Explore the vast range of titles available.

Immunotherapy has led to a paradigm shift in the treatment of many advanced malignancies. Despite the success in treatment of tumors like non-small cell lung cancer (NSCLC) and melanoma, checkpoint inhibition-based immunotherapy has limitations. Many tumors, such as pancreatic cancer, are less responsive to checkpoint inhibitors, where patients tend to have a limited duration of benefit and where clinical responses are more robust in patients who are positive for predictive biomarkers. One of the critical factors that influence the efficacy of immunotherapy is the tumor microenvironment (TME), which contains a heterogeneous composition of immunosuppressive cells. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) alter the immune landscape of the TME and serve as facilitators of tumor proliferation, metastatic growth and immunotherapy resistance. Small molecule inhibitors that target these components of the TME have been developed. This special issue review focuses on two promising classes of immunomodulatory small molecule inhibitors: colony stimulating factor-1 receptor (CSF-1R) and focal adhesion kinase (FAK). Small molecule inhibitors of CSF-1R reprogram the TME and TAMs, and lead to enhanced T-cell-mediated tumor eradication. FAK small molecule inhibitors decrease the infiltration MDSCs, TAMs and regulatory T-cells. Additionally, FAK inhibitors are implicated as modulators of stromal density and cancer stem cells, leading to a TME more conducive to an anti-tumor immune response. Immunomodulatory small molecule inhibitors present a unique opportunity to attenuate immune escape of tumors and potentiate the effectiveness of immunotherapy and traditional cytotoxic therapy.

\"A brand new collection of remarkable travel tales from 'Silver Travellers'. Dervla Murphy travelling in Havana at the age of 74, Matthew Parris swimming the Thames at 60, and Colin Thubron climbing the last stronghold of the Assassins in his 60s are among the writers recounting their adventures, often defying expectations - and the odds - and going outside their comfort zone to take a less-travelled path in later life. Published with participation from the Silver Travel Advisor, this single volume brings together contributions - some original, some previously published - from independent-minded souls whose experiences have been entertaining, amusing, thrilling, and even a little irresponsible. Other contributors include Roger Bray, 'Green Goddess' Diana Moran and our very own Hilary Bradt.\"--Wheelers.co.nz.

Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed. Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6–21·3). 38 (35·5% [95% CI 26·5–45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. Incyte Corporation.

Background Immunotherapy has demonstrated a limited clinical efficacy in approximately 5% of cholangiocarcinoma. The main challenges for an effective immunotherapy response in cholangiocarcinoma arise from the tumor microenvironment, which is poorly understood. Methods For a comprehensive analysis of the tumor microenvironment in cholangiocarcinoma, we performed multiplex immunohistochemistry with two 15-marker immune panels and Nanostring assays for a comprehensive analysis of 104 surgically resected cholangiocarcinomas including intrahepatic, hilar, and distal cholangiocarcinoma. We also validated some key findings with a batch integration analysis of published single cell RNA sequencing data. Results This study found that natural killer cells occupy the largest immune cell compartment in cholangiocarcinoma. Granzyme-B + CD8 + effector T cells are significantly associated with better overall survival in both intrahepatic and distal cholangiocarcinoma. Above 85% of intrahepatic cholangiocarcinomas with higher density of PD-1 − EOMES − CD8 + effector T cells are associated with long-term survival. However, only the density of PD-1 − EOMES − CD8 + T cells in the tumor areas, but not in the peripheries of the tumors, is prognostic. In all three cholangiocarcinoma subtypes, T regulator cells are significantly associated with a poor prognosis; however, M1 and M2 tumor-associated macrophages or PD-L1 + tumor-associated macrophage demonstrate different prognostic values. Combining PD-L1 + M1 or M2, PD-L1 − M1 or M2 tumor-associated macrophages, and T regulator cells to subgroup intrahepatic and distal cholangiocarcinoma, the prognosis is significantly better distinguished. Moreover, PD-L1 − M2 tumor-associated macrophages is associated with a good prognosis in intrahepatic and distal cholangiocarcinoma, suggesting this subtype of M2 tumor-associated macrophages may be antitumoral. Interestingly, lower densities of various types of immunosuppressive cells are associated with decreased infiltration of effector T cells in distal and hilar cholangiocarcinoma, but not in intrahepatic cholangiocarcinoma. In intrahepatic cholangiocarcinoma, PD-L1 + tumor-associated macrophages exert their immunosuppressive function likely through promoting T cell exhaustion. Conclusions This study suggests that the densities of Granzyme-B + CD8 + effector T cells and non-exhausted PD-1 − EOMES − CD8 + T cells and the PD-L1 status in the tumor-associated macrophages are prognostic makers in cholangiocarcinomas. The study also supports targeting PD-L1 + tumor-associated macrophages as the immunotherapy for cholangiocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) represents an immune quiescent tumor that is resistant to immune checkpoint inhibitors. Previously, our group has shown that a GM-CSF-secreting allogenic pancreatic tumor cell vaccine (GVAX) may prime the tumor microenvironment by inducing intratumoral T cell infiltration. Here, we show that untreated PDACs express minimal indoleamine-2,3-dioxygenase (IDO1); however, GVAX therapy induced IDO1 expression on tumor epithelia as well as vaccine-induced tertiary lymphoid aggregates. IDO1 expression plays a role in regulating the polarization of Th1, Th17, and possibly T regulatory cells in PDAC tumors. IDO1 inhibitor enhanced antitumor efficacy of GVAX in a murine model of PDACs. The combination of vaccine and IDO1 inhibitor enhanced intratumoral T cell infiltration and function, but adding anti-PD-L1 antibody to the combination did not offer further synergy and in fact may have had a negative interaction, decreasing the number of intratumoral effector T cells. Additionally, IDO1 inhibitor in the presence of vaccine therapy did not significantly modulate intratumoral myeloid-derived suppressor cells quantitatively, but diminished their suppressive effect on CD8+ proliferation. Our study supports the combination of IDO1 inhibitor and vaccine therapy; however, it does not support the combination of IDO1 inhibitor and anti-PD-1/PD-L1 antibody for T cell-inflamed tumors such as PDACs treated with vaccine therapy.

