Morbidity and mortality after antireflux and hiatal hernia surgery across a spectrum of ages.

BACKGROUND: Antireflux surgery (ARS) and hiatal hernia repair (HHR) are common surgical procedures with modest morbidity. Increasing age is a risk factor for complications; however, details regarding acute morbidity are lacking. This study aimed to describe the incidence rates and types of morbidities across the spectrum of ages. METHODS: A total of 2342 consecutive cases were retrospectively reviewed from 2003 to 2020 for 30-day complications. All complications were assessed using the Clavien-Dindo (CD) grading system. Patients were divided into 5 age groups: ≤59, 60 to 69, 70 to 79, 80 to 89, and ≥90 years. RESULTS: The numbers per age group were 1100 patients aged ≤59 years, 684 patients aged 60 to 69 years, 458 patients aged 70 to 79 years, 458 patients aged 80 to 89 years, and 6 patients aged ≥90 years. A total of 427 complications (18.2%) occurred, including 2 mortalities, each in the 60- to 69-year age group and the 70- to 79-year age group, for a mortality rate of 0.2%. The complication rate increased from 13.5% (149) in patients aged ≤59 years to 35.0% (35) in patients aged ≥80 years (P = .006), with CD grades I and II accounting for >70% of complications, except in patients aged ≥80 years (57.1%). CD grades IIIa and IIIb were higher in patients aged ≥80 years (26.5% [P = .001] and 11.8% [P = .021], respectively). CD grade IVa and IVb complications were rare overall. CONCLUSION: There is a modest rate of morbidity that increases as patients age, regardless of hernia type, elective or primary surgery, with most being minor complications (CD grade≤II). Our data should help patients, referring physicians, and surgeons counsel patients regarding the effect of increasing age in ARS and HHR.

Thirty- and 90-Day Morbidity and Mortality by Clavien-Dindo 30 and 90 Days after Surgery for Antireflux and Hiatal Hernia.

BACKGROUND: The historic morbidity and mortality rates of anti-reflux and hiatal hernia surgery are reported as 3-21% and 0.2-0.5%, respectively. These data come from either large national/population level or small institutional studies, with the former focusing on broad 30-day outcomes while lacking granular data on complications and their severity. Institutional studies tend to focus on long-term and quality of life outcomes. Our objective is to describe and evaluate the incidence of 30 and 90-day morbidity and mortality in a large, single institution dataset. STUDY DESIGN: We retrospectively reviewed 2342 cases of anti-reflux and hiatal hernia surgery from 2003-2020 for intra-operative complications causing post-operative sequelae, as well as morbidity and mortality within 90 days. All complications were graded using the Clavien-Dindo (CD) Grading System. The highest-grade of complication was used per patient during 30-day and 31-90-day intervals. RESULTS: Out of 2342 patients, the overall 30-day morbidity and mortality rates were 18.2% (427/2342) and 0.2% (4/2342), respectively. Most of the complications were CD<3a at 13.1% (306/2342). In the 31-90-day post-operative period, morbidity and mortality rates decreased to 3.1% (78/2338) and 0.09% (2/2338). CD<3a complications accounted for 1.9% (42/2338). CONCLUSIONS: Anti-reflux and hiatal hernia surgery are safe operations with rare mortality and modest rates of morbidity. However, the majority of complications patients experience are minor (CD<3a) and are easily managed. A minority of patients will experience major complications (CD≥3a) that require additional procedures and management to secure a safe outcome. These data are helpful to inform patients of the risks of surgery, and guide physicians for optimal consent.

The impact of a regionally based translational cancer research collaborative in Australia using the FAIT methodology.

