Search

Introduction: Fear of cancer recurrence (FCR) is prevalent and distressing among survivors of cancer. Evidence-based mind-body and cognitive-behavioral skills lack integration and testing in scalable formats., Objective: This pilot randomized controlled trial (NCT04876599) tested a synchronous, virtual mind-body group resiliency intervention for FCR (IN FOCUS)., Method: Adults with elevated FCR (FCR Inventory severity ≥ 16; 16-21 = elevated, 22-36 = clinically elevated) after completing primary treatment for non-metastatic cancer were randomly assigned (1:1) to eight weekly sessions of IN FOCUS or usual care (UC; synchronous, virtual community group support referral). Feasibility metrics included ≥ 70% retention per arm (primary outcome), ≥ 75% attendance in ≥ 6 sessions, ≥ 75% adherence to relaxation skills practice ≥ 3 days per week and by delivery fidelity (% content covered in video-recorded sessions). Acceptability was assessed quantitatively via ratings of enjoyableness, convenience, helpfulness, odds of future use, and satisfaction (benchmark ≥ 80% of ratings ≥ 4 on 1-5 Likert scale) and qualitatively via individual exit interviews. Linear mixed models explicated slopes in FCR (secondary) and resiliency (exploratory; Current Experiences Scale) from baseline to 2 months (primary endpoint) and 5 months using intention-to-treat., Results: From July 2021 to March 2022, 64 survivors enrolled (25-73 years old, M = 7 years since diagnosis). IN FOCUS was feasible and acceptable (91% retention; attendance median = 7 sessions, 97% relaxation practice adherence, 95% content fully covered; 82% of acceptability ratings ≥ 4). Interviews (n = 59) revealed benefits in both arms. By 2 months, compared to UC, IN FOCUS reduced FCR to a medium-to-large effect (Mdiff = -2.4; 95% CI = -4.2, -0.7; d = 0.66). By 5 months, FCR effects had attenuated (Mdiff = -0.16, 95% CI -1.97, 1.65; d = -0.04), although levels of resiliency had increased with a medium-to-large effect (Mdiff = 10.0; 95% CI = 4.9, 15.1; d = 0.78)., Conclusions: For survivors of non-metastatic cancer, a synchronous, virtual mind-body resiliency program for FCR is feasible, acceptable, and seemingly beneficial compared to a community group referral., (© 2024 John Wiley & Sons Ltd.)

Purpose of Review: There is a long history of implantation of absorbable and nonabsorbable materials to treat stress urinary incontinence (SUI) and pelvic organ prolapse (POP). The focus of this review is to review the development of new materials for use in the surgical management of both pelvic conditions following an unacceptable level of severe complications in the use of polypropylene mesh (PPM). We discuss current concepts relating to the development of new materials with particular reference to our experience with polyurethane mesh., Recent Findings: Our review highlights the strategies that manufacturers and researchers are employing to improve PPM using collagen gels and stem cells, or to find alternatives. We conclude that current preclinical safety testing is inadequate, and the field requires better in vivo testing. Specifically, we highlight novel techniques demonstrating the degradation of polypropylene potentially elucidating the link between PPM degradation and induction of inflammation leading to adverse side effects., Summary: This field badly needs innovation in developing new materials and in testing these to ensure materials will benefit patients. A collaboration between materials scientists and clinicians is needed to facilitate the translation of basic research and preclinical testing into patient benefit for the treatment of SUI and POP., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1-confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10-26%), and DCR was 61% (62/101; 95% CI, 51-71%). Median DOR was not reached (NR; 95% CI, 5.7 months-NR), and median PFS was 3.5 months (95% CI, 2.7-4.1 months), at a median follow-up of 10.3 months (range, 0.5-42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 ., (© 2024. The Author(s).)

The failure of polypropylene mesh is marked by significant side effects and debilitation, arising from a complex interplay of factors. One key contributor is the pronounced physico-mechanical mismatch between the polypropylene (PP) fibres and surrounding tissues, resulting in substantial physical damage, inflammation, and persistent pain. However, the primary cause of sustained inflammation due to polypropylene itself remains incompletely understood. This study comprises a comprehensive, multi-pronged investigation to unravel the effects of implantation on a presumed inert PP mesh in sheep. Employing both advanced and conventional techniques to discern the physical and chemical transformations of the implanted PP. Our analyses reveal a surface degradation and oxidation of polypropylene fibres after 60 days implantation, persisting and intensifying at the 180-day mark. The emergence and accumulation of PP debris in the tissue surrounding the implant also increased with implantation time. We demonstrate observable physical and mechanical alterations in the fibre surface and stiffness. Our study shows surface alterations which indicate that PP is evidently less chemically inert than was initially presumed. These findings underscore the need for a re-evaluation of the biocompatibility and long-term consequences of using PP mesh implants., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: N.T.H.F has provided expert testimony for lawsuits concerning surgical mesh. This testimony was provided subsequent to the analysis and submission of this manuscript. J.D research program has previously received funding from Johnson & Johnson, Blasingame, Burch, Garrard and Ashley (Atlanta, GA), Clayton Utz (Sydney, Australia)., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pancreatic cancer has the worst prognosis of all common tumors. Earlier cancer diagnosis could increase survival rates and better assessment of metastatic disease could improve patient care. As such, there is an urgent need to develop biomarkers to diagnose this deadly malignancy. Analyzing circulating extracellular vesicles (cEVs) using 'liquid biopsies' offers an attractive approach to diagnose and monitor disease status. However, it is important to differentiate EV-associated proteins enriched in patients with pancreatic ductal adenocarcinoma (PDAC) from those with benign pancreatic diseases such as chronic pancreatitis and intraductal papillary mucinous neoplasm (IPMN). To meet this need, we combined the novel EVtrap method for highly efficient isolation of EVs from plasma and conducted proteomics analysis of samples from 124 individuals, including patients with PDAC, benign pancreatic diseases and controls. On average, 912 EV proteins were identified per 100µL of plasma. EVs containing high levels of PDCD6IP, SERPINA12 and RUVBL2 were associated with PDAC compared to the benign diseases in both discovery and validation cohorts. EVs with PSMB4, RUVBL2 and ANKAR were associated with metastasis, and those with CRP, RALB and CD55 correlated with poor clinical prognosis. Finally, we validated a 7-EV protein PDAC signature against a background of benign pancreatic diseases that yielded an 89% prediction accuracy for the diagnosis of PDAC. To our knowledge, our study represents the largest proteomics profiling of circulating EVs ever conducted in pancreatic cancer and provides a valuable open-source atlas to the scientific community with a comprehensive catalogue of novel cEVs that may assist in the development of biomarkers and improve the outcomes of patients with PDAC.

Androgenic alopecia (AGA) affects both men and women worldwide. New blood vessel formation can restore blood supply and stimulate the hair regrowth cycle. Recently, our group reported that 2-deoxy-D-ribose (2dDR) is 80%-90% as effective as VEGF in the stimulation of neovascularization in in vitro models and in a chick bioassay. In this study, we aimed to assess the effect of 2dDR on hair growth. We prepared an alginate gel containing 2dDR, polypropylene glycol, and phenoxyethanol. AGA was developed in C57BL6 mice by intraperitoneally injecting testosterone (TE). A dihydrotestosterone (DHT)-treated group was used as a negative control, a minoxidil group was used as a positive control, and we included groups treated with 2dDR gel and a combination of 2dDR and minoxidil. Each treatment was applied for 20 days. Both groups treated with 2dDR gel and minoxidil stimulated the morphogenesis of hair follicles. H&E-stained skin sections of C57BL/6 mice demonstrated an increase in length, diameter, hair follicle density, anagen/telogen ratio, diameter of hair follicles, area of the hair bulb covered in melanin, and an increase in the number of blood vessels. Masson's trichrome staining showed an increase in the area of the hair bulb covered in melanin. The effects of the FDA-approved drug (minoxidil) on hair growth were similar to those of 2dDR (80%-90%). No significant benefit were observed by applying a combination of minoxidil with 2dDR. We conclude that 2dDR gel has potential for the treatment of androgenic alopecia and possibly other alopecia conditions where stimulation of hair regrowth is desirable, such as after chemotherapy. The mechanism of activity of 2dDR remains to be established., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Anjum, Zulfiqar, Chaudhary, Rehman, Bullock, Yar and MacNeil.)

