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Better understanding of breathlessness perception addresses an unmet clinical need for more effective treatments for intractable dyspnoea, a prevalent symptom of multiple medical conditions. The insular-cortex is predominantly activated in brain-imaging studies of dyspnoea, but its precise role remains unclear. We measured experimentally-induced hypercapnic air-hunger in three insular-glioma patients before and after surgical resection. Tests involved one-minute increments in inspired CO2, raising end-tidal PCO2 to 7.5\u2009mmHg above baseline (38.5\u2009\u00b1\u20095.7\u2009mmHg), whilst ventilation was constrained (10.7\u2009\u00b1\u20092.3\u2009L/min). Patients rated air-hunger on a visual analogue scale (VAS). Patients had lower stimulus-response (2.8\u2009\u00b1\u20092 vs. 11\u2009\u00b1\u20094 %VAS/mmHg; p\u2009=\u20090.004), but similar threshold (40.5\u2009\u00b1\u20093.9 vs. 43.2\u2009\u00b1\u20095.1\u2009mmHg), compared to healthy individuals. Volunteered comments implicated diminished affective valence. After surgical resection; sensitivity increased in one patient, decreased in another, and other was unable to tolerate the ventilatory limit before any increase in inspired CO2.We suggest that functional insular-cortex is essential to register breathlessness unpleasantness and could be targeted with neuromodulation in chronically-breathless patients. Neurological patients with insula involvement should be monitored for blunted breathlessness to inform clinical management.
\n \n\n \n \nPURPOSE: While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC. EXPERIMENTAL DESIGN: We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort. RESULTS: A total of 985 subjects (median follow-up 5.03 years, range: 4.73-5.21 years) were included. The final biomarker classifier, comprising p16 and survivin immunohistochemistry, high-risk human papillomavirus (HPV) DNA in situ hybridization, and tumor-infiltrating lymphocytes, predicted benefit from combined surgery + adjuvant chemo/radiotherapy over primary chemoradiotherapy in the high-risk group [3-year overall survival (OS) 63.1% vs. 41.1%, respectively, HR = 0.32; 95% confidence interval (CI), 0.16-0.65; P = 0.002], but not in the low-risk group (HR = 0.4; 95% CI, 0.14-1.24; P = 0.114). On further adjustment by propensity scores, the adjusted HR in the high-risk group was 0.34, 95% CI = 0.17-0.67, P = 0.002, and in the low-risk group HR was 0.5, 95% CI = 0.1-2.38, P = 0.384. The concordance index was 0.73. CONCLUSIONS: We have developed a prognostic classifier, which also appears to demonstrate moderate predictive ability. External validation in a prospective setting is now underway to confirm this and prepare for clinical adoption.
\n \n\n \n \nOBJECTIVE: The purpose of this study was to develop and evaluate the performance of RPC-Net (Recursive Prosthetic Control Network), a novel method using simple neural network architectures to translate electromyographic activity into hand position with high accuracy and computational efficiency. METHODS: RPC-Net uses a regression-based approach to convert forearm electromyographic signals into hand kinematics. We tested the adaptability of the algorithm to different conditions and compared its performance with that of solutions from the academic literature. RESULTS: RPC-Net demonstrated a high degree of accuracy in predicting hand position from electromyographic activity, outperforming other solutions with the same computational cost. Including previous position data consistently improved results across subjects and conditions. RPC-Net showed robustness against a reduction in the number of electromyography electrodes used and shorter input signals, indicating potential for further reduction in computational cost. CONCLUSION: The results demonstrate that RPC-Net is capable of accurately translating forearm electromyographic activity into hand position, offering a practical and adaptable tool that may be accessible in clinical settings. SIGNIFICANCE: The development of RPC-Net represents a significant advancement. In clinical settings, its application could enable prosthetic devices to be controlled in a way that feels more natural, improving the quality of life for individuals with limb loss.