BACKGROUND: Translating research, achieving impact, and assessing impact are important aspirations for all research collaboratives but can prove challenging. The Hunter Cancer Research Alliance (HCRA) was funded from 2014 to 2021 to enhance capacity and productivity in cancer research in a regional centre in Australia. This study aimed to assess the impact and benefit of the HCRA to help inform future research investments of this type. METHOD: The Framework to Assess the Impact from Translational health research (FAIT) was selected as the preferred methodology. FAIT incorporates three validated methodologies for assessing impact: 1) Modified Payback; 2) Economic Analysis; and 3) Narrative overview and case studies. All three FAIT methods are underpinned by a Program Logic Model. Data were collected from HCRA and the University of Newcastle administrative records, directly from HCRA members, and website searches. RESULTS: In addition to advancing knowledge and providing capacity building support to members via grants, fellowships, scholarships, training, events and targeted translation support, key impacts of HCRA-member research teams included: (i) the establishment of a regional biobank that has distributed over 13,600 samples and became largely self-sustaining; (ii) conservatively leveraging $43.8 M (s.a.$20.5 M - $160.5 M) in funding and support from the initial $9.7 M investment; (iii) contributing to clinical practice guidelines and securing a patent for identification of stem cells for endometrial cell regeneration; (iv) shifting the treatment paradigm for all tumour types that rely on nerve cell innervation, (v) development and implementation of the world's first real-time patient treatment verification system (Watchdog); (vi) inventing the effective 'EAT' psychological intervention to improve nutrition and outcomes in people experiencing radiotherapy for head and neck cancer; (vi) developing effective interventions to reduce smoking rates among priority groups, currently being rolled out to disadvantaged populations in NSW; and (vii) establishing a Consumer Advisory Panel and Consumer Engagement Committee to increase consumer involvement in research. CONCLUSION: Using FAIT methodology, we have demonstrated the significant impact and downstream benefits that can be achieved by the provision of infrastructure-type funding to regional and rural research collaboratives to help address inequities in research activity and health outcomes and demonstrates a positive return on investment.

Understanding the value of brain donation for research to donors, next-of-kin and clinicians: A systematic review.

PURPOSE: Post-mortem brain donation affords the opportunity to characterise disease by exploring global neuropathological changes. Such opportunities are essential to progress knowledge of CNS tumours such as Glioblastoma. A comprehensive understanding of the experience of consenting to brain donation is crucial to maximising consent rates while providing patient-centred care. This review aimed to synthesise the reported facilitators and barriers according to potential donors, next-of-kin (NOK) and clinician respondents. DESIGN: Database searches included Embase, Medline, PsycINFO, Psychology and Behavioural Science and Scopus. Search terms focused on motivations, attitudes and psychosocial experiences of brain donation. Exclusions included organ transplantation and brain death. All studies were assessed for quality and validity using tools from the Joanna Briggs Institute. To determine perceptions of benefit and harm, a method guided by the thematic analysis of Braun and Clarke was employed to reflexively assess and identify common themes and experiences. RESULTS: 40 studies (15 qualitative, 25 quantitative) were included involving participants with paediatric cancer, neurodegenerative and psychological diseases. Perceptions of benefit included benefit to future generations, aiding scientific research, avoidance of waste, improved treatments and the belief that donation will bring consolation or aid in the grieving process. Perceptions of harm included a perceived conflict with religious beliefs, disfigurement to the donor, emotional distress at the time of autopsy and discord or objections within the family. CONCLUSION: Brain donation can afford a sense of purpose, meaning and empowerment for donors and their loved ones. Careful strategies are required to mitigate or reduce potential harms during the consent process.

Targeting XBP1 mRNA splicing sensitizes glioblastoma to chemotherapy.

Glioblastoma (GBM) is the most frequent and deadly primary brain tumor in adults. Temozolomide (TMZ) is the standard systemic therapy in GBM but has limited and restricted efficacy. Better treatments are urgently needed. The role of endoplasmic reticulum stress (ER stress) is increasingly described in GBM pathophysiology. A key molecular mediator of ER stress, the spliced form of the transcription factor x-box binding protein 1 (XBP1s) may constitute a novel therapeutic target; here we report XBP1s expression and biological activity in GBM. Tumor samples from patients with GBM (n = 85) and low-grade glioma (n = 20) were analyzed by immunohistochemistry for XBP1s with digital quantification. XBP1s expression was significantly increased in GBM compared to low-grade gliomas. XBP1s mRNA showed upregulation by qPCR analysis in a panel of patient-derived GBM cell lines. Inhibition of XBP1 splicing using the small molecular inhibitor MKC-3946 significantly reduced GBM cell viability and potentiated the effect of TMZ in GBM cells, particularly in those with methylated O6-methylguanine-DNA methyl transferase gene promoter. GBM cells resistant to TMZ were also responsive to MKC-3946 and the long-term inhibitory effect of MKC-3946 was confirmed by colony formation assay. In conclusion, this data reveals that XBP1s is overexpressed in GBM and contributes to cancer cell growth. XBP1s warrants further investigation as a clinical biomarker and therapeutic target in GBM.