Inhibition of Polo-like kinase 1 (Plk1) is a promising new target and therapeutic strategy in metastatic colorectal cancer, especially those with KRAS mutations. New data support further development of onvansertib, and highlights the role of circulating tumor DNA in phase I clinical trials. See related article by Ahn et al., p. 2039., (©2024 American Association for Cancer Research.)

Background Limited data are available on radiation segmentectomy (RS) for treatment of hepatocellular carcinoma (HCC) using yttrium 90 ( 90 Y) resin microsphere doses determined by using a single-compartment medical internal radiation dosimetry (MIRD) model. Purpose To evaluate the efficacy and safety of RS treatment of HCC with 90 Y resin microspheres using a single-compartment MIRD model and correlate posttreatment dose with outcomes. Materials and Methods This retrospective single-center study included adult patients with HCC who underwent RS with 90 Y resin microspheres between July 2014 and December 2022. Posttreatment PET/CT and dosimetry were performed. Adverse events were assessed using the Common Terminology Criteria for Adverse Events, version 5.0. Per-lesion and overall response rates (ie, complete response [CR], objective response, disease control, and duration of response) were assessed at imaging using the Modified Response Evaluation Criteria in Solid Tumors, and overall survival (OS) was assessed using Kaplan-Meier analysis. Results Among 67 patients (median age, 69 years [IQR, 63-78 years]; 54 male patients) with HCC, median tumor absorbed dose was 232 Gy (IQR, 163-405 Gy). At 3 months, per-lesion and overall (per-patient) CR was achieved in 47 (70%) and 41 (61%) of 67 patients, respectively. At 6 months ( n = 46), per-lesion rates of objective response and disease control were both 94%, and per-patient rates were both 78%. A total of 88% (95% CI: 79 99) and 72% (95% CI: 58, 90) of patients had a per-lesion and overall duration of response of 1 year or greater. At 1 month, a grade 3 clinical adverse event (abdominal pain) occurred in one of 67 (1.5%) patients. Median posttreatment OS was 26 months (95% CI: 20, not reached). Disease progression at 2 years was lower in the group that received 300 Gy or more than in the group that received less than 300 Gy (17% vs 61%; P = .047), with no local progression in the former group through the end of follow-up. Conclusion Among patients with HCC who underwent RS with 90 Y resin microspheres, 88% and 72% achieved a per-lesion and overall duration of response of 1 year or greater, respectively, with one grade 3 adverse event. In patients whose tumors received 300 Gy or more according to posttreatment dosimetry, a disease progression benefit was noted. © RSNA, 2024 Supplemental material is available for this article.

Objective: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed., Design: To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites., Results: Comparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92)., Conclusion: A combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC., Competing Interests: Competing interests: ABu has received consulting fees from Exelixis and Geistlich Pharma. KM declares research funding from Celgene and Trovagene. AJA has consulted for Oncorus, Inc., Arrakis Therapeutics, and Merck & Co., Inc, and has research funding from Mirati Therapeutics, Syros, Deerfield, Inc., and Novo Ventures that is unrelated to this work. AM is listed as an inventor on a patent that has been licensed by Johns Hopkins University to Thrive Earlier Detection and serves as a consultant for Tezcat Biosciences. BG, RS and YD have filed patents on cfDNA analysis technology, and received research funding from GRAIL. BMW declares research funding from Celgene, Eli Lilly Novartis and Revolution Medicines, and consulting for Celgene, GRAIL, Ipsen and Mirati., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objective: Emotional eating is prevalent among college women. Deficits in interoceptive awareness, or the ability to perceive and identify internal sensations, are associated with emotional eating. Separately examining the specific components of interoceptive awareness, appetite and emotional awareness, in relation to emotional eating may improve prevention and treatment of emotional eating in college women. Participants : 143 women at an urban Northeastern university. Methods: This was a cross-sectional study using self-report measures of interoceptive awareness, appetite and emotional awareness, emotional eating, and depression. Simultaneous regression analyses examined the independent association of appetite and emotional awareness with emotional eating, controlling for depression. Results: Consistent with hypotheses, lower interoceptive awareness was associated with higher emotional eating. Appetite and emotional awareness, were each uniquely associated with emotional eating independent of depression, even when entered simultaneously. Conclusions: Future prevention and treatment of emotional eating in college women should target improvements in appetite and emotional awareness.

Developing multifunctional wound dressings capable of inducing rapid angiogenesis and with antibacterial activity would be attractive for diabetic and superficial wound healing. Hydrogels delivered from tubes have several desirable features -they are easy to apply, keep the wound moist, reduce the entry of microorganisms and avoid the need for painful dressing removal. Previously we reported that 2 deoxy-D-ribose (2dDR) delivered from a variety of dressings is capable of promoting wound healing by stimulating angiogenesis. Alginate hydrogels are an ideal vehicle to deliver a bioactive agent capable of promoting wound healing. In this study we developed and evaluated a tube hydrogel capable of delivering 2dDR with the aim of achieving a stable, convenient to administer and biologically effective wound treatment. Further, we included the stabilizer 2-phenoxy ethanol which provided antimicrobial activity. We synthesized hydrogels by the Green method, using simple mixing of sodium alginate, propylene glycol, 2-phenoxy ethanol and 2dDR in water. FTIR (Fourier transformation infrared spectroscopy) analysis confirmed an absence of undesirable chemical changes in the gel components, and SEM images of the freeze-dried gels showed porous structures. When 2dDR alginate gel (2dDR-SA hydrogel) was placed in PBS at 37°C, almost 92% of 2dDR was released within 7 days. When tested on cultured cells, 2dDR-SA hydrogels did not inhibit metabolic activity or proliferation, achieving up to 90 and 98% of control respectively over 7 days. 2dDR-SA hydrogel also showed anti-bacterial activity against E. coli, Pseudomonas aeruginosa, Staphylococcus aureus, and MRSA which was attributable to the stabilizer 2-phenoxy ethanol in the hydrogel. Stimulation of angiogenesis in the chorioallantoic membrane assay by 2dDR-SA hydrogel was found to be significant compared to the blank-SA. Wound healing potential was studied in full-thickness wounds in rats where acceleration of wound healing was seen. H&E staining of the wound tissue showed an enhanced number of blood vessels and re-epithelization, and a reduced number of inflammatory cells in 2dDR-SA treated animals compared to blank-hydrogels while Masson's trichrome staining showed increased collagen deposition. In summary we describe a convenient to apply hydrogel which has promise for use in a range of superficial skin wounds including applications in chronic wound care.

