Strengthening rural community water safety planning in Pacific Island countries: evidence and lessons from Solomon Islands, Vanuatu, and Fiji.

Pacific Island Countries (PICs) collectively have the lowest rates of access to safely managed or basic drinking water and sanitation globally. They are also the least urbanised, have dynamic socioeconomic and increasing climate-linked challenges. Community-based water managers need to respond to variability in water availability and quality caused by a range of hazards. Water Safety Planning (WSP), a widely adopted approach to assessing water supply, offers a risk-based approach to mitigating both existing and future hazards. WSP is adaptable, and making modifications to prescribed WSP to adapt it to the local context is common practice. Within the Pacific Community Water Management Plus research project, we used formative research and co-development processes to understand existing local modifications, whether further modifications are required, and, to develop additional modifications to WSP in Fiji, Vanuatu and Solomon Islands. The types of additional local modifications we recommend reflect the unique context of PICs, including adjusting for community management of water supplies and required collective action, community governance systems, levels of social cohesion in communities, and preferred adult-learning pedagogies. Incorporating modifications that address these factors into future WSP will improve the likelihood of sustained and safe community water services in Pacific and similar contexts.

Solomon Islands Oncology Unit: Sustainability in Terms of Outcomes.

Bush et al emphasize that the key to establishing enduring and efficient global health systems lies in prioritizing local stakeholders and, above all, the welfare of patients.

UK and Ireland Joint Advisory Group (JAG) consensus statements for training and certification in diagnostic endoscopic ultrasound (EUS).

BACKGROUND AND AIMS: International endoscopy societies vary in their approach for credentialing individuals in endoscopic ultrasound (EUS) to enable independent practice; however, there is no consensus in this or its implementation. In 2019, the Joint Advisory Group on GI Endoscopy (JAG) commissioned a working group to examine the evidence relating to this process for EUS. The aim of this was to develop evidence-based recommendations for EUS training and certification in the UK. METHODS: Under the oversight of the JAG quality assurance team, a modified Delphi process was conducted which included major stakeholders from the UK and Ireland. A formal literature review was made, initial questions for study were proposed and recommendations for training and certification in EUS were formulated after a rigorous assessment using the Grading of Recommendation Assessment, Development and Evaluation tool and subjected to electronic voting to identify accepted statements. These were peer reviewed by JAG and relevant stakeholder societies before consensus on the final EUS certification pathway was achieved. RESULTS: 39 initial questions were proposed of which 33 were deemed worthy of assessment and finally formed the key recommendations. The statements covered four key domains, such as: definition of competence (13 statements), acquisition of competence (10), assessment of competence (5) and postcertification mentorship (5). Key recommendations include: (1) minimum of 250 hands-on cases before an assessment for competency can be made, (2) attendance at the JAG basic EUS course, (3) completing a minimum of one formative direct observation of procedural skills (DOPS) every 10 cases to allow the learning curve in EUS training to be adequately studied, (4) competent performance in summative DOPS assessments and (5) a period of mentorship over a 12-month period is recommended as minimum to support and mentor new service providers. CONCLUSIONS: An evidence-based certification pathway has been commissioned by JAG to support and quality assure EUS training. This will form the basis to improve quality of training and safety standards in EUS in the UK and Ireland.

A single microbubble formulation carrying 5-fluorouridine, Irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction.

FOLFIRINOX and FOLFOXIRI are combination chemotherapy treatments that incorporate the same drug cocktail (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) but exploit an altered dosing regimen when used in the management of pancreatic and colorectal cancer, respectively. Both have proven effective in extending life when used to treat patients with metastatic disease but are accompanied by significant adverse effects. To facilitate improved tumour-targeting of this drug combination, an ultrasound responsive microbubble formulation loaded with 5-fluorouridine, irinotecan and oxaliplatin (FIRINOX MB) was developed and its efficacy tested, together with the non-toxic folinic acid, in preclinical murine models of pancreatic and colorectal cancer. A significant improvement in tumour growth delay was observed in both models following ultrasound targeted microbubble destruction (UTMD) mediated FIRINOX treatment with pancreatic tumours 189% and colorectal tumours 82% smaller at the conclusion of the study when compared to animals treated with a standard dose of FOLFIRINOX. Survival prospects were also improved for animals in the UTMD mediated FIRINOX treatment group with an average survival of 22.17 ± 12.19 days (pancreatic) and 44.40 ± 3.85 days (colorectal) compared to standard FOLFIRINOX treatment (15.83 ± 4.17 days(pancreatic) and 37.50 ± 7.72 days (colon)). Notably, this improved efficacy was achieved using FIRINOX MB that contained 5-fluorouricil, irinotecan and oxaliplatin loadings that were 13.44-fold, 9.19-fold and 1.53-fold lower than used for the standard FOLFIRINOX treatment. These results suggest that UTMD enhances delivery of FIRINOX chemotherapy, making it significantly more effective at a substantially lower dose. In addition, the reduced systemic levels of 5-fluorouracil, irinotecan and oxaliplatin should also make the treatment more tolerable and reduce the adverse effects often associated with this treatment.