\n \n\n \n \nIn a rapidly changing healthcare environment, we need a robust evidence base to inform effective education and training. This study aimed to examine factors perceived to determine career progression in clinical education research in the UK. Six online focus groups were conducted, with 35 participants from a range of medical, dental, nursing, and allied health professions who identified as aspiring or early career clinical education researchers. Transcripts underwent thematic analysis. Two themes and associated subthemes were constructed to illustrate perceived factors impacting on career development: (1) A cultural challenge from clinical norms. Challenges included differences between the epistemological assumptions of biomedical and clinical research, and the underlying philosophy of education research, which is more closely aligned with the knowledge generation of the social sciences. This led to difficulty communicating the impact of education research to patient care. There were also blurred boundaries between education delivery and research, with the latter lacking a clearly defined group identity. (2) Structures, systems and relationships for career progression. Practical considerations included time and funding (or lack thereof), the opportunity to undertake formal training, networking and role models. This research highlights a number of systemic barriers and facilitators to careers in clinical education research and offers targets of intervention to enable a sustainable academic workforce in clinical education research.
\n \n\n \n \nBACKGROUND: Extension of prostate cancer beyond the primary site by local invasion or nodal metastasis is associated with poor prognosis. Despite significant research on tumour evolution in prostate cancer metastasis, the emergence and evolution of cancer clones at this early stage of expansion and spread are poorly understood. We aimed to delineate the routes of evolution and cancer spread within the prostate and to seminal vesicles and lymph nodes, linking these to histological features that are used in diagnostic risk stratification. METHODS: We performed whole-genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and lymph nodes of five treatment-naive patients with locally advanced disease. We spatially mapped the clonal composition of cancer across the prostate and the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes in each individual by analysing a total of\u2009>\u200919,000 copy number corrected single nucleotide variants. RESULTS: In each patient, we identified sample locations corresponding to the earliest part of the malignancy. In patient 10, we mapped the spread of cancer from the apex of the prostate to the seminal vesicles and identified specific genomic changes associated with the transformation of adenocarcinoma to amphicrine morphology during this spread. Furthermore, we show that the lymph node metastases in this patient arose from specific cancer clones found at the base of the prostate and the seminal vesicles. In patient 15, we observed increased mutational burden, altered mutational signatures and histological changes associated with whole genome duplication. In all patients in whom histological heterogeneity was observed (4/5), we found that the distinct morphologies were located on separate branches of their respective evolutionary trees. CONCLUSIONS: Our results link histological transformation with specific genomic alterations and phylogenetic branching. These findings have implications for diagnosis and risk stratification, in addition to providing a rationale for further studies to characterise the genetic changes causally linked to morphological transformation. Our study demonstrates the value of integrating multi-region sequencing with histopathological data to understand tumour evolution and identify mechanisms of prostate cancer spread.
\n \n\n \n \nBACKGROUND: Trauma is a leading cause of morbidity and mortality in children worldwide. There is a need for development and provision of efficient paediatric trauma services based on adequate information and funding which are lacking in low- and middle-income countries. AIMS: This study was carried out to assess the scale of the problem, identify the most common causes of trauma in Pan African Paediatric Surgical Association (PAPSA) zone and to define the limiting factors for provision of the necessary services required to reduce the potential mortality and disability. MATERIALS AND METHODS: Data were collected through an electronic form sent out in PAPSA platform. Members were requested to provide prospective data on all paediatric major trauma admitted to or seen at their health facilities between the beginning of April 2019 and the end of June 2020. Hospital location, child's age, gender, type of injury, mechanism of injury, severity, initial management, method of transport, time to arrive to hospital, availability of surgical specialities, length of hospital stay and injury outcome were analysed. RESULTS: There were 531 entries. The mean age was 3.53 years and median age 1.34 years. Male-to-female ratio was 2:1. The leading causes for injuries were falls 194 (36.53%) and motor vehicle crashes (MVCs) 176 (33.15%) followed by obstetrical 42 (7.9%), thermal 27 (5.1%) and domestic injuries 22 (4.1%). The most common injuries were limb fractures 181 (34.1%) and traumatic brain injury 111 (20.9%). Public and private transport were used in 313 (58.9%), while ambulance service was used in only 54 (10.1%). Distances to a health facility varied between 1 and 157 km. 70.2% of cases did not receive any primary care, while definitive care was received in 95.5% of the cases. Outcome was full recovery in 90.6% of patients, morbidity in 8.1% and a mortality rate of 1.3%. CONCLUSIONS: Most of the injuries were in the under 5-year age group. The two main causes of trauma in children in this study were the falls from height and MVCs. Long distance travels to reach health-care facilities were noticeable in this study, together with substantial lack of adequate ambulance facilities and shortage in necessary subspecialty services such as neurosurgical, orthopaedics and rehabilitation. Implementing proposed recommendations can reduce the burden.