One to two-thirds of all medically admitted patients have comorbid psychiatric concerns. To address the cognitive, behavioral, and emotional factors that affect medical hospitalization, psychological or psychiatric consultation-liaison (CL) services are consulted. The current study was designed to understand patient satisfaction with a CL psychology service and how it was associated with satisfaction with overall hospitalization, taking into consideration relevant factors. Adults medically admitted to an academic teaching hospital (N = 220), who were seen at least once by the CL psychology service, completed satisfaction and demographic questionnaires. Most patients reported being satisfied with the CL psychology service, with women reporting higher satisfaction than men. Satisfaction with the CL psychology service was associated with satisfaction with overall hospitalization, but did not differ based on age, race/ethnicity, education, income, length of stay, number of visits, or presence of psychiatric diagnosis. The results suggest that CL psychology services may contribute to improving overall patient experience., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Preclinical studies have shown that modulation of the tumor microvasculature with anti-angiogenic agents decreases tumor perfusion and may increase the efficacy of radiofrequency ablation (RFA) in hepatocellular carcinoma (HCC). Retrospective studies suggest that sorafenib given prior to RFA promotes an increase in the ablation zone, but prospective randomized data are lacking., Aims: We conducted a randomized, double-blind, placebo-controlled phase II trial to evaluate the efficacy of a short-course of sorafenib prior to RFA for HCC tumors sized 3.5-7 cm (NCT00813293)., Methods: Treatment consisted of sorafenib 400 mg twice daily for 10 days or matching placebo, followed by RFA on day 10. The primary objectives were to assess if priming with sorafenib increased the volume and diameter of the RFA coagulation zone and to evaluate its impact on RFA thermal parameters. Secondary objectives included feasibility, safety and to explore the relationship between tumor blood flow on MRI and RFA effectiveness., Results: Twenty patients were randomized 1:1. Priming with sorafenib did not increase the size of ablation zone achieved with RFA and did not promote significant changes in thermal parameters, although it significantly decreased blood perfusion to the tumor by 27.9% (p = 0.01) as analyzed by DCE-MRI. No subject discontinued treatment owing to adverse events and no grade 4 toxicity was observed., Conclusion: Priming of sorafenib did not enhance the effect of RFA in intermediate sized HCC. Future studies should investigate whether longer duration of treatment or a different antiangiogenic strategy in the post-procedure setting would be more effective in impairing tumor perfusion and increasing RFA efficacy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains a significant health issue. For most patients, there are no options for targeted therapy, and existing treatments are limited by toxicity. The HOPE trial (Harnessing Organoids for PErsonalized Therapy) was a pilot feasibility trial aiming to prospectively generate patient-derived organoids (PDO) from patients with PDAC and test their drug sensitivity and correlation with clinical outcomes., Experimental Design: PDOs were established from a heterogeneous population of patients with PDAC including both basal and classical PDAC subtypes., Results: A method for classifying PDOs as sensitive or resistant to chemotherapy regimens was developed to predict the clinical outcome of patients. Drug sensitivity testing on PDOs correlated with clinical responses to treatment in individual patients., Conclusions: These data support the investigation of PDOs to guide treatment in prospective interventional trials in PDAC., (©2021 American Association for Cancer Research.)

Background RX-3117 is an oral small molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by cancer cells over-expressing uridine cytidine kinase 2 (UCK2). Single agent RX-3117 demonstrated efficacy in a phase I trial in patients with metastatic (met) pancreatic adenocarcinoma (PC). RX-3117 plus nab-paclitaxel (nab-Pac) was evaluated as a first line treatment in met-PC cancer. Methods This was a multicenter open label phase I/II 2-stage study investigating the combination of RX3117 plus nab-Pac in the frontline treatment of patients with met-PC. The phase I portion comprised a dose de-escalation design with primary objectives of determining the safety, tolerability and recommended phase 2 dose (RP2D) of RX-3117 (orally 700, 600, or 500 mg/day for 5 consecutive days with 2 days off/week) plus nab-Pac (intravenous (IV) 125 mg/m2 once weekly) for 3 weeks with 1 week off per a 4-week cycle. The primary objective was to determine the antitumor efficacy. Results 46 patients were enrolled (22 male/24 female; median age 67; 91% Caucasian). The RP2D of RX-3117 plus nab-Pac was 700 mg/day. No dose-limiting toxicities were observed (DLTs). The overall response rate (ORR) was 23.1% and disease control rate (DCR) 74.4%. RX-3117 pharmacokinetics (PK) results were similar to previously reported monotherapy phase 1 trial. All patients experienced a treatment emergent adverse event (TEAE) with the most common diarrhea, nausea, and fatigue.10.9% of patients experienced a serious adverse event (SAE) related to the combination. Conclusion RX-3117 plus nab-Pac in newly diagnosed met-PC patients demonstrated tolerability, safety, and early treatment efficacy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To compare detection rates of NET liver metastases of MRI and Ga-68-DOTATATE PET/CT to provide more clarity when selecting diagnostic imaging tests for NET staging., Methods: In this IRB-approved single-institution retrospective study, all patients with pathology-proven NET who underwent Ga-68-DOTATATE and MRI scans within 8 weeks of each other (3/2017-2/2020) were reviewed. Number of metastases for each patient on diffusion-weighted imaging (DWI), dynamic contrast-enhanced (DCE) MRI, and Ga-68 DOTATATE were recorded by two blinded radiologists, followed by consensus review with two separate blinded readers for MRI and nuclear medicine. Per-lesion and -modality scoring at each lesion location were then performed in consensus. Per-patient linear regression was performed comparing MRI and Ga-68 DOTATATE detection rates for each reader and in consensus, and per-lesion-matched pair difference means were used to compare detection frequency between modalities., Results: 32 patients (mean age 59 years, 59.4% male) and 90 liver metastases were analyzed. Intraclass coefficients (ICC) [95% CI] between the two readers were 0.97 [0.95, 0.99], 0.89 [0.82, 0.94], and 0.98 [0.97, 0.99] for Ga-68 DOTATATE, DWI, and DCE, respectively. Matched per-lesion mean differences were + 0.17 ± 0.07 (p = 0.01) and + 0.22 ± 0.06 (p =  < 0.001) for DWI versus Ga-68 DOTATATE and DCE vs Ga-68 DOTATATE, respectively, favoring MRI. Case-based linear regressions estimate that DWI and DCE detect 1.28 [1.07, 1.49] and 1.33 [1.12, 1.54] lesions, respectively, for each one detected on Ga-68 DOTATATE., Conclusion: MRI detects more hepatic NET metastasis in comparison to Ga-68 DOTATATE. Liver MRI should be performed in concert with Ga-68 DOTATATE in NET staging., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: For cancer survivors, there is a paucity of fear of recurrence (FOR) interventions that integrate empirically supported mind-body and psychological skills for managing FOR and are delivered in scalable formats., Objective: To adapt an evidence-based resiliency intervention to address FOR among cancer survivors., Methods: A multidisciplinary team of researchers, clinicians, and patient stakeholders followed an iterative intervention adaptation process (ORBIT). In Step 1, we sought to define key FOR management skills through a literature review and feedback from stakeholders. In Step 2, we integrated findings into a treatment manual and refined procedures for in-person delivery to groups of cancer survivors, defined as adults who had completed primary cancer treatment for non-metastatic cancer. In Step 3, we conducted a single arm trial to assess initial acceptability and change in FOR severity with 23 cancer survivors (N=4 intervention groups). In Step 4, we conducted additional qualitative interviews with 28 cancer survivors (N=6 focus groups stratified by FOR severity, N=15 individual interviews) to define adaptive and maladaptive strategies for coping with FOR and to identify preferences for delivery. In Step 5, we refined the treatment manual and procedures for testing in a future pilot randomized feasibility trial., Results: We identified critical feedback using a combination of qualitative and quantitative methods. The single arm trial suggested preliminary feasibility and sustained reductions in FOR severity, yet need for refinement (i.e., eligibility, delivery modality), prompting additional qualitative interviews for further targeting. The resulting intervention (IN FOCUS) is comprised of virtual, synchronous, group-delivered sessions that offer an integrated approach to FOR management by teaching cognitive-behavioral techniques, meditation, relaxation training, adaptive health behaviors, and positive psychology skills. Sessions are targeted by applying skills to FOR and associated healthcare engagement., Conclusions: IN FOCUS is a targeted intervention for teaching mind-body resiliency skills to groups of cancer survivors with elevated FOR. Next steps are testing feasibility in a pilot randomized trial., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Purpose: To evaluate outcomes of patients with intrahepatic cholangiocarcinoma (iCCA) undergoing neoadjuvant yttrium-90 ( 90 Y) transarterial radioembolization (TARE) with resin microspheres prescribed using the Medical Internal Radiation Dose (MIRD) model., Materials and Methods: This retrospective institutional review board-approved study included 37 patients with iCCA treated with 90 Y-TARE from October 2015 to September 2020. The primary outcome was overall survival (OS) from 90 Y-TARE. The secondary outcomes were progression-free survival (PFS), Response Evaluation Criteria In Solid Tumors 1.1 imaging response, and downstaging to resection. Patients with tumor proximity to the middle hepatic vein (<1 cm) and/or insufficient future liver remnant were treated with neoadjuvant intent (n = 21). Patients were censored at the time of surgery or at the last follow-up for the Kaplan-Meier survival analysis., Results: For 31 patients (69 years; interquartile range, 64-74 years; 20 men [65%]) included in the study, the first-line therapy was 90 Y-TARE for 23 (74%) patients. Imaging assessment at 6 months showed a disease control rate of 86%. The median PFS was 5.4 months (95% confidence interval [CI], 3-not reached). The PFS was higher after first-line 90 Y-TARE (7.4 months [95% CI, 5.3-not reached]) than that after subsequent 90 Y-TARE (2.7 months [95% CI, 2-not reached]) (P = .007). The median OS was 22 months (95% CI, 7.3-not reached). The 1- and 2-year OS rates were 60% (95% CI, 41%-86%) and 40% (95% CI, 19.5%-81%). In patients treated with neoadjuvant intent, 11 of 21 patients (52%) underwent resections. The resection margins were R0 and R1 in 8 (73%) and 3 (27%) of 11 patients, respectively. On histological review in 10 patients, necrosis of ≥90% tumor was achieved in 7 of 10 patients (70%)., Conclusions: First-line 90 Y-TARE prescribed using the MIRD model as neoadjuvant therapy for iCCA results in good survival outcome and R0 resection for unresectable patients., (Copyright © 2021 SIR. Published by Elsevier Inc. All rights reserved.)

