A Pilot Study of Pembrolizumab in Combination With Y90 Radioembolization in Subjects With Poor Prognosis Hepatocellular Carcinoma.

BACKGROUND: Combination checkpoint inhibition therapy with yttrium-90 (Y90) radioembolization represents an emerging area of interest in the treatment of advanced hepatocellular carcinoma (HCC). HCRN GI15-225 is an open-label, single-arm multicenter, pilot study (NCT03099564). METHODS: Eligible patients had poor prognosis, localized HCC defined as having portal vein thrombus, multifocal disease, and/or diffuse disease that were not eligible for liver transplant or surgical resection. Patients received pembrolizumab 200 mg intravenously every 3 weeks in conjunction with glass yttrium-90 (Y90) radioembolization TheraSphere. Primary endpoint was 6-month progression-free survival (PFS6) per RECIST 1.1. Secondary endpoints included time to progression (TTP), objective response rate (ORR), overall survival (OS), and safety/tolerability. RESULTS: Between October 23, 2017 and November 24, 2020, 29 patients were enrolled: 2 were excluded per protocol. Fifteen of the remaining 27 patients were free of progression at 6 months (55.6%; 95% CI, 35.3-74.5) with median PFS 9.95 months (95% CI, 4.14-15.24) and OS 27.30 months (95% CI, 10.15-39.52). One patient was not evaluable for response due to death; among the remaining 26 patients, ORR was 30.8% (95% CI, 14.3-51.8) and DCR was 84.6% (95% CI, 65.1-95.6). CONCLUSION: In patients with localized, poor prognosis HCC, pembrolizumab in addition to glass Y90 radioembolization demonstrated promising efficacy and safety consistent with prior observations (ClinicalTrials.gov Identifier: NCT03099564; IRB Approved: 16-3255 approved July 12, 2016).

General practice and specialist palliative care teams: an exploration of their working relationship from the perspective of clinical staff working in New Zealand.

With the future focus on palliative and end-of-life care provision in the community, the role of the general practice team and their relationship with specialist palliative care providers is key to responding effectively to the projected increase in palliative care need. Studies have highlighted the potential to improve co-ordination and minimise fragmentation of care for people living with palliative care need through a partnership between generalist services and specialist palliative care. However, to date, the exact nature of this partnership approach has not been well defined and debate exists about how to make such partnerships work successfully. The aim of this study was to explore how general practice and specialist palliative care team (SPCT) members view their relationship in terms of partnership working. Five focus group discussions with general practices and SPCT members (n = 35) were conducted in 2012 in two different regions of New Zealand and analysed using a general inductive approach. The findings indicate that participants' understanding of partnership working was informed by their identity as a generalist or specialist, their existing rules of engagement and the approach they took towards sustaining the partnership. Considerable commitment to partnership working was shown by all participating teams. However, their working relationship was based primarily on trust and personal liaison, with limited formal systems in place to enable partnership working. Tensions between the cultures of 'generalism' and 'specialism' also provided challenges for those endeavouring to meet palliative care need collaboratively in the community. Further research is required to better understand the factors associated with successful partnership working between general practices and specialist palliative care in order to develop robust strategies to support a more sustainable model of community palliative care.

Histoplasmosis mimicking primary lung neoplasm.

A 70-year-old man, ex-smoker with a 3-pack-year smoking history, presented with a 5-week history of persistent cough. There were no positive findings on clinical examination. The patient's chest X-ray showed a nodular density in the right lung, initially thought to be malignant. After an extensive workup which included CT-guided lung biopsies, bronchoscopies, positron emission tomography scanning, among many other investigations, discussion at the respiratory multidisciplinary team meeting, and a right upper lobe lung resection, a diagnosis of histoplasmosis was performed.

Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse.

Escape of prostate cancer (PCa) cells from ionizing radiation-induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.

Evaluating the role and value of a national office to coordinate Liverpool Care Pathway implementation in New Zealand.

BACKGROUND: New Zealand is one of 20 countries implementing the Liverpool Care Pathway for the Dying Patient (LCP) to improve quality care of the dying. The LCP is an integrated care pathway that guides healthcare professionals to deliver evidence-based, best practice care to dying patients and their families in the last days and hours of life, irrespective of diagnosis or care setting. Currently the LCP Central Team coordinates LCP implementation and dissemination for all international collaborating countries except New Zealand, from its base in Liverpool in the UK. With the support of the LCP Central Team, New Zealand is the first country to establish a National Office to assume the responsibility for promoting the sustainable implementation of the LCP within its own borders and context of end-of-life care. AIMS: To evaluate the role and value of a New Zealand National LCP Office (NZ LCP Office) from the perspective of key stakeholders. METHODS: A mixed methods approach was applied, which intentionally combined two different survey methods in sequence. In Phase 1, key stakeholders (n = 28) were interviewed to explore their perspectives for the role and value of the NZ LCP Office. Findings from Phase 1 informed an online questionnaire distributed to a larger group of key stakeholders (n = 36, 62% response rate) in Phase 2. RESULTS: When considering the role of the NZ LCP Office, key stakeholders identified two core services as highly important, namely the promotion of the sustainable implementation of LCP and the provision of a national LCP information network. Other key initiatives identified by key stakeholders as important included the NZ LCP Office continuing to work in consultation and collaboration with the LCP Central Team and to be a voice for end-of-life care issues in New Zealand. The value or benefit of the NZ LCP Office was endorsed, in that service performance was rated as good or very good by at least 90% of the respondents, plus 40% of participants perceived the NZ LCP Office had contributed to positive changes in LCP document compliance, program integrity and improvement in care of the dying to a moderate extent. CONCLUSION: Having a National LCP Office in New Zealand to coordinate sustainable LCP implementation and maintain the integrity of the LCP program within the context of the country's own healthcare system was seen as crucial by key stakeholders.

Palliative Care Partnership: a successful model of primary/secondary integration.

The health reforms of the 1990s and early 21st century have seen unheralded change in the delivery of health services in New Zealand, and the concept of integration of primary and specialist or secondary services into a seamless health delivery service is one of the key planks of national and regional healthcare planning in New Zealand. This paper reports on a successful primary secondary integration project. Starting with commentary on the historical difficulties that acted as a catalyst to this initiative, it reports on the development process, how the model works in practice, and outlines some initial evaluation work done as part of its quality improvement component. Given the collaborative nature of this project and its scope across primary and specialist care sectors, the authors believe this model has implications and relevance across a wide spectrum of the New Zealand health service.