Nanocarriers for pancreatic cancer imaging, treatments, and immunotherapies.

Pancreatic tumors are highly desmoplastic and immunosuppressive. Delivery and distribution of drugs within pancreatic tumors are compromised due to intrinsic physical and biochemical stresses that lead to increased interstitial fluid pressure, vascular compression, and hypoxia. Immunotherapy-based approaches, including therapeutic vaccines, immune checkpoint inhibition, CAR-T cell therapy, and adoptive T cell therapies, are challenged by an immunosuppressive tumor microenvironment. Together, extensive fibrosis and immunosuppression present major challenges to developing treatments for pancreatic cancer. In this context, nanoparticles have been extensively studied as delivery platforms and adjuvants for cancer and other disease therapies. Recent advances in nanotechnology have led to the development of multiple nanocarrier-based formulations that not only improve drug delivery but also enhance immunotherapy-based approaches for pancreatic cancer. This review discusses and critically analyzes the novel nanoscale strategies that have been used for drug delivery and immunomodulation to improve treatment efficacy, including newly emerging immunotherapy-based approaches. This review also presents important perspectives on future research directions that will guide the rational design of novel and robust nanoscale platforms to treat pancreatic tumors, particularly with respect to targeted therapies and immunotherapies. These insights will inform the next generation of clinical treatments to help patients manage this debilitating disease and enhance survival rates.

Polymeric Nanoparticle-Based Vaccine Adjuvants and Delivery Vehicles.

As vaccine formulations have progressed from including live or attenuated strains of pathogenic components for enhanced safety, developing new adjuvants to more effectively generate adaptive immune responses has become necessary. In this context, polymeric nanoparticles have emerged as a promising platform with multiple advantages, including the dual capability of adjuvant and delivery vehicle, administration via multiple routes, induction of rapid and long-lived immunity, greater shelf-life at elevated temperatures, and enhanced patient compliance. This comprehensive review describes advances in nanoparticle-based vaccines (i.e., nanovaccines) with a particular focus on polymeric particles as adjuvants and delivery vehicles. Examples of the nanovaccine approach in respiratory infections, biodefense, and cancer are discussed.

Polyanhydride nanoparticles stabilize pancreatic cancer antigen MUC4ß.

Pancreatic cancer (PC) is one of the most lethal malignancies and represents an increasing and challenging threat, especially with an aging population. The identification of immunogenic PC-specific upregulated antigens and an enhanced understanding of the immunosuppressive tumor microenvironment have provided opportunities to enable the immune system to recognize cancer cells. Due to its differential upregulation and functional role in PC, the transmembrane mucin MUC4 is an attractive target for immunotherapy. In the current study we characterized the antigen stability, antigenicity and release kinetics of a MUC4ß-nanovaccine to guide further optimization and, in vivo evaluation. Amphiphilic polyanhydride copolymers based on 20 mol % 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane and 80 mol % 1,6-bis(p-carboxyphenoxy)hexane were used to synthesize nanoparticles. Structurally stable MUC4ß protein was released from the particles in a sustained manner and characterized by gel electrophoresis and fluorescence spectroscopy. Modest levels of protein degradation were observed upon release. The released protein was also analyzed by MUC4ß-specific monoclonal antibodies using ELISA and showed no significant loss of epitope availability. Further, mice immunized with multiple formulations of combination vaccines containing MUC4ß-loaded nanoparticles generated MUC4ß-specific antibody responses. These results indicate that polyanhydride nanoparticles are viable MUC4ß vaccine carriers, laying the foundation for evaluation of this platform for PC immunotherapy.

Polyanhydride Nanoparticles Induce Low Inflammatory Dendritic Cell Activation Resulting in CD8+ T Cell Memory and Delayed Tumor Progression.