2-deoxy- D -Ribose (2dDR) was first identified in 1930 in the structure of DNA and discovered as a degradation product of it later when the enzyme thymidine phosphorylase breaks down thymidine into thymine. In 2017, our research group explored the development of wound dressings based on the delivery of this sugar to induce angiogenesis in chronic wounds. In this review, we will survey the small volume of conflicting literature on this and related sugars, some of which are reported to be anti-angiogenic. We review the evidence of 2dDR having the ability to stimulate a range of pro-angiogenic activities in vitro and in a chick pro-angiogenic bioassay and to stimulate new blood vessel formation and wound healing in normal and diabetic rat models. The biological actions of 2dDR were found to be 80 to 100% as effective as VEGF in addition to upregulating the production of VEGF. We then demonstrated the uptake and delivery of the sugar from a range of experimental and commercial dressings. In conclusion, its pro-angiogenic properties combined with its improved stability on storage compared to VEGF, its low cost, and ease of incorporation into a range of established wound dressings make 2dDR an attractive alternative to VEGF for wound dressing development.

Purpose: Weight concern, including fear of weight gain and sensitivity to weight gain, is indicative of disordered eating in individuals with underweight or healthy weight. It is unknown, however, whether or how these constructs present in individuals with excess weight, particularly among those with binge-eating disorder (BED). This study sought to characterize fear of weight gain and sensitivity to weight gain and examine their relationship with disordered eating and depression symptoms, in individuals seeking weight loss treatment, both with and without BED., Methods: Adults seeking weight loss treatment in an urban primary care clinic (N = 131) completed the Eating Disorder Examination interview and Beck Depression Inventory. Height and weight were collected., Results: Clinical levels of fear of weight gain and sensitivity to weight gain were present in this sample. Individuals with BED reported experiencing fear of weight gain (48.6%), significantly more than those without BED (20.9%); both groups reported similar and clinically elevated sensitivity to weight gain. Both constructs were related to greater levels of disordered eating and depression symptoms, at times based on BED status. Fear of weight gain was associated with overvaluation of weight and shape for those without BED only. Objective and subjective bulimic episodes were unrelated to fear of weight gain or sensitivity to weight gain, regardless of BED status., Conclusion: Fear of weight gain and sensitivity to weight gain were common in this sample and may be maladaptive, as evidenced by associations with elevated eating psychopathology. Future studies should examine these variables within larger samples and should employ longitudinal designs., Level of Evidence: Level III: case-control analytic study.

Skeletal muscle and adipose tissue express the vitamin D receptor and may be a mechanism through which vitamin D supplementation slows cancer progression and reduces cancer death. In this exploratory analysis of a double-blind, multicenter, randomized phase II clinical trial, 105 patients with advanced or metastatic colorectal cancer who were receiving chemotherapy were randomized to either high-dose vitamin D 3 (4000 IU) or standard-dose (400 IU) vitamin D 3 . Body composition was measured with abdominal computed tomography at enrollment (baseline) and after cycle 8 of chemotherapy (16 weeks). As compared with standard-dose vitamin D 3 , high-dose vitamin D 3 did not significantly change body weight [-0.7 kg; (95% CI: -3.5, 2.0)], body mass index [-0.2 kg/m 2 ; (95% CI: -1.2, 0.7)], muscle area [-1.7 cm 2 ; (95% CI: -9.6, 6.3)], muscle attenuation [-0.4 HU; (95% CI: -4.2, 3.2)], visceral adipose tissue area [-7.5 cm 2 ; (95% CI: -24.5, 9.6)], or subcutaneous adipose tissue area [-8.3 cm 2 ; (95% CI: -35.5, 18.9)] over the first 8 cycles of chemotherapy. Among patients with advanced or metastatic colorectal cancer, the addition of high-dose vitamin D 3 , vs standard-dose vitamin D 3 , to standard chemotherapy did not result in any changes in body composition.

Purpose: To evaluate the efficacy and safety of pegvorhyaluronidase alfa (PEGPH20) plus nab-paclitaxel/gemcitabine (AG) in patients with hyaluronan-high metastatic pancreatic ductal adenocarcinoma (PDA)., Patients and Methods: HALO 109-301 was a phase III, randomized, double-blind, placebo-controlled study. Patients ≥ 18 years of age with untreated, metastatic, hyaluronan-high PDA were randomly assigned 2:1 to PEGPH20 plus AG or placebo plus AG. Treatment was administered intravenously in 4-week cycles (3 weeks on, 1 week off) until progression or intolerable adverse events: PEGPH20 3.0 µg/kg twice per week for cycle 1 and once per week thereafter; nab-paclitaxel 125 mg/m 2 once per week; and gemcitabine 1,000 mg/m 2 once per week. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Response was independently assessed per RECIST v1.1., Results: At data cutoff, 494 patients were randomly assigned, with 492 (327 for PEGPH20 and 165 for placebo) included in intention-to-treat analyses. Baseline characteristics were balanced for PEGPH20 plus AG versus placebo plus AG. There were 330 deaths, with a median OS of 11.2 months for PEGPH20 plus AG versus 11.5 months for placebo plus AG (hazard ratio [HR], 1.00; 95% CI, 0.80 to 1.27; P = .97); median PFS was 7.1 months versus 7.1 months (HR, 0.97 [95% CI, 0.75 to 1.26]); ORR was 47% versus 36% (ORR ratio, 1.29 [95% CI, 1.03 to 1.63]). Grade ≥ 3 adverse events with a ≥ 2% higher rate with PEGPH20 plus AG than with placebo plus AG included fatigue (16.0% v 9.6%), muscle spasms (6.5% v 0.6%), and hyponatremia (8.0% v 3.8%)., Conclusion: The addition of PEGPH20 to AG increased the ORR but did not improve OS or PFS. The safety profile of PEGPH20 plus AG was consistent with that found in previous studies. These results do not support additional development of PEGPH20 in metastatic PDA.

