients) and Johns Hopkins Medical Institutions (JHMI; 188 patients) cohorts was quantified by Affymetrix exon arrays and multivariable analysis performed. Wound scratch migration and invasion assays were performed with the WoundMaker™ tool and IncuCyte™ FLR imaging systems. Results: NRP1 levels were elevated in humanCRPC xenografts, metastatic and castrate resistant clinical PCa samples (p <0.0001), and PCa cell lines. NRP1 suppression significantly reduced metastasis of human xenografts in zebrafish and the migratory and invasive behaviour of metastatic PCa cells (p=0.0002). Multivariable analysis identified NRP1 as a significant independent prognostic indicator of metastasis and prostate cancer specific mortality in two large clinical cohorts (Mayo Clinic and JHMI; p=0.008/0.048 and 0.013/0,034 respectively). We show that NRP1 knockdown promotes E-Cadherin expression and loss of vimentin in mesenchymal PCa cells. Conclusion: These results will provide the preclinical data necessary to rationalise the use of anti-NRP1 directed adjuvant therapies for clinical use in PCa patients receiving ATTs, and will pave the way for larger scale preclinical and clinical trials in the PCa setting. Citation Format: Marianna Volpert, Brian Tse, Ellca Ratther, Nataly Stylianou, Mannan Nouri, Melanie Lehman, Stephen McPherson, Mani Roshan-Moniri, Mandeep Takhar, Nicholas Erho, Mohamed Alshalafa, Elai Davicioni, Robert Jenkins, Ashley Ross, Jeffrey Karnes, Robert Den, Ladan Fazli, Martin Gleave, Elizabeth Williams, Paul Rennie, Ralph Buttyan, Pamela Russell, Colleen Nelson, Brett Hollier. Neuropilin-1 is up-regulated in the adaptive response of prostate tumors to androgen targeted therapies and is prognostic of metastatic progression and patient mortality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4908. doi:10.1158/1538-7445.AM2017-4908

BackgroundReconstruction in a vessel‐depleted neck is challenging. The success rates can be markedly decreased because of unavailability of suitable recipient vessels. In order to obtain a reliable flow, recipient vessels away from the zone of fibrosis, radiation, or infection need to be explored. The aim of this report is to present our experience and clinical outcomes using the retrograde flow coming from the distal transverse cervical artery (TCA) as a source for arterial inflow for complex head and neck reconstruction in patients with a vessel‐depleted neck.MethodsBetween July 2010 and June 2016, nine patients with a vessel‐depleted neck underwent secondary head and neck reconstruction using the retrograde TCA as recipient vessel for microanastomosis. The mean age was 49.6 years (range, 36 to 68 years). All patients had previous bilateral neck dissections and all, except one, had also received radiotherapy. Indications included neck contracture release (n = 3), oral (n = 1), mandibular (n = 3) and pharyngoesophageal (n = 2) reconstruction necessitating free anterolateral thigh (n = 3) and medial sural artery (n = 1) perforator flaps, fibula (n = 3) and ileocolon (n = 2) flaps respectively.ResultsThere was 100% flap survival rate with no re‐exploration or any partial flap loss. One case of intra‐operative arterial vasospasm at the anastomotic suture line was managed intra‐operatively with vein graft interposition. There were no other complications or donor site morbidity during the follow‐up period.ConclusionsIn a vessel‐depleted neck, the reverse flow of the TCA may be a reliable option for complex secondary head and neck reconstruction in selected patients.

Tumor-initiating cells (TIC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of TIC induction or maintenance in lung cancer is not fully understood. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC phenotypes, including tumorspheres, cell motility, tumorigenesis, as well as in vitro and in vivo responses to chemotherapy and targeted therapy. In human lung cancers, high NFATc2 expression predicted poor tumor differentiation, adverse recurrence-free and cancer-specific overall survivals. Mechanistic investigations identified NFATc2 response elements in the 3’ enhancer region of SOX2, and NFATc2/SOX2 coupling upregulates ALDH1A1 by binding to its 5’ enhancer. Through this axis, oxidative stress induced by cancer drug treatment is attenuated, leading to increased resistance in a mutation-independent manner. Targeting this axis provides a novel approach for the long-term treatment of lung cancer through TIC elimination.

AbstractObjectivesWe assessed the effectiveness and safety of cryoballoon ablation (CBA) in the Chinese population with paroxysmal atrial fibrillation (AF) with a 1‐year follow‐up and determined the association of early recurrence of atrial tachyarrhythmias (ERAT) with late recurrence (LR).MethodsA total of 114 patients (age 61 ± 10 years, 78 males) with paroxysmal AF who underwent CBA were consecutively enrolled. After procedures, patients were observed for 3 days with continuous electrocardiogram monitoring in the hospital with routine follow‐up visits at 3 months, 6 months, and 1 year. Documented atrial tachyarrhythmia >30 seconds was defined as recurrence. ERAT was defined as any recurrence during the first 3 months, and LR was recurrence between 3 and 12 months.ResultsWith the first 3 months as blanking period, 76% of patients were free of LR at 12 months. Five patients (4%) experienced complications, including phrenic nerve palsy, stroke, and groin complications. Forty‐five percent of patients had ERAT in the first 3 months and 31% of patients had ERAT in the first 3 days. Patients with ERAT had higher LR rate (LRR) than those without ERAT (43% vs 8%, P < 0.001). The LRR of patients with ERAT only in the first 3 days was lower than those with ERAT both in the first 3 days and in 4–90 days (29% vs 64%, P = 0.036).ConclusionsCBA was an effective and safe treatment option for paroxysmal AF. Patients with ERAT had higher LRR after CBA of AF. The time when ERAT occurred had an impact on LRR.

Background: Serious adverse events (SAEs) and subject replacements occur frequently in phase 1 oncology clinical trials. Whether baseline quality-of-life (QOL) or social support can predict risk for SAEs or subject replacement among these patients is not known. Methods: Between 2011–2013, 92 patients undergoing screening for enrollment into one of 22 phase 1 solid tumor clinical trials at Roswell Park Cancer Institute were included in this study. QOL Questionnaires (EORTC QLQ-C30 and FACT-G), Medical Outcomes Study Social Support Survey (MOSSSS), Charlson comorbidity scores (CCS) and Royal Marsden scores (RMS) were obtained at baseline. Frequency of dose limiting toxicities (DLTs), subject replacement and SAEs that occurred within the first 4 cycles of treatment were recorded. Fisher’s exact test and Mann-Whitney-Wilcoxon test were used to study the association between categorical and continuous variables, respectively. A linear transformation was used to standardize QOL scores. p-value ≤ 0.05 was considered statistically significant. Results: Baseline QOL, MOSSSS, CCS and RMS were not associated with subject replacement nor DLTs. Baseline EORTC QLQ-C30 scores were significantly lower among patients who encountered SAEs within the first 4 cycles (p = 0.04). Conclusions: Lower (worse) EORTC QLQ-C30 score at baseline is associated with SAE occurrence during phase 1 oncology trials.