The Membrane Protein Sortilin Is a Potential Biomarker and Target for Glioblastoma.

Glioblastoma (GBM) is a devastating brain cancer with no effective treatment, and there is an urgent need for developing innovative biomarkers as well as therapeutic targets for better management of the disease. The membrane protein sortilin has recently been shown to participate in tumor cell invasiveness in several cancers, but its involvement and clinical relevance in GBM is unclear. In the present study, we explored the expression of sortilin and its potential as a clinical biomarker and therapeutic target for GBM. Sortilin expression was investigated by immunohistochemistry and digital quantification in a series of 71 clinical cases of invasive GBM vs. 20 non-invasive gliomas. Sortilin was overexpressed in GBM and, importantly, higher expression levels were associated with worse patient survival, pointing to sortilin tissue expression as a potential prognostic biomarker for GBM. Sortilin was also detectable in the plasma of GBM patients by enzyme-linked immunosorbent assay (ELISA), but no differences were observed between sortilin levels in the blood of GBM vs. glioma patients. In vitro, sortilin was detected in 11 brain-cancer-patient-derived cell lines at the anticipated molecular weight of 100 kDa. Interestingly, targeting sortilin with the orally bioavailable small molecule inhibitor AF38469 resulted in decreased GBM invasiveness, but cancer cell proliferation was not affected, showing that sortilin is targetable in GBM. Together, these data suggest the clinical relevance for sortilin in GBM and support further investigation of GBM as a clinical biomarker and therapeutic target.

ProNGF Expression and Targeting in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most lethal adult brain cancer. Temozolomide (TMZ), the standard chemotherapeutic drug used in GBM, has limited benefit and alternate therapies are needed to improve GBM treatment. Nerve growth factor (NGF) and its precursor proNGF are increasingly recognized as stimulators of human tumor progression. The expression and stimulatory effect of NGF on GBM cell growth has previously been reported, but the status of proNGF in GBM is unreported. In this study, we have investigated proNGF expression and biological activity in GBM. A clinical cohort of GBM (n = 72) and low-grade glioma (n = 20) was analyzed by immunohistochemistry for proNGF and digital quantification. ProNGF expression was significantly increased in GBM compared to low grade gliomas and proNGF was also detected in patient plasma samples. ProNGF was also detected in most GBM cell lines by Western blotting. Although anti-proNGF blocking antibodies inhibited cell growth in GBM cells with methylated MGMT gene promoter, targeting proNGF could not potentiate the efficacy of TMZ. In subcutaneous xenograft of human GBM cells, anti-proNGF antibodies slightly reduced tumor volume but had no impact on TMZ efficacy. In conclusion, this data reveals that proNGF is overexpressed in GBM and can stimulate cancer cell growth. The potential of proNGF as a clinical biomarker and therapeutic target warrants further investigations.

Postmortem brain donations vs premortem surgical resections for glioblastoma research: viewing the matter as a whole.

There have been limited improvements in diagnosis, treatment, and outcomes of primary brain cancers, including glioblastoma, over the past 10 years. This is largely attributable to persistent deficits in understanding brain tumor biology and pathogenesis due to a lack of high-quality biological research specimens. Traditional, premortem, surgical biopsy samples do not allow full characterization of the spatial and temporal heterogeneity of glioblastoma, nor capture end-stage disease to allow full evaluation of the evolutionary and mutational processes that lead to treatment resistance and recurrence. Furthermore, the necessity of ensuring sufficient viable tissue is available for histopathological diagnosis, while minimizing surgically induced functional deficit, leaves minimal tissue for research purposes and results in formalin fixation of most surgical specimens. Postmortem brain donation programs are rapidly gaining support due to their unique ability to address the limitations associated with surgical tissue sampling. Collecting, processing, and preserving tissue samples intended solely for research provides both a spatial and temporal view of tumor heterogeneity as well as the opportunity to fully characterize end-stage disease from histological and molecular standpoints. This review explores the limitations of traditional sample collection and the opportunities afforded by postmortem brain donations for future neurobiological cancer research.

Mind Over Matter: Confronting Challenges in Post-Mortem Brain Biobanking for Glioblastoma Multiforme.