Background: Delayed neovascularisation of tissue-engineered (TE) complex constructs is a major challenge that causes their failure post-implantation. Although significant progress has been made in the field of angiogenesis, ensuring rapid neovascularisation still remains a challenge. The use of pro-angiogenic agents is an effective approach to promote angiogenesis, and vascular endothelial growth factor (VEGF) has been widely studied both at the biological and molecular levels and is recognised as a key stimulator of angiogenesis. However, the exogenous use of VEGF in an uncontrolled manner has been shown to result in leaky, permeable and haemorrhagic vessels. Thus, researchers have been actively seeking alternative agents to upregulate VEGF production rather than exogenous use of VEGF in TE systems. We have previously revealed the potential of 2-deoxy-d-ribose (2dDR) as an alternative pro-angiogenic agent to induce angiogenesis and accelerates wound healing. However, to date, there is not any clear evidence on whether 2dDR influences the angiogenic cascade that involves VEGF., Methods: In this study, we explored the angiogenic properties of 2dDR either by its direct application to human aortic endothelial cells (HAECs) or when released from commercially available alginate dressings and demonstrated that when 2dDR promotes angiogenesis, it also increases the VEGF production of HAECs., Results: The VEGF quantification results suggested that VEGF production by HAECs was increased with 2dDR treatment but not with other sugars, including 2-deoxy-l-ribose (2dLR) and d-glucose (DG). The stability studies demonstrated that approximately 40-50% of the 2dDR had disappeared in the media over 14 days, either in the presence or absence of HAECs, and the reduction was higher when cells were present. The concentration of VEGF in the media also fell after day 4 associated with the reduction in 2dDR., Conclusion: This study suggests that 2dDR (but not other sugars tested in this study) stimulates angiogenesis by increasing the production of VEGF. We conclude 2dDR appears to be a practical and effective indirect route to upregulating VEGF for several days, leading to increased angiogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The purpose of this study was to examine whether social problem solving (SPS) would relate to posttraumatic growth (PTG), particularly new life possibilities in breast cancer survivors. Participants included 85 women who had undergone surgical intervention for breast cancer at least 6 months prior to study participation. Participant ages ranged from 29 to 88 years. The majority of the sample was White (86%), married (58%), and had received at least some postsecondary education (73%), and all participants spoke English. This IRB-approved cross-sectional study was part of a larger study examining psychosocial protective and risk factors in breast cancer survivors at a university-affiliated private hospital. We hypothesized that better SPS ability would relate to PTG new possibilities above and beyond age, annual income, and time since surgery. Results from this study indicate that a positive problem orientation and lack of impulsive/careless problem-solving style appear to play a role in posttraumatic growth among breast cancer survivors, particularly in developing beliefs about one's ability to positively change one's life. Given the established benefits of active/approach coping in cancer populations, it makes sense that similar interventions such as problem-solving therapy, a cognitive-behavioral therapy that includes challenging and reframing negative beliefs about self and situation, may promote new possibility beliefs in this population.

The World Health Organization identified the promotion of "Nurturing Care Environments" as a global health priority. Responsive caregiving, 1 of 5 domains describing nurturing care, is critical for healthy child development. Relatively little research has evaluated population-level interventions aimed to increase responsive caregiving during the first 1,000 days of an infant's life. In this pilot study, we evaluated an intervention designed for population-level dissemination that targeted responsive caregiving. The self-guided behavioral skills training aimed to teach mothers to imitate infant vocalizations. The intervention was delivered within an on-line asynchronous training. All 3 mothers increased vocal imitative behavior following training without receiving coaching or behavior-specific feedback from an implementer. The results offer a preliminary proof of concept with implications for population-level intervention design and evaluation., (© 2020 Society for the Experimental Analysis of Behavior (SEAB).)

Background In pancreatic ductal adenocarcinoma (PDAC), the chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-C motif) receptor 2 (CCR2) axis plays a key role in immunosuppressive properties of the tumor microenvironment, patient prognosis, and chemoresistance. This phase Ib study assessed the effects of the orally administered CCR2 inhibitor PF-04136309 in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic PDAC. Methods Patients received PF-04136309 twice daily (BID) continuously plus nab-paclitaxel (125 mg/m 2 ) and gemcitabine (1000 mg/m 2 ) administered on days 1, 8, and 15 of each 28-day cycle. The primary objectives were to evaluate safety and tolerability, characterize dose-limiting toxicities (DLTs), and determine the recommended phase II dose (RP2D) of PF-04136309. Results In all, 21 patients received PF-04136309 at a starting dose of 500 mg or 750 mg BID. The RP2D was identified to be 500 mg BID. Of 17 patients treated at the 500 mg BID starting dose, three (17.6%) experienced a total of four DLTs, including grade 3 dysesthesia, diarrhea, and hypokalemia and one event of grade 4 hypoxia. Relative to the small number of patients (n = 21), a high incidence (24%) of pulmonary toxicity was observed in this study. The objective response rate for 21 patients was 23.8% (95% confidence interval: 8.2-47.2%). Levels of CD14 + CCR2+ inflammatory monocytes (IM) decreased in the peripheral blood, but did not accumulate in the bone marrow. Conclusions PF-04136309 in combination with nab-paclitaxel plus gemcitabine had a safety profile that raises concern for synergistic pulmonary toxicity and did not show an efficacy signal above nab-paclitaxel and gemcitabine. ClinicalTrials.gov identifier: NCT02732938.

Background: Our overall objective is to develop a single-stage in-theatre skin replacement by combining small explants of skin with a synthetic biodegradable dermal scaffold. The aim of the current study is to determine the concentration of fibrin constituents and their handling properties for both adhering skin explants to the scaffold and encouraging cellular outgrowth to achieve reepithelialization., Methods: Small skin explants were combined with several concentrations of thrombin (2.5,4.5,and 6.5 I.U) and fibrinogen (18.75,67, and 86.5 mg/ml), cultured in Green's media for 14 days and cellular outgrowth was measured using Rose Bengal staining. They were also cultured on electrospun scaffolds for 14 and 21 days. Hematoxylin and eosin (H&E) staining was undertaken to visualize the interface between skin explants and scaffolds and metabolic activity and collagen production were assessed., Results: A thrombin/fibrinogen combination of 2.5 I. U/ml /18.75 mg/ml showed significantly greater cell viability as assessed by Rose Bengal stained areas at days 7 and 14. This was also seen in DAPI images and H&E stains skin explant/scaffold constructs. Fibrin with a concentration of thrombin 2.5 I.U./ml took 5-6 min to set, which is convenient for distributing skin explants on the scaffold., Conclusion: The study identified concentrations of thrombin (2.5 I.U/ml) and fibrinogen (18.75 mg/ml), which were easy to handle and aided the retention of skin explants and permitted cell outgrowth from explants., Competing Interests: None., (© 2020 The Author(s).)

The physiological wound healing process involves a cascade of events which could be affected by several factors resulting in chronic, non-healing wounds. The latter represent a great burden especially when bacterial biofilms are formed. The rise in antibiotic resistance amongst infectious microorganisms leads to the need of novel approaches to treat this clinical issue. In this context, the use of advanced biomaterials, which can enhance the physiological expression and secretion of the growth factors involved in the wound healing process, is gaining increasing attention as a robust and appealing alternative approach. Among them, mesoporous glasses are of particular interest due to their excellent textural properties and to the possibility of incorporating and releasing specific therapeutic species, such as metallic ions. One of the most attractive therapeutic ions is copper thanks to its proangiogenic and antibacterial effects. In this contribution, copper containing mesoporous glass nanoparticles were proposed as a multifunctional device to treat chronic wounds. The developed nanoparticles evidenced a very high specific surface area (740 m 2 /g), uniform pores of 4 nm and an almost total release of the therapeutic ion within 72 h of soaking. The produced nanoparticles were biocompatible and, when tested against Gram positive and Gram negative bacterial species, demonstrated antibacterial activity against both planktonic and biofilm bacteria in 2D cell monolayers, and in a 3D human model of infected skin. Their proangiogenic effect was tested with both the aortic ring and the chick chorioallantoic membrane assays and an increase in endothelial cell outgrowth at a concentration range between 30 and 300 ng/mL was shown. Overall, in this study biocompatible, multifunctional Cu-containing mesoporous glass nanoparticles were successfully produced and demonstrated to exert both antibacterial and proangiogenic effects., (Copyright © 2020 Paterson, Bari, Bullock, Turner, Montalbano, Fiorilli, Vitale-Brovarone, MacNeil and Shepherd.)