INTRODUCTION: Adjuvants and immunotherapies designed to activate adaptive immunity to eliminate infectious disease and tumors have become an area of interest aimed at providing a safe and effective strategy to prevent or eliminate disease. Existing approaches would benefit from the development of immunization regimens capable of inducing efficacious cell-mediated immunity directed toward CD8+ T cell-specific antigens. This goal is critically dependent upon appropriate activation of antigen-presenting cells (APCs) most notably dendritic cells (DCs). In this regard, polyanhydride particles have been shown to be effectively internalized by APCs and induce activation. METHODS: Here, a prophylactic vaccine regimen designed as a single-dose polyanhydride nanovaccine encapsulating antigen is evaluated for the induction of CD8+ T cell memory in a model system where antigen-specific protection is restricted to CD8+ T cells. Bone marrow-derived dendritic cells (BMDCs) are used as an in vitro model system to evaluate the magnitude and phenotype of APC activation. Primary DCs, particularly those with described ability to activate CD8+ T cells, are also evaluated for their in vitro responses to polyanhydride nanoparticles. RESULTS: Herein, polyanhydride nanoparticles are shown to induce potent in vitro upregulation of costimulatory molecules on the cell surface of BMDCs. In contrast to the classically used TLR agonists, nanoparticles did not induce large amounts of pro-inflammatory cytokines, did not induce characteristic metabolic response of DCs, nor produce innate antimicrobial effector molecules, such as nitric oxide (NO). The polyanhydride nanovaccine results in protective CD8+ T cell responses as measured by inhibition of tumor progression and survival. DISCUSSION: Together, these results suggest that the use of a polyanhydride-based nanovaccine can be an effective approach to inducing antigen-specific CD8+ T cell memory by providing antigen delivery and DC activation while avoiding overt inflammatory responses typically associated with traditional adjuvants.

Correlates of psychosocial adjustment in deaf adolescents with and without cochlear implants: a preliminary investigation.

The number of children who have received cochlear implants (CIs) has increased dramatically in the past two decades. In view of potential concerns about their psychosocial adjustment, our aim was to assess the effect of implants on the adolescents' psychosocial functioning among a group of 57 deaf adolescents with and without CIs, using published and validated measures completed by the adolescents themselves, their parents, and teachers. Adolescents with CI tended to be more hearing acculturated, whereas those without CI tended to be more Deaf acculturated. Despite some differences in background characteristics between the two groups, there were no differences between them on the psychosocial variables assessed in this study, regardless of the reporting sources. Rather than having a direct effect on the psychosocial outcomes assessed in this study, it is through the mediating effect of acculturation and school setting that CI status exerts an influence over many of this study's outcomes. Recommendations for future research are made in light of our findings.

[Treatment of faecal incontinence in surgical specialist practice]. / Behandling af faekal inkontinens i speciallaegepraksis.

INTRODUCTION: An analysis of the treatment of faecal incontinence in a surgical specialist practice with a particular interest in this disorder. MATERIAL AND METHODS: From May 2003 to December 2005, a total of 61 patients, 49 women and 12 men with a median age of 72 and 67 years, respectively, were referred for diagnosis and treatment of faecal incontinence. The median Wexner incontinence score was 11 and median quality of life score, on a visual analogue scale ranging from 0 to 10, was 5. Treatment included surgical correction of recto-anal mucosal prolapse and grade 3 to 4 haemorrhoids, medical treatment and sphincter training. Patients were followed-up by a questionnaire after a median period of 23 months (range: 18-31). RESULTS: Six patients were immediately referred for hospital treatment. Ten patients in whom the result of conservative treatment was unsatisfactory were referred for treatment in specialized colorectal departments after 3-11 months. A total of 41 of the 45 patients returned the questionnaire. The median Wexner incontinence score fell from 11 to 5 (p < 0,01) and the median quality of life score dropped from 5 to 2 (p < 0,01). A total of 38 of the 51 patients who underwent conservative treatment were satisfied with the result and did not request referral to hospital for further treatment (75%; 95% confidence limit: 60-86). CONCLUSION: Patients suffering from a moderate degree of faecal incontinence which is not obviously of traumatic origin, including childbirth, may be treated conservatively with a satisfactory result in a surgical specialist practice with special interest in this disorder.