Over the past 10 years, there has been limited progress for the treatment of brain cancer and outcomes for patients are not much improved. For brain cancer researchers, a major obstacle to biomarker driven research is limited access to brain cancer tissue for research purposes. The Mark Hughes Foundation Brain Biobank is one of the first post-mortem adult brain banks in Australia to operate with protocols specifically developed for brain cancer. Located within the Hunter New England Local Health District and operated by Hunter Cancer Biobank, the boundaries of service provided by the Brain Bank extend well into the surrounding regional and rural areas of the Local Health District and beyond. Brain cancer biobanking is challenging. There are conflicting international guidelines for best practice and unanswered questions relating to scientific, psychosocial and operational practices. To address this challenge, a best practice model was developed, informed by a consensus of existing data but with consideration of the difficulties associated with operating in regional or resource poor settings. The regional application of this model was challenged following the presentation of a donor located in a remote area, 380km away from the biobank. This required biobank staff to overcome numerous obstacles including long distance patient transport, lack of palliative care staff, death in the home and limited rural outreach services. Through the establishment of shared goals, contingency planning and the development of an informal infrastructure, the donation was facilitated within the required timeframe. This experience demonstrates the importance of collaboration and networking to overcome resource insufficiency and geographical challenges in rural cancer research programmes.

Development, implementation and user experience of the Veterans Health Administration (VHA) dialysis dashboard.

BACKGROUND: Adults with end-stage renal disease (ESRD) requiring chronic dialysis continue to suffer from poor health outcomes and represent a population rightfully targeted for quality improvement. Electronic dashboards are increasingly used in healthcare to facilitate quality measurement and improvement. However, detailed descriptions of the creation of healthcare dashboards are uncommonly available and formal inquiry into perceptions, satisfaction, and utility by clinical users has been rarely conducted, particularly in the context of dialysis care. Therefore, we characterized the development, implementation and user experience with Veterans Health Administration (VHA) dialysis dashboard. METHODS: A clinical-quality dialysis dashboard was implemented, which displays clinical performance measures (CPMs) for Veterans with ESRD receiving chronic hemodialysis at all VHA facilities. Data on user experience and perceptions were collected via an e-mail questionnaire to dialysis medical directors and nurse managers at these facilities. RESULTS: Since 2016 the dialysis dashboard reports monthly on CPMs for approximately 3000 Veterans receiving chronic hemodialysis across 70 VHA dialysis facilities. Of 141 dialysis medical directors and nurse managers, 61 completed the questionnaire. Sixty-six percent of respondents did not find the dashboard difficult to access, 64% agreed that it is easy to use, 59% agreed that its layout is good, and the majority agreed that presentation of data is clear (54%), accurate (56%), and up-to-date (54%). Forty-eight percent of respondents indicated that it helped them improve patient care while 12% did not. Respondents indicated that they used the dialysis dashboard for clinical reporting (71%), quality assessment/performance improvement (QAPI) (62%), and decision-making (23%). CONCLUSIONS: Most users of the VHA dialysis dashboard found it accurate, up-to-date, easy to use, and helpful in improving patient care. It meets diverse user needs, including administrative reporting, clinical benchmarking and decision-making, and quality assurance and performance improvement (QAPI) activities. Moreover, the VHA dialysis dashboard affords national-, regional- and facility-level assessments of quality of care, guides and motivates best clinical practices, targets QAPI efforts, and informs and promotes population health management improvement efforts for Veterans receiving chronic hemodialysis.

Targeting Access to Kidney Care Via Telehealth: The VA Experience.

The Veterans Affairs (VA) is the largest integrated health care system in the United States and is responsible for the care of a population with a disproportionately high rate of CKD. As such, ensuring access to kidney health services is a VA imperative. One facet of the VA's strategy to reduce CKD is to leverage the use of teletechnology to expand the VA's outreach to Veterans with kidney disease. A wide array of teletechnology services have been deployed to both pull in Veterans and push out kidney health services to Veterans in their preferred health care venue. Teletechnology, thus, expands Veteran choice, facilitates their access to care, and furthers the goal of delivering patient-centered kidney specialty care. The VA has demonstrated the feasibility of virtual delivery of kidney specialty care services and education via synchronous and asynchronous approaches. The challenges ahead include determining the relative health care value of kidney telehealth services, identifying Veterans most likely to benefit from specific technologies and optimizing the adoption of effective kidney telehealth services by both providers and patients alike to ensure optimal and timely kidney health care delivery.