Acute gastrointestinal (GI) immune-related adverse events (irAE) are commonly reported by patients with cancer undergoing treatment with immune checkpoint inhibitors (CPI); however chronic irAEs are rare. We present a case of a 71-year-old woman with metastatic gastro-oesophageal junction (GOJ) adenocarcinoma who developed delayed-onset chronic intestinal pseudo-obstruction (CIPO) while receiving second-line pembrolizumab. Repeated CT scans of the abdomen/pelvis found no small bowel obstruction, and evaluations for bowel inflammation, infection and paraneoplastic syndrome were negative. Bowel rest and glucocorticoids were associated with transient symptom resolution; however, symptoms recurred within 1 month. The patient was ultimately supported with total parenteral nutrition and intestinal motility agents. After 4 months, the GOJ cancer remained stable with no signs of progression. As CPI use expands, the incidence of rare irAEs, such as CIPO, may increase., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The use of VEGFR TKIs for the adjuvant treatment of renal cell carcinoma (RCC) remains controversial. We investigated the effects of adjuvant VEGFR TKIs on circulating cytokines in the ECOG-ACRIN 2805 (ASSURE) trial., Experimental Design: Patients with resected high-risk RCC were randomized to sunitinib, sorafenib, or placebo. Plasma from 413 patients was analyzed from post-nephrectomy baseline, 4 weeks, and 6 weeks after treatment initiation. Mixed effects and Cox proportional hazards models were used to test for changes in circulating cytokines and associations between disease-free survival (DFS) and cytokine levels., Results: VEGF and PlGF increased after 4 weeks on sunitinib or sorafenib ( P < 0.0001 for both) and returned to baseline at 6 weeks on sunitinib (corresponding to the break in the sunitinib schedule) but not sorafenib (which was administered continuously). sFLT-1 decreased after 4 weeks on sunitinib and 6 weeks on sorafenib ( P < 0.0001). sVEGFR-2 decreased after both 4 and 6 weeks of treatment on sunitinib or sorafenib ( P < 0.0001). Patients receiving placebo had no significant changes in cytokine levels. CXCL10 was elevated at 4 and 6 weeks on sunitinib and sorafenib but not on placebo. Higher baseline CXCL10 was associated with worse DFS (HR 1.41 per log increase in CXCL10, Bonferroni-adjusted P = 0.003). This remained significant after adjustment for T-stage, Fuhrman grade, and ECOG performance status., Conclusions: Among patients treated with adjuvant VEGFR TKIs for RCC, drug-host interactions mediate changes in circulating cytokines. Elevated baseline CXCL10 was associated with worse DFS. Studies to understand functional consequences of these changes are under way., (©2019 American Association for Cancer Research.)

While vascular endothelial growth factor (VEGF) is an acknowledged potent pro-angiogenic agent there is a need to deliver it at an appropriate concentration for several days to achieve angiogenesis. The aim of this study was to produce microspheres of biodegradable polylactic-co-glycolic acid (PLGA) tailored to achieve sustained release of VEGF at an appropriate concentration over seven days, avoiding excessive unregulated release of VEGF that has been associated with the formation of leaky blood vessels. Several formulations were examined to produce microspheres loaded with both human serum albumin (HSA) and VEGF to achieve release of VEGF between 3 and 10 ng per ml for seven days to match the therapeutic window desired for angiogenesis. In vitro experiments showed an increase in endothelial cell proliferation in response to microspheres bearing VEGF. Similarly, when microspheres containing VEGF were added to the chorionic membrane of fertilised chicken eggs, there was an increase in the development of blood vessels over seven days in response, which was significant for microspheres bearing VEGF and HSA, but not VEGF alone. There was an increase in both blood vessel density and branching - both signs of proangiogenic activity. Further, there was clearly migration of cells to the VEGF loaded microspheres. In summary, we describe the development of an injectable delivery vehicle to achieve spatiotemporal release of physiologically relevant levels of VEGF for several days and demonstrate the angiogenic response to this. We propose that such a treatment vehicle would be suitable for the treatment of ischemic tissue or wounds., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Importance: In observational studies, higher plasma 25-hydroxyvitamin D (25[OH]D) levels have been associated with improved survival in metastatic colorectal cancer (CRC)., Objective: To determine if high-dose vitamin D3 added to standard chemotherapy improves outcomes in patients with metastatic CRC., Design, Setting, and Participants: Double-blind phase 2 randomized clinical trial of 139 patients with advanced or metastatic CRC conducted at 11 US academic and community cancer centers from March 2012 through November 2016 (database lock: September 2018)., Interventions: mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D3 (n = 69) or standard-dose vitamin D3 (n = 70) daily until disease progression, intolerable toxicity, or withdrawal of consent., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) assessed by the log-rank test and a supportive Cox proportional hazards model. Testing was 1-sided. Secondary end points included tumor objective response rate (ORR), overall survival (OS), and change in plasma 25(OH)D level., Results: Among 139 patients (mean age, 56 years; 60 [43%] women) who completed or discontinued chemotherapy and vitamin D3 (median follow-up, 22.9 months), the median PFS for high-dose vitamin D3 was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS events) for standard-dose vitamin D3 (log-rank P = .07); multivariable hazard ratio for PFS or death was 0.64 (1-sided 95% CI, 0 to 0.90; P = .02). There were no significant differences between high-dose and standard-dose vitamin D3 for tumor ORR (58% vs 63%, respectively; difference, -5% [95% CI, -20% to 100%], P = .27) or OS (median, 24.3 months vs 24.3 months; log-rank P = .43). The median 25(OH)D level at baseline for high-dose vitamin D3 was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D3 (difference, -2.6 ng/mL [95% CI, -6.6 to 1.4], P = .30); at first restaging, 32.0 ng/mL vs 18.7 ng/mL (difference, 12.8 ng/mL [95% CI, 9.0 to 16.6], P < .001); at second restaging, 35.2 ng/mL vs 18.5 ng/mL (difference, 16.7 ng/mL [95% CI, 10.9 to 22.5], P < .001); and at treatment discontinuation, 34.8 ng/mL vs 18.7 ng/mL (difference, 16.2 ng/mL [95% CI, 9.9 to 22.4], P < .001). The most common grade 3 and higher adverse events for chemotherapy plus high-dose vs standard-dose vitamin D3 were neutropenia (n = 24 [35%] vs n = 21 [31%], respectively) and hypertension (n = 9 [13%] vs n = 11 [16%])., Conclusions and Relevance: Among patients with metastatic CRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy resulted in a difference in median PFS that was not statistically significant, but with a significantly improved supportive hazard ratio. These findings warrant further evaluation in a larger multicenter randomized clinical trial., Trial Registration: ClinicalTrials.gov Identifier: NCT01516216.

Purpose: Sorafenib is a standard first-line treatment for advanced hepatocellular carcinoma (HCC). The phase III SHARP trial showed a median time-to-progression (mTTP) of 5.5 months, overall response rate (ORR) of 2%, and median overall survival (mOS) of 10.7 months with sorafenib. FOLFOX4 has shown modest activity in advanced HCC. We evaluated the combination of sorafenib and modified (m)FOLFOX in a single-arm, multicenter phase II study., Patients and Methods: The study included Child-Pugh A patients with advanced HCC and no prior systemic therapies. Patients received sorafenib 400 mg twice a day for 2 weeks, followed by concurrent mFOLFOX [5-fluorouracil (5-FU) 1,200 mg/m 2 /day for 46 hours, leucovorin 200 mg/m 2 , and oxaliplatin 85 mg/m 2 biweekly]. The primary endpoint was mTTP with an alternative hypothesis of 7 months, and secondary endpoints included ORR, mOS, and circulating biomarkers., Results: The study enrolled 40 patients: HCV/EtOH/HBV, 43%/28%/13%; Child-Pugh A5, 70%. Notable grade 3/4 adverse events (AE) included AST/ALT elevation (28%/15%), diarrhea (13%), hyperbilirubinemia (10%), hand-foot syndrome (8%), and bleeding (8%). mTTP was 7.7 months [95% confidence interval (CI): 4.4-8.9], ORR 18%, and mOS 15.1 months (7.9-16.9). Sorafenib + mFOLFOX increased plasma PlGF, VEGF-D, sVEGFR1, IL12p70, and CAIX and CD4 + and CD8 + effector T lymphocytes and decreased plasma sVEGFR2 and s-c-KIT and regulatory T cells (Tregs). Shorter TTP was associated with high baseline sVEGFR1. Shorter TTP and OS were associated with increases in Tregs and CD56 Dim natural killer (NK) cells after sorafenib alone and plasma sMET after combination treatment (all P < 0.05)., Conclusions: Sorafenib + mFOLFOX met the prespecified endpoint with encouraging efficacy but moderate hepatotoxicity. Thus, this regimen may be effective in select patients with adequate liver reserve. Biomarker evaluations suggested a correlation between time-to-progression (TTP) and angiogenic biomarkers and circulating Tregs., (©2018 American Association for Cancer Research.)

Purpose: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses., Methods: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression., Results: We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5-13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30-0.99; P = 0.05)., Conclusion: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

Objective: Overweight/obesity and chronic pain frequently co-occur and demonstrate a bidirectional relationship. Modifiable risk factors, such as eating behaviors and mental health symptoms, may be important to understand this relationship and improve interventions in Veterans., Design: Cross-sectional., Setting: Veterans Health Administration Medical Center outpatient clinic., Subjects: The sample of Veterans (N = 126) was mostly male (89.7%), White (76%), and non-Hispanic (94%) with average age of 61.9 years (SD = 8.5) and average body mass index (BMI) of 38.5 (SD = 7.5)., Methods: Veterans referred for weight loss treatment (MOVE!) at VA Connecticut completed self-report questionnaires, and electronic medical records were reviewed., Results: Mean self-reported pain rating was 4.5 out of 10 (SD = 2.3). Moderate to severe pain was endorsed by 60% of the sample. Veterans with higher pain intensity and interference reported higher global eating disorder symptoms, emotional overeating, night eating, insomnia severity, and mental health symptoms (all p's < 0.01). However, pain intensity and interference were not associated with BMI., Conclusions: For Veterans seeking behavioral weight loss treatment, higher pain intensity and interference were associated with more severe eating disorder, sleep, and mental health symptoms. A better description of the clinical characteristics of Veterans with pain who participate in MOVE! highlights their unique needs and may improve treatments to address pain in the context of weight loss treatment., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Preterm premature rupture of fetal membranes is a leading cause of preterm delivery. Preterm labour can compromise fetal survival, and even if a pregnancy affected by preterm premature rupture of fetal membrane continues, major complications associated with leakage of amniotic fluid and risk of infection can affect the normal development and survival of the baby. There are limited management options for preterm premature rupture of fetal membrane other than delivery of the baby if ascending infection (chorioamnionitis) is suspected. We have previously reported the development and characterisation of an implantable membrane with the aim of using it to occlude the internal os of the cervix, in order to prevent amniotic fluid loss, allow fluid reaccumulation and reduce the risk of chorioamnionitis. For this, an electrospun biocompatible and distensible bilayer membrane was designed with mechanical properties similar to the human amniotic membrane. In this study, we consider the effects of sterilization on the membrane, how to insert the membrane and visualise it using routine clinical methods. To do this, we used e-beam sterilisation and examined the ability of the membrane to adhere to ex vivo human cervical tissues. We also studied its insertion into a custom-synthesised model of a 20-week pregnant uterus and imaged the membrane using ultrasound. Sterilisation produced minor effects on physical and mechanical properties, but these did not affect the capacity of the membrane to be sutured or to provide a fluid barrier. We demonstrated that fibrin glue can successfully adhere the bilayer membrane to cervical tissues. Finally, we demonstrated that the membrane can be inserted through the cervix as well as visualized in place using ultrasound imaging and an endoscope. In summary, we suggest this membrane is a candidate for further development in an appropriate animal model, supported by appropriate imaging, to precede possible future human studies if judged to demonstrate satisfactory safety and efficacy profiles.

Background: Despite controversy surrounding the construct of food addiction, its relationship with obesity and the validity of the Yale Food Addiction Scale (YFAS), have become emerging fields of study. No prior research has examined the prevalence and correlates of food addiction, and validation of the Modified Yale Food Addiction Scale (mYFAS), in a non-research based weight management clinic setting., Objective: The current study sought to examine the validity of a brief version of the Yale Food Addiction Scale in weight loss seeking patients, and to determine whether food addiction contributes to excess weight in this patient population., Participants: The sample consisted of 126 Veterans with overweight/obesity who attended an orientation session for a weight management program. Participants (mean age = 61.8 years, mean BMI = 38.0, male = 89.7%, Caucasian = 76.0%) completed questionnaires related to food addiction, weight and eating, and mental health and behavior., Results: Ten percent of the sample met diagnostic threshold for food addiction. Correlational analysis revealed that food addiction was significantly and highly correlated with BMI, emotional eating, night eating and screens for depression and insomnia (p's < 0.001); significantly correlated with eating pathology, and screening for PTSD (p's < 0.05); and inversely correlated with screening for alcohol use disorders (p < 0.01). The prevalence of food addiction was significantly higher in participants with Binge Eating Disorder (75%) compared to participants without (5.4%; p < 0.001). Food addiction uniquely accounted for 15% of the variance of BMI, almost three times more than general eating disorder pathology., Discussion: This study provides further evidence for the validity of the mYFAS, and clinical significance of the food addiction construct among weight loss seeking patients in non-research based weight management settings. Findings confirm that food addiction contributes to excess weight among clinic patients seeking weight reduction above and beyond the effects of disordered eating. It is recommended that clinicians and researchers consider an addiction framework for addressing comorbid overweight and food addiction among afflicted individuals seeking weight loss., (Published by Elsevier Inc.)

Introduction: We aimed to compare alternative synthetic scaffolds suitable for future implantation and to examine the use of an inhibitor of lysyl oxidase (beta-amino-propionitrile [β-APN]) to reduce contraction in these implants., Methods: Three synthetic scaffolds were compared to natural dermis as substrates for the production of tissue-engineered skin. For natural dermis, Euroskin was used to provide a cell-free cadaveric dermis. Synthetic scaffolds consisted of microfibrous poly-L-lactic acid (PLA), nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), and a micro-/nanofibrous trilayer of PLA-PHBV-PLA. The latter were all electrospun and then all four scaffolds (three synthetic, one natural) were placed in six well plates. A culture well was formed on the scaffold using a 1 cm diameter stainless steel ring and 1.5×10 5 oral fibroblasts were seeded one side; after two days of culture, the ring was placed on the other side of the scaffolds and 3×10 5 oral keratinocytes were seeded on to the scaffolds and cultured with keratinocytes uppermost. After a further two days of culture, scaffolds were cut to 1 cm 2 and raised to an air-liquid interface on stainless steel grids; some were treated with 200 μg/mL β-APN throughout the culture period (28 days). Contraction in vitro was assessed by serial digital photography of cell-seeded scaffolds and cell-free scaffolds three times a week for 28 days. All cell-seeded scaffolds were assessed for cell metabolic activity, mechanical properties, histology, and morphology by scanning electron microscopy (SEM)., Results: The mean fibre diameters and pore sizes of PLA and PHBV scaffolds were 2.4±0.77, 0.85±0.21 μm (p<0.001), and 10.8±2.3, 4.3±1.1 μm (p<0.001), respectively. Oral fibroblasts and keratinocytes were tightly adhered and grew well on both surfaces of trilayer. The ultimate tensile strength (UTS) and Young's modulus (YM) of PLA samples were significantly lower than Euroskin (p<0.001 and p<0.05, respectively); only the UTS of the trilayer samples was slightly significantly lower (p<0.05). Metabolic activity was significantly increased for cells on all scaffolds, without significant differences between them from Day 0 to Day 28. There were no adverse effects of β-APN on cell viability. With respect to contraction, cells on trilayer and PHBV monolayers did not undergo any significant contraction; however, cells on PLA monolayer and Euroskin contracted 25.3% and 56.4%, respectively, over 28 days. The addition of 200 μg/ml β-APN significantly reduced contraction of Euroskin compared with the control (p<0.01); however, β-APN did not affect PLA contraction during this culture period (p>0.05)., Conclusions: This study shows that a trilayer micro-nano-3D porous synthetic scaffold is suitable for oral keratinocyte and fibroblast growth with good cell viability and minimal contraction. This material also has good mechanical properties and histological analyses showed its ability to mimic normal human oral mucosal morphology. Furthermore, synthetic trilayer scaffolds have advantages over biological scaffolds - there is no risk of disease transmission or immunological rejection and they appear resistant to contraction. We suggest they present a good alternative to allodermis for future use in urethral reconstruction.

Importance: Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few biomarkers are available to inform patient outcomes., Objective: To evaluate the alterations of the 4 main driver genes in pancreatic adenocarcinoma and patient outcomes after cancer resection., Design, Setting, and Participants: This study analyzed protein expression and DNA alterations for the KRAS, CDKN2A, SMAD4, and TP53 genes by immunohistochemistry and next-generation sequencing in formalin-fixed, paraffin-embedded tumors in 356 patients with resected pancreatic adenocarcinoma who were treated at the Dana-Farber/Brigham and Women's Cancer Center (October 26, 2002, to May 21, 2012), University of Rochester Medical Center (March 1, 2006, to November 1, 2013), or Stanford Cancer Institute (September 26, 1995, to May 22, 2013). Associations of driver gene alterations with disease-free survival (DFS) and overall survival (OS) were evaluated using Cox proportional hazards regression with estimation of hazard ratios (HRs) and 95% CIs and adjustment for age, sex, tumor characteristics, institution, and perioperative treatment. Data were collected September 9, 2012, to June 28, 2016, and analyzed December 17, 2016, to March 14, 2017., Main Outcomes and Measures: The DFS and OS among patients with resected pancreatic adenocarcinoma., Results: Of the 356 patients studied, 191 (53.7%) were men and 165 (46.3%) were women, with a median (interquartile range [IQR]) age of 67 (59.0-73.5) years. Patients with KRAS mutant tumors had worse DFS (median [IQR], 12.3 [6.7 -27.2] months) and OS (20.3 [11.3-38.3] months) compared with patients with KRAS wild-type tumors (DFS, 16.2 [8.9-30.5] months; OS, 38.6 [16.6-63.1] months) and had 5-year OS of 13.0% vs 30.2%. Particularly poor outcomes were identified in patients with KRAS G12D-mutant tumors, who had a median (IQR) OS of 15.3 (9.8-32.7) months. Patients whose tumors lacked CDKN2A expression had worse DFS (median, 11.5 [IQR, 6.2-24.5] months) and OS (19.7 [10.9-37.1] months) compared with patients who had intact CDKN2A (DFS, 14.8 [8.2-30.5] months; OS, 24.6 [14.1-44.6] months). The molecular status of SMAD4 was not associated with DFS or OS, whereas TP53 status was associated only with shorter DFS (HR, 1.33; 95% CI, 1.02-1.75; P = .04). Patients had worse DFS and OS if they had a greater number of altered driver genes. Compared with patients with 0 to 2 altered genes, those with 4 altered genes had worse DFS (HR, 1.79 [95% CI, 1.24-2.59; P = .002]) and OS (HR, 1.38 [95% CI, 0.98-1.94; P = .06]). Five-year OS was 18.4% for patients with 0 to 2 gene alterations, 14.1% for those with 3 alterations, and 8.2% for those with 4 alterations., Conclusions and Relevance: Patient outcomes are associated with alterations of the 4 main driver genes in resected pancreatic adenocarcinoma.

Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.

Background: Few studies have simultaneously assessed the prognostic value of the multiple classification systems for lymph node (LN) metastases in resected pancreatic ductal adenocarcinoma (PDAC)., Methods: In 600 patients with resected PDAC, we examined the association of LN parameters (AJCC 7th and 8th editions, LN ratio (LNR), and log odds of metastatic LN (LODDS)) with pattern of recurrence and patient survival using logistic regression and Cox proportional hazards regression, respectively. Regression models adjusted for age, sex, margin status, tumour grade, and perioperative therapy., Results: Lymph node metastases classified by AJCC 7th and 8th editions, LNR, and LODDS were associated with worse disease free-survival (DFS) and overall survival (OS) (all P trend <0.01). American Joint Committee on Cancer 8th edition effectively predicted DFS and OS, while minimising model complexity. Lymph node metastases had weaker prognostic value in patients with positive margins and distal resections (both P interaction <0.03). Lymph node metastases by AJCC 7th and 8th editions did not predict the likelihood of local disease as the first site of recurrence., Conclusions: American Joint Committee on Cancer 8th edition LN classification is an effective and practical tool to predict outcomes in patients with resected PDAC. However, the prognostic value of LN metastases is attenuated in patients with positive resection margins and distal pancreatectomies.

Objective: To assess if simple cholecystectomy with adjuvant therapy could provide outcomes comparable to extended cholecystectomy., Background: Current guidelines recommend extended/radical cholecystectomy for T2/T3 gallbladder cancer; however, many tumors are discovered incidentally at laparoscopic cholecystectomy., Methods: The national Cancer Data Base 2004 to 2014 was queried for patients with pT2/T3 gallbladder adenocarcinoma who underwent resection. Adjuvant therapy was defined as chemotherapy, with or without radiotherapy, within 90 days of surgery. Baseline characteristics and overall survival were compared by χ and Kaplan-Meier method, respectively. One-to-one propensity score matching for receipt of adjuvant therapy was used to account for potential selection bias., Results: A total of 6825 patients were identified. Diagnosis was made predominantly (78.9%) at the time of surgery or on pathology; 31.8% (2168) received adjuvant therapy. The majority, 88.8% (6060), had a simple cholecystectomy. Patients who received adjuvant therapy versus surgery alone were more likely to: be younger, privately insured, have no comorbidities, pT3 disease, positive lymph nodes, positive resection margins, and extended cholecystectomy. After matching, median survival was significantly longer for extended cholecystectomy with adjuvant therapy (23.3 months) than cholecystectomy with adjuvant therapy (16.4 months), which was significantly longer than either simple (12.4 months) or extended (10.7 months) cholecystectomy alone (all log-rank P<0.001)., Conclusions: Adjuvant therapy prolongs survival after resection of T2/T3 tumors. Simple cholecystectomy with adjuvant therapy appears to be superior to extended resection alone in the short term and may serve as a potential alternative to re-resection in select high-risk individuals.

Background: Polypropylene mesh used as a mid-urethral sling is associated with severe clinical complications in a significant minority of patients. Current in vitro mechanical testing shows that polypropylene responds inadequately to mechanical distension and is also poor at supporting cell proliferation., Aims and Objectives: Our objective therefore is to produce materials with more appropriate mechanical properties for use as a sling material but which can also support cell integration., Methods: Scaffolds of two polyurethanes (PU), poly-L-lactic acid (PLA) and co-polymers of the two were produced by electrospinning. Mechanical properties of materials were assessed and compared to polypropylene. The interaction of adipose derived stem cells (ADSC) with the scaffolds was also assessed. Uniaxial tensiometry of scaffolds was performed before and after seven days of cyclical distension. Cell penetration (using DAPI and a fluorescent red cell tracker dye), viability (AlamarBlue assay) and total collagen production (Sirius red assay) were measured for ADSC cultured on scaffolds., Results: Polypropylene was stronger than polyurethanes and PLA. However, polypropylene mesh deformed plastically after 7 days of sustained cyclical distention, while polyurethanes maintained their elasticity. Scaffolds of PU containing PLA were weaker and stiffer than PU or polypropylene but were significantly better than PU scaffolds alone at supporting ADSC., Conclusions: Therefore, prolonged mechanical distension in vitro causes polypropylene to fail. Materials with more appropriate mechanical properties for use as sling materials can be produced using PU. Combining PLA with PU greatly improves interaction of cells with this material.