How to determine future EHR ROI. Agent-based modeling and simulation offers a new alternative to traditional techniques.

Effectively determining the future return-on-investment of regional healthcare delivery and electronic healthcare record systems requires consideration of many alternative designs for their performance, cost and ability to meet stakeholder expectations. Successfully testing, validating and communicating the expected consequences of alternative business practices, processes, protocols and policies requires an objective analytical approach. Agent-based modeling and simulation (ABMS), a technique for determining the system-level results of complex, interacting, and often conflicting individual-level decisions, provides such an approach. ABMS of healthcare delivery can provide actionable guidance for decision makers by enabling healthcare experts to define the individual, agent-level rules of operation; allowing them to see how the agent rules play out over time in a detailed real-world context; providing them with the tools to assess the consequences of alternative plans; and giving them a clear method for communicating results to the broader stakeholder community.

[Flatufonia--or the musical anus]. / Flatufoni--eller den musikalske anus.

The art of the musical anus is reviewed in the light of its most prominent performers and of anorectal physiological aspects related to this specific musical performance.

Sacral nerve stimulation for faecal incontinence following a rectosigmoid resection for colorectal cancer.

INTRODUCTION: Following recto-sigmoid resection some patients may become faecally incontinent and remain so despite conservative treatment. This multicentre prospective study assessed the use of sacral nerve stimulation (SNS) in this group. METHODS: All patients had more than or equal to 4 days of faecal incontinence for solid or liquid stools over a 21-day period following recto-sigmoid resection for colorectal carcinoma. The operation had to have been deemed curative. They had to have failed pharmacological and biofeedback treatment. RESULTS: Three male patients met these criteria. One had had a colo-anal and two a colo-rectal anastomosis for rectal carcinoma. All patients had intact internal and external anal sphincters. Two patients had a successful temporary stimulation period and proceeded to permanent implantation. Pre-operative symptom duration was 1 year in the permanently implanted patients. They were followed up for 12 months. SNS improved the number of faecally incontinent episodes in both patients. Ability to defer was improved in both patients from 0--5 min to 5--15 min. The faecal incontinence-specific ASCRS quality of life assessment improved in all four subcategories. CONCLUSION: This study demonstrates that SNS may be effective in the treatment of patients with faecal incontinence following recto-sigmoid resection if conservative treatment has failed.

Sacral nerve stimulation for treatment of fecal incontinence in a patient with muscular dystrophy: report of a case.

Fecal incontinence is a common condition that causes major impairment of social life. Sacral nerve stimulation is a promising treatment in idiopathic fecal incontinence when conventional treatments have failed. However, new indications for sacral nerve stimulation are emerging. The present case shows that sacral nerve stimulation for treatment of fecal incontinence may be justified in other diseases in which fecal incontinence is a major problem.

Sacral nerve stimulation in fecal incontinence.

PURPOSE: The effect of sacral nerve stimulation was studied in 45 patients with fecal incontinence. METHODS: All patients were initially tested in general anesthesia. Sacral nerves 2, 3, and 4 were tested on both sides. If a perineal/perianal muscular response to sacral nerve stimulation could be obtained, electrodes were implanted for a three-week test-stimulation period. If sacral nerve stimulation resulted in at least a 50 percent reduction in incontinence episodes during the test period, a system for permanent sacral nerve stimulation was implanted. RESULTS: When tested in general anesthesia, 43 of 45 patients had a muscular response to sacral nerve stimulation and had electrodes implanted for the three-week test period. Percutaneous electrodes were used in 34 patients, and 23 of these had at least a 50 percent reduction in incontinence episodes, whereas the electrodes dislocated in 7 patients and 4 had a poor response. Permanent electrodes with percutaneous extension electrodes were used primarily in 9 patients and after dislocation of percutaneous electrodes in an additional 6 patients; 14 of these had a good result. In the last patient, no clinical response to stimulation with the permanent electrode could be obtained. A permanent stimulation system was implanted in 37 patients. After a median of six (range, 0-36) months follow-up, five patients had the system explanted: three because the clinical response faded out, and two because of infection. Incontinence score (Wexner, 0-20) for the 37 patients with a permanent system for sacral nerve stimulation was reduced from median 16 (range, 9-20) before sacral nerve stimulation to median 6 (range, 0-20) at latest follow-up ( P < 0.0001). There was no differences in effect of sacral nerve stimulation in patients with idiopathic incontinence (n = 19) compared with spinal etiology (n = 8) or obstetric cause of incontinence (n = 5). Sacral nerve stimulation did not influence anal pressures or rectal volume tolerability. CONCLUSIONS: Sacral nerve stimulation in fecal incontinence shows promising results. Patients with idiopathic, spinal etiology, or persisting incontinence after sphincter repair may benefit from this minimally invasive treatment.

Children with cochlear implants: changing parent and deaf community perspectives.

OBJECTIVE: To examine changing parent and deaf community perspectives related to pediatric cochlear implantation. DESIGN: This research is based primarily on 2 nonrandom study designs. In the first study, conducted by the Gallaudet University Research Institute, Washington, DC, in the spring of 1999, a 12-page questionnaire was distributed to 1841 parents of children with cochlear implants; 439 questionnaires were returned. In the second study, we conducted 56 interviews with parents of 62 children with implants (and 1 without). SUBJECTS: Parents of children with cochlear implants; Gallaudet University faculty, staff, students, and alumni. RESULTS: While parents frequently receive conflicting information about educational and communication options for their child, they generally support signing before and after implantation. The parents of a child with an implant have a great interest in their child's spoken language development, and most would like to have had their child receive an implant earlier. Children with implants are educated in a variety of educational settings. Mainstreamed children with implants often continue to require classroom support services, and children with implants are frequently not isolated from both deaf and hearing peers. Parents have mixed experiences when getting information from persons in the deaf community. COMMENT: Opposition to pediatric cochlear implantation within the deaf community is giving way to the perception that it is one of a continuum of possibilities for parents to consider. To ensure optimal use of the cochlear implant, parents need to remain involved in their child's social and educational development.

Sacral spinal nerve stimulation for faecal incontinence: multicentre study.

BACKGROUND: In patients with faecal incontinence in whom conservative treatment fails, options are limited for those with a functionally deficient but morphologically intact sphincter. We investigated the effect of sacral nerve stimulation on continence and quality of life. METHODS: In this multicentre prospective trial, 37 patients underwent a test stimulation period, followed by implantation of a neurostimulator for chronic stimulation in 34. Effect on continence was assessed by daily bowel-habit diaries over a 3-week period and on quality of life by the disease-specific American Society of Colon and Rectal Surgeons (ASCRS) questionnaire and the standard short form health survey questionnaire (SF-36). Every patient served as his or her own control. FINDINGS: Frequency of incontinent episodes per week fell (mean 16.4 vs 3.1 and 2.0 at 12 and 24 months; p<0.0001) for both urge and passive incontinence during median follow-up of 23.9 months. Mean number of days per week with incontinent episodes also declined (4.5 vs 1.4 and 1.2 at 12 and 24 months, p<0.0001), as did staining (5.6 vs 2.4 at 12 months; p<0.0001) and pad use (5.9 vs 3.7 at 12 months; p<0.0001). Ability to postpone defecation was enhanced (at 12 months, p<0.0001), and ability to completely empty the bowel was slightly raised during follow-up (at 12 months, p=0.4122). Quality of life improved in all four ASCRS scales (p<0.0001) and in seven of eight SF-36 scales, though only social functioning was significantly improved (p=0.0002). INTERPRETATION: Sacral nerve stimulation greatly improves continence and quality of life in selected patients with morphologically intact or repaired sphincter complex offering a treatment for patients in whom treatment options are limited.

[Sacral nerve stimulation in fecal incontinence]. / Sakralnervestimulation ved analinkontinens.

INTRODUCTION: Sacral nerve stimulation for the treatment of faecal incontinence has gained increasing use in Europe over the last two years. Experience with the first patients treated in Denmark is described here. MATERIAL AND METHODS: Fourteen patients with severe faecal incontinence were given sacral nerve stimulation. The first treatment was temporary, and if this was successful they had a device for permanent stimulation implanted. RESULTS: The result of the test stimulation was good in ten of the 14 patients and a permanent system was implanted. After a median of 4.5 months' stimulation, nine of the ten patients continued to respond to respond well. DISCUSSION: Sacral nerve stimulation in the treatment of faecal incontinence shows promising results. Compared to other more advanced forms of treatment, this method is minimally invasive.

Long-term efficacy of dynamic graciloplasty for fecal incontinence.

PURPOSE: Patients with end-stage fecal incontinence in whom all standard medical and surgical treatment has failed or is not expected to be effective can be treated by dynamic graciloplasty. The aim of this study was to review the long-term efficacy data. METHODS: Success was defined as a greater than 50 percent decrease in the frequency of incontinent episodes. Measured physiologic parameters included enema retention time and the difference in resting and squeezing pressures with and without stimulation. Measured quality-of-life parameters included the Medical Outcomes Study Short Form 36 Health Status Questionnaire, a Fecal Incontinence TyPE Specification, the Zung Self-Rating Depression Scale, the "state" portion of the State-Trait Anxiety Inventory, and the Visual Analog Scale, which were administered at baseline and through follow-up. Independent monitors collected data as part of a multicenter trial for patients who underwent dynamic graciloplasty from May 1993 to November 1999. RESULTS: There were 129 patients entered in the study, 115 of whom met eligibility criteria and were included in the efficacy outcome analysis. Twenty-seven patients entered the study with a preexisting functioning stoma; the remaining 88 patients did not have a functioning stoma at the time of enrollment. Success was achieved in 62 percent of nonstoma patients at 12 months; these results were sustained at 18-month and 24-month follow-up assessments (55 and 56 percent, respectively). The success rate in the stoma patients increased from 37.5 percent (9 of 24 patients) at 12 months to 62 percent (13 of 21 patients) at 18 months and was 43 percent at 24 months (9 of 21 patients), which reflects the increased number of patients whose stomas were closed. Although the measured physiologic continence parameters generally improved, these changes did not correlate with continence outcome. The group of patients (stoma and nonstoma) who underwent dynamic graciloplasty showed statistically significant improvements in quality of life as measured by Medical Outcomes Study Short Form 36 physical function (P = 0.006) and social functioning (P = 0.02) assessment. CONCLUSIONS: Dynamic graciloplasty was successful in the majority of patients with end-stage fecal incontinence. This result was usually achieved by 12 months after surgery in patients who did not have stomas and by 18 months in patients who had stomas at the time of dynamic graciloplasty surgery. These various improvements conferred by dynamic graciloplasty persisted during the two-year follow-up.

[Chronic idiopathic anal pain syndrome]. / Kronisk idiopatisk analt smertesyndrom.

INTRODUCTION: The study was undertaken to analyse whether intra-anal ultrasound examination, anorectal physiological evaluation, and histopathological examination of patients suffering from chronic idiopathic anal pain presented any common features and to analyse the results of various treatments. MATERIAL AND METHODS: Eighteen patients who met the criteria for chronic idiopathic anal pain were studied. Treatment included 0.2% glyceryl nitrate ointment, ultrasound guided injection of botulinum toxin in the intrasphincteric space, analgesics, and colostomy. RESULTS: Anal physiological examinations were normal in all but one patient. Intra-anal ultrasonography demonstrated abnormalities in 12 patients. Defecography showed in one patient a small distal invagination but was otherwise normal. Glyceryl nitrate ointment had an effect in one of four patients, and botulinum toxin in four of nine. Two patients needed a colostomy for definitive pain relief, and in 12 of the 18 patients the final treatment was analgesics. DISCUSSION: The methods used in this study did not contribute to the understanding of the pathogenesis of chronic anal pain. The treatment is experimental, but injection of botulinum toxin may be tried on the hypothesis that dystonia in the anal sphincter may play a pathogenetic role.