\n \n\n \n \nPoly(adenosine diphosphate ribose) polymerase (PARP) has emerged as an effective therapeutic strategy against cancer that targets the DNA damage repair enzyme. PARP-targeting compounds radiolabeled with an Auger electron-emitting radionuclide can be trapped close to damaged DNA in tumor tissue, where high ionizing potential and short range lead Auger electrons to kill cancer cells through the creation of complex DNA damage, with minimal damage to surrounding normal tissue. Here, we report on [123I]CC1, an 123I-labeled PARP inhibitor for radioligand therapy of cancer. Methods: Copper-mediated 123I iododeboronation of a boronic pinacol ester precursor afforded [123I]CC1. The level and specificity of cell uptake and the therapeutic efficacy of [123I]CC1 were determined in human breast carcinoma, pancreatic adenocarcinoma, and glioblastoma cells. Tumor uptake and tumor growth inhibition of [123I]CC1 were assessed in mice bearing human cancer xenografts (MDA-MB-231, PSN1, and U87MG). Results: In vitro and in\u00a0vivo studies showed selective uptake of [123I]CC1 in all models. Significantly reduced clonogenicity, a proxy for tumor growth inhibition by ionizing radiation in\u00a0vivo, was observed in\u00a0vitro after treatment with as little as 10\u2009Bq [123I]CC1. Biodistribution at 1\u2009h after intravenous administration showed PSN1 tumor xenograft uptake of 0.9\u2009\u00b1\u20090.06 percentage injected dose per gram of tissue. Intravenous administration of a relatively low amount of [123I]CC1 (3 MBq) was able to significantly inhibit PSN1 xenograft tumor growth but was less effective in xenografts that expressed less PARP. [123I]CC1 did not cause significant toxicity to normal tissues. Conclusion: Taken together, these results show the potential of [123I]CC1 as a radioligand therapy for PARP-expressing cancers.
\n \n\n \n \nMolecular radionuclide therapy (MRT) is an effective treatment for both localised and disseminated tumours. Biomarkers can be used to identify potential subtypes of tumours that are known to respond better to standard MRT protocols. These enrolment-based biomarkers can further be used to develop dose-response relationships using image-based dosimetry within these defined subtypes. However, the biological identity of the cancers treated with MRT are commonly not well-defined, particularly for neuroendocrine neoplasms. The biological heterogeneity of such cancers has hindered the establishment of dose-responses and minimum tumour dose thresholds. Biomarkers could also be used to determine normal tissue MRT dose limits and permit greater injected doses of MRT in patients. An alternative approach is to understand the repair capacity limits of tumours using radiobiology-based biomarkers within and outside patient cohorts currently treated with MRT. It is hoped that by knowing more about tumours and how they respond to MRT, biomarkers can provide needed dimensionality to image-based biodosimetry to improve MRT with optimized protocols and personalised therapies.