Background Approximately 95% of advanced colorectal cancer patients (CRC) have mismatch repair MMR-proficient (MMRp) tumors, which do not respond to PD1 blockade alone. Preclinical studies have shown that combined histone deacetylases (HDAC) and/or DNA methyltransferases (DNMT) inhibition can induce susceptibility to immune checkpoint therapy and inhibit tumor growth. We conducted a pilot trial evaluating PD-1 immune checkpoint inhibitor therapy in combination with DNMT and HDAC inhibitors in MMRp CRC. The study was designed with a biological endpoint of change in immune cell infiltration, to determine the optimal epigenetic combination that optimizes the tumor microenvironment. This trial was designed to test that hypothesis. Results From January 2016 to November 2018, 27 patients were enrolled with median age of 57 (range 40–69) years. Median progression-free survival and overall survival were 2.79 months and 9.17, respectively. One patient in Arm C achieved a durable partial response by RECIST criteria, lasting for approximately 19 months. The most common treatment-related hematological adverse events in all arms were anemia (62%), lymphopenia (54%) and thrombocytopenia (35%), and non-hematological AEs were anorexia (65%), nausea (77%), and vomiting (73%). Conclusions The combination of 5-azacitidine and romidepsin with pembrolizumab was safe and tolerable in patients with advanced MMRp CRC, but with a minimal activity. Further mechanistic investigations are needed to understand epigenetic-induced immunologic shift and to expand the potential applicability of checkpoint inhibitors in this setting.

Background Pancreatic cancer (PDAC) often responds poorly to chemotherapy, represents an unmet clinical need and new therapeutic approaches are urgently required. Desmoplasia is a hallmark of PDAC. Multiple preclinical studies suggest cancer associated fibroblasts (CAF) support cancer growth, and attention has recently turned towards inclusion of anti-stromal agents into chemotherapy trials. Our objective was to evaluate safety and tolerability of oral paricalcitol in combination with systemic chemotherapy in patients with advanced PDAC. Methods This was a phase II, single-arm study in patients with advanced PDAC who had received no prior systemic chemotherapy. Gemcitabine and NAB-paclitaxel were administered weekly for 3 of every 4 weeks (days 1, 8 and 15) and paricalcitol administered orally every day of a 28-day cycle. Patients were treated until disease progression with an interim analysis. The primary efficacy endpoint was progression free survival (PFS). Secondary efficacy endpoints were evaluation of overall survival (OS), time to treatment failure (TTF) and tumour response rate (TRR). Results Fifteen patients were enrolled. Median PFS was 14.6 weeks with 95% CI of (7.9–24.0). Estimated PFS rate at 24 weeks was 18.0% with 95% CI of (2.9–43.4). Five patients achieved stable disease; one achieved a partial response. Confirmed tumour response rate was 8.3% with 90% CI of (0.4–33.9). Mild hypercalcaemia, previously associated with vitamin D receptor agonists, occurred in nine (60%) patients, moderate (Grade 3) hypercalcaemia in 2 patients and there was no grade 4/5 hypercalcaemia. The study did not meet its primary objective and discontinued following interim analysis. Conclusions Oral paricalcitol was safely combined with chemotherapy. The prespecified efficacy threshold for 6-month progression free survival probability (≥ 70%) was not met. The study was stopped early after the planned interim analysis as the criterion pre-specified in order to move to the next stage of the study was not met. Efficacy of paricalcitol in advanced PDAC was lower than expected, with a non-significant trend towards decreased PFS. Our study has implications for interpretation and design of clinical trials incorporating paricalcitol for patients with advanced pancreatic cancer. Trial registration ClinicalTrials.gov identifier: NCT04617067, registration date 10/27/2020.

Background Paramedicine is undergoing a transformative shift as practitioners seek recognition beyond traditional emergency response roles toward being fully integrated healthcare professionals. Central to this evolution is the process of professionalisation, marked by efforts to expand scope of practice, formalise education and regulation, and achieve greater systemic integration. Despite these developments, significant barriers remain. Purpose This study explores key barriers to the professionalisation of paramedics across five developed healthcare systems, highlighting shared and context-specific challenges. Methods A qualitative study underpinned by a critical theory paradigm was conducted using semi-structured interviews. Over a five-month period (Dec 2022–Apr 2023), 15 expert stakeholders from clinical, educational, policy, and leadership roles in paramedicine and pre-hospital emergency care were recruited across five countries. Interviews were conducted via Microsoft Teams, transcribed verbatim, and analysed thematically with a reflexive and interpretive approach. Results Four main themes were developed: Current Barriers to Expansion– including outdated legislation, inconsistent regulatory frameworks, limited funding, workforce shortages, and insufficient integration within healthcare systems. Elevating Professional Status– focusing on the need for protected titles, standardised education, credentialing, and a stronger professional identity. Impact of COVID-19– participants reflected on the profession’s temporary visibility during the pandemic, followed by policy and funding shifts that diluted that momentum. Future Continuing and Emerging Barriers– encompassing structural and cultural resistance, lack of leadership pathways, and challenges in sustaining innovation and collaboration. Conclusion The study highlights persistent barriers to paramedic professionalisation, including fragmented regulation, uneven educational standards, and systemic underinvestment. Although COVID-19 demonstrated the adaptability and potential of the profession, sustaining progress requires targeted policy reform, stronger regulatory frameworks, investment in education and leadership, and commitment to workforce development. Recognising paramedics as integral healthcare providers is essential to advancing the profession and improving patient care.

Background While paramedicine is an evolving profession globally, there remain many disparities around titles and roles within the various jurisdictions that may not be fully captured in the literature. Aim The aim of this study is to gain a multi-national perspective on the current and future roles within paramedicine, highlighting the challenges and opportunities that shape the profession’s ongoing evolution. Methods A mixed-methods approach was adopted for this survey, incorporating both quantitative and qualitative data. A survey link was distributed internationally to paramedicine professionals via email, journals, and social media. Quantitative data were analysed using Microsoft Excel’s statistical functions, with results presented as frequencies, percentages, and numerical summaries. Qualitative data were analysed using narrative synthesis and integrated with quantitative findings to provide a comprehensive overview. Results The study gathered responses from 158 participants representing 59 organisations across 16 countries. Ireland had the highest number of respondents ( n  = 56) followed by Australia ( n  = 41) and England ( n  = 21). Participants outlined current paramedic roles ( n  = 54) and future roles planned within their respective organisations ( n  = 39). Participants described aspirational, non-traditional roles that they felt paramedics may adopt into the future ( n  = 86). Respondents practitioner titles varied across a range of clinical, managerial, and academic specialties, with examples provided ( n  = 33). Respondents provided various descriptions of the clinical levels of practitioners available within their organisations ( n  = 41).Various ambulance care models were identified with various combinations ( n  = 24). Paramedic medical oversight was predominantly provided by a physician ( n  = 56) although ( n  = 22) other examples were described. Regulation of paramedic practice provided descriptions of various regulatory bodies ( n  = 8) with examples of paramedic models of regulation described ( n  = 9). Respondents described various patient safety framework models implemented within their respective organisations ( n  = 10). Conclusion The findings from this study highlight that paramedicine is rapidly evolving in response to varying local healthcare needs and sector-specific challenges. Rather than striving for a uniform standard of practice, the results suggest that paramedicine should be viewed as a flexible and adaptive domain, capable of specialising across diverse clinical, managerial, and academic settings. The diverse titles, roles, and models described by participants reflect the growing complexity of the profession. Furthermore, the study indicates that paramedic practice is often shaped by local contexts, such as organisational needs and healthcare gaps, which create innovative opportunities for expanding the scope of the profession. By embracing this variability and focusing on the development of versatile healthcare practitioners who can adapt to societal needs, paramedicine can continue to evolve effectively within well-governed healthcare systems.