Sonodynamic therapy complements PD-L1 immune checkpoint inhibition in a murine model of pancreatic cancer.

The emergence of immune checkpoint inhibitors (ICI's) in the past decade has proven transformative in the area of immuno-oncology. The PD-1/PD-L1 axis has been particularly well studied and monoclonal antibodies developed to block either the receptor (anti PD-1) or its associated ligand (anti PD-L1) can generate potent anti-tumour immunity in certain tumour models. However, many "immune cold" tumours remain unresponsive to ICI's and strategies to stimulate the adaptive immune system and make these tumours more susceptible to ICI treatment are currently under investigation. Sonodynamic therapy (SDT) is a targeted anti-cancer treatment that uses ultrasound to activate a sensitiser with the resulting generation of reactive oxygen species (ROS) causing direct cell death by apoptosis and necrosis. SDT has also been shown to stimulate the adaptive immune system in a pre-clinical model of colorectal cancer. In this manuscript, we investigate the ability of microbubble mediated SDT to control tumour growth in a bilateral tumour mouse model of pancreatic cancer by treating the target tumour with SDT and observing the effects at the off-target untreated tumour. The results demonstrated a significant 287% decrease in tumour volume when compared to untreated animals 11 days following the initial treatment with SDT, which reduced further to 369% when SDT was combined with anti-PD-L1 ICI treatment. Analysis of residual tumour tissues remaining after treatment revealed increased levels of infiltrating CD4+ and CD8+ T-lymphocytes (respectively 4.65 and 3.16-fold more) in the off-target tumours of animals where the target tumour was treated with SDT and anti-PD-L1, when compared to untreated tumours. These results suggest that SDT treatment elicits an adaptive immune response that is potentiated by the anti-PD-L1 ICI in this particular model of pancreatic cancer.

Synthesis of a gemcitabine-modified phospholipid and its subsequent incorporation into a single microbubble formulation loaded with paclitaxel for the treatment of pancreatic cancer using ultrasound-targeted microbubble destruction.

Gemcitabine and nab-paclitaxel (Abraxane®) is a standard of care chemotherapy combination used in the treatment of patients with advanced pancreatic cancer. While the combination has shown a survival benefit when compared to gemcitabine monotherapy, it is associated with significant off-target toxicity. Ultrasound targeted microbubble destruction (UTMD) has emerged as an effective strategy for the site-specific deposition of drug-payloads. However, loading a single microbubble formulation with two drug payloads can be challenging and often involves several manipulations post-microbubble preparation that can be cumbersome and generally results in low / inconsistent drug loadings. In this manuscript, we report the one-pot synthesis of a gemcitabine functionalised phospholipid and use it to successfully generate stable microbubble formulations loaded with gemcitabine (Lipid-Gem MB) or a combination of gemcitabine and paclitaxel (Lipid-Gem-PTX MB). Efficacy of the Lipid-Gem MB and Lipid-Gem-PTX MB formulations, following ultrasound (US) stimulation, was evaluated in a three-dimensional (3D) PANC-1 spheroid model of pancreatic cancer and a mouse model bearing ectopic BxPC-3 tumours. The results demonstrated a significant reduction in the cell viability in spheroids for both formulations reducing from 90 ± 10% to 62 ± 5% for Lipid-Gem MB and 84 ± 10% to 30 ± 6% Lipid-Gem-PTX MB following US irradiation. When compared with a clinically relevant dose of free gemcitabine and paclitaxel (i.e. non-particle bound) in a BxPC-3 murine pancreatic tumour model, both formulations also improved tumour growth delay with tumours 40 ± 20% and 40 ± 30% smaller than the respective free drug formulation when treated with Lipid-Gem MB and Lipid-Gem-PTX MB respectively, at the conclusion of the experiment. These results highlight the potential of UTMD mediated Gem / PTX as a treatment for pancreatic cancer and the facile preparation of Lipid-Gem-PTX MBs using a gemcitabine functionalised lipid should expedite clinical translation of this technology.

An ultrasound responsive microbubble-liposome conjugate for targeted irinotecan-oxaliplatin treatment of pancreatic cancer.

Survival rates in pancreatic cancer have remained largely unchanged over the past four decades with less than 5% of patients surviving five years following initial diagnosis. FOLFIRINOX chemotherapy, a combination of folinic acid, 5-fluoruracil, irinotecan and oxaliplatin, has shown the greatest survival benefit for patients with advanced disease but is only indicated for those with good physical performance status due to its extreme off-target toxicity. Ultrasound targeted microbubble destruction (UTMD) has emerged as an effective strategy for the targeted delivery of drug payloads to solid tumours and involves using low intensity ultrasound to disrupt (burst) MBs in the tumour vasculature, releasing encapsulated or attached drugs in a targeted manner. In this manuscript, we describe the preparation of a microbubble-liposome complex (IRMB-OxLipo) carrying two of the three cytotoxic drugs present in the FOLFIRINOX combination, namely irinotecan and oxaliplatin. Efficacy of the IRMB-OxLipo complex following UTMD was determined in Panc-01 3D spheroid and BxPC-3 human xenograft murine models of pancreatic cancer. The results revealed that tumours treated with the IRMB-OxLipo complex and ultrasound were 136% smaller than tumours treated with the same concentration of irinotecan/oxaliplatin but delivered in a conventional manner, i.e. as a non-complexed mixture. This suggests that UTMD facilitates a more effective delivery of irinotecan/oxaliplatin improving the overall effectiveness of this drug combination and to the best of our knowledge, is the first reported example of a microbubble-liposome complex used to deliver these two chemotherapies.

Gemcitabine loaded microbubbles for targeted chemo-sonodynamic therapy of pancreatic cancer.

Pancreatic cancer remains one of the most lethal forms of cancer with a 10-year survival of <1%. With little improvement in survival rates observed in the past 40 years, there is a significant need for new treatments or more effective strategies to deliver existing treatments. The antimetabolite gemcitabine (Gem) is the most widely used form of chemotherapy for pancreatic cancer treatment, but is known to produce significant side effects when administered systemically. We have previously demonstrated the benefit of combined chemo-sonodynamic therapy (SDT), delivered using oxygen carrying microbubbles (O2MB), as a targeted treatment for pancreatic cancer in a murine model of the disease. In this manuscript, we report the preparation of a biotin functionalised Gem ligand for attachment to O2MBs (O2MB-Gem). We demonstrate the effectiveness of chemo-sonodynamic therapy following ultrasound-targeted-microbubble-destruction (UTMD) of the O2MB-Gem and a Rose Bengal loaded O2MB (O2MB-RB) as a targeted treatment for pancreatic cancer. Specifically, UTMD using the O2MB-Gem and O2MB-RB conjugates reduced the viability of MIA PaCa-2, PANC-1, BxPC3 and T110299 pancreatic cancer cells by >60% (p < 0.001) and provided significant tumour growth delay (>80%, p < 0.001) compared to untreated animals when human xenograft MIA PaCa-2 tumours were treated in SCID mice. The toxicity of the O2MB-Gem conjugate was also determined in healthy non-tumour bearing MF1 mice and revealed no evidence of renal or hepatic damage. Therefore, the results presented in this manuscript suggest that chemo-sonodynamic therapy using the O2MB-Gem and O2MB-RB conjugates, is potentially an effective targeted and safe treatment modality for pancreatic cancer.

Oxygen generating nanoparticles for improved photodynamic therapy of hypoxic tumours.

Photodynamic therapy (PDT) is a clinically approved anti-cancer treatment that involves the activation of an otherwise inactive sensitiser drug with light, which in the presence of molecular oxygen, generates cytotoxic reactive oxygen species (ROS). As oxygen is a key requirement for the generation of ROS in PDT and given the fact that hypoxia is a characteristic of most solid cancerous tumours, treating hypoxic tumours using PDT can be a challenge. In this manuscript, we have prepared a CaO2 nanoparticle (NP) formulation coated with a pH-sensitive polymer to enable the controlled generation of molecular oxygen as a function of pH. The polymer coat was designed to protect the particles from decomposition while in circulation but enable their activation at lower pH values in hypoxic regions of solid tumours. The oxygen generating capability of the polymer coated NPs was demonstrated in aqueous solution with minimal oxygen produced at pH7.4, whereas it increased significantly when the pH was reduced to 6.2. The polymer coated CaO2 NPs were also observed to significantly increase tumour pO2 levels (p<0.05) in mice bearing ectopic human xenograft MIA PaCa-2 pancreatic tumours with an average increase in tumour pO2 of 6.5mmHg in the period 10-30min following administration. A statistically significant improvement in PDT mediated efficacy (p<0.001) was also observed when the particles were administered to mice bearing the same tumours 20min prior to PDT treatment. These results suggest that the polymer coated CaO2 NP formulation offers significant potential as an in situ method for oxygen generation to enhance the efficacy of treatments that depend on the presence of oxygen to elicit a cytotoxic effect.

Magnetically responsive microbubbles as delivery vehicles for targeted sonodynamic and antimetabolite therapy of pancreatic cancer.

Magnetically responsive microbubbles (MagMBs), consisting of an oxygen gas core and a phospholipid coating functionalised with Rose Bengal (RB) and/or 5-fluorouracil (5-FU), were assessed as a delivery vehicle for the targeted treatment of pancreatic cancer using combined antimetabolite and sonodynamic therapy (SDT). MagMBs delivering the combined 5-FU/SDT treatment produced a reduction in cell viability of over 50% when tested against a panel of four pancreatic cancer cell lines in vitro. Intravenous administration of the MagMBs to mice bearing orthotopic human xenograft BxPC-3 tumours yielded a 48.3% reduction in tumour volume relative to an untreated control group (p<0.05) when the tumour was exposed to both external magnetic and ultrasound fields during administration of the MagMBs. In contrast, application of an external ultrasound field alone resulted in a 27% reduction in tumour volume. In addition, activated caspase and BAX protein levels were both observed to be significantly elevated in tumours harvested from animals treated with the MagMBs in the presence of magnetic and ultrasonic fields when compared to expression of those proteins in tumours from either the control or ultrasound field only groups (p<0.05). These results suggest MagMBs have considerable potential as a platform to enable the targeted delivery of combined sonodynamic/antimetabolite therapy in pancreatic cancer.

Endoscopic ultrasound in Barrett's oesophagitis with dysplasia.

PURPOSE: With the advent of conservative therapies including photodynamic therapy and endoscopic mucosal resection for Barrett's and high grade dysplasia, accurate staging has become increasingly important. We report our experience with endoscopic ultrasound (EUS) in these patients. MATERIALS AND METHODS: Retrospective review of 25 consecutive patients referred for EUS for assessment of Barrett's with high grade dysplasia and /or stricture or polyp. The findings were compared with subsequent surgical pathology, or endoscopy and biopsy follow up. RESULTS: Nine patients were found to have invasive tumour on EUS and this was confirmed in all 9 either by oesophagectomy, OGD and oncology follow up, or by endoscopic mucosal resection. Eight patients underwent oesophagectomy, 5 for invasive tumour and 3 for dysplasia only, with pathological agreement with EUS findings in 7 out of 8 cases. The one discrepancy was a EUS case of mucosal thickening only with no invasion, but pathology showed a T1 lesion. Thirteen patients with no evidence of invasion were managed conservatively, with 11 patients being followed up for 6-12 months with serial OGD and biopsy, and no cases of more invasive disease occurring. Therefore, in our experience the sensitivity, specificity and positive predictive value of EUS in complex Barrett's is 90%, 100% and 100% respectively. CONCLUSION: EUS is valuable in the assessment of high grade dysplasia in cases where conservative therapy is being considered, defining those with more deeply invasive tumour for whom radical treatment is the only option.

Overview of the investigation and management of cystic neoplasms of the pancreas.

BACKGROUND: Cystic neoplasms of the pancreas contribute to 10-20% of pancreatic tumours. Malignant cystic tumours of the pancreas behave similar to adenocarcinomas and thus warrant aggressive management. However, certain benign cystic neoplasms do not require operative intervention. It is, therefore, important to differentiate benign lesions from malignant lesions and from those with malignant potential. AIMS: To provide an overview of the role of radiological investigations in the management of cystic neoplasms of the pancreas, with emphasis on the characteristic features of aggressive tumours. The role of different imaging modalities is discussed, and an investigative algorithm suggested. METHODS: A literature review was carried out on Medline, Cochrane library, and PubMed using the MeSH terms 'pancreas' and 'cysts' to source relevant papers. Search criteria were limited to English literature, meta-analyses, systematic reviews, prospective and retrospective case series, published during or after 1998. DISCUSSION: Each pancreatic cystic lesion has characteristic radiological findings. However, the diagnostic accuracy of individual imaging techniques is still limited. A combination of imaging modalities is essential for preoperative diagnosis. CT complemented by endoscopic ultrasound and cyst fluid analysis appears to be the most promising investigation in diagnosing cystic neoplasms. Follow-up with serial imaging is useful for lesions of uncertain aetiology.