\n \n\n \n \nRationale: The evaluation of early treatment response is critical for patient prognosis and treatment planning. When the current methods rely on invasive protocols that evaluate the expression of DNA damage markers on patient biopsy samples, we aim to evaluate a non-invasive PET imaging approach to monitor the early expression of the phosphorylated histone \u03b3H2AX in the context of pancreatic cancer targeted radionuclide therapy. Pancreatic ductal adenocarcinoma has a poor patient prognosis due to the absence of curative treatment for patients with advanced disease. There is therefore a critical need for the fast clinical translation of new therapeutic options. In line with these observations, our group has been focusing on the development of radiotheranostic agents based on a fully human monoclonal antibody (5B1) with exceptional affinity for CA19.9, an antigen overexpressed in PDAC. Two on-going clinical trials resulted from these efforts, one with 89Zr (diagnosis) and one with 177Lu (\u03b2-particle therapy). More recently, we successfully developed and evaluated in PDAC mouse models a targeted \u03b1-therapy strategy with high clinical translation potential. We aim to expedite the clinical translation of the developed radioimmunotherapy approaches by investigating the early therapeutic response and effect of radiation therapy in a PDAC mouse model via PET imaging. Methods: Mice bearing BxPC3 tumor xenografts were treated with \u03b1- and \u03b2-particle pretargeted radioimmunotherapy (PRIT), external beam radiotherapy (EBRT), or sham-treated (vehicle). The phosphorylated histone \u03b3H2AX produced as a response to DNA double strand breaks was quantified with the PET radiotracer, [89Zr]Zr-DFO-anti-\u03b3H2AX-TAT. Results: PET imaging studies in BxPC3 PDAC mouse models demonstrated increased uptake of [89Zr]Zr-DFO-anti-\u03b3H2AX-TAT (6.29 \u00b1 0.15 %IA/g) following \u03b2-PRIT in BxPC3 PDAC xenografts as compared to the saline control group (4.58 \u00b1 0.76 %IA/g) and EBRT control group (5.93 \u00b1 0.76 %IA/g). Similarly, significantly higher uptake of [89Zr]Zr-DFO-anti-\u03b3H2AX-TAT was observed in tumors of the 225Ac-PRIT and EBRT (10 Gy) cohorts (7.37 \u00b1 1.23 and 6.80 \u00b1 1.24 %IA/g, respectively) compared to the negative control cohort (5.08 \u00b1 0.95 %IA/g). Ex vivo \u03b3H2AX immunohistochemistry and immunofluorescence analysis correlated with in vivo89Zr-anti-\u03b3H2AX PET/CT imaging with increased \u03b3H2AX positive cell and \u03b3H2AX foci per cell in the treated cohorts. When \u03b1-PRIT resulted in prolonged overall survival of treated animals (107.5 days) as compared to \u03b2-PRIT (73.0 days), no evidence of difference in [89Zr]Zr-DFO-anti-\u03b3H2AX-TAT uptake at the tumor site was observed, highlighting that DNA damage is not the sole radiobiology paradigm and that off-targeted (bystander) effects should be considered. Conclusions: PET imaging studies with [89Zr]Zr-DFO-anti-\u03b3H2AX-TAT following \u03b1- and \u03b2-particle PRIT in a BxPC3 PDAC subcutaneous xenograft mouse model allowed the monitoring of tumor radiobiological response to treatment.
\n \n\n \n \nIn recent years, targeted radionuclide therapy (TRT) has emerged as a promising strategy for cancer treatment. In contrast to conventional radiotherapy, TRT delivers ionizing radiation to tumors in a targeted manner, reducing the dose that healthy tissues are exposed to. Existing TRT strategies include the use of 177Lu-DOTATATE, 131I-metaiodobenzylguanidine, Bexxar, and Zevalin, clinically approved agents for the treatment of neuroendocrine tumors, neuroblastoma, and non-Hodgkin lymphoma, respectively. Although promising results have been obtained with these agents, clinical evidence acquired to date suggests that only a small percentage of patients achieves complete response. Consequently, there have been attempts to improve TRT outcomes through combinations with other therapeutic agents; such strategies include administering concurrent TRT and chemotherapy, and the use of TRT with known or putative radiosensitizers such as poly(adenosine diphosphate ribose) polymerase and mammalian-target-of-rapamycin inhibitors. In addition to potentially achieving greater therapeutic effects than the respective monotherapies, these strategies may lead to lower dosages or numbers of cycles required and, in turn, reduce unwanted toxicities. As of now, several clinical trials have been conducted to assess the benefits of TRT-based combination therapies, sometimes despite limited preclinical evidence being available in the public domain to support their use. Although some clinical trials have yielded promising results, others have shown no clear survival benefit from particular combination treatments. Here, we present a comprehensive review of combination strategies with TRT reported in the literature to date and evaluate their therapeutic potential.
\n \n\n \n \nPURPOSE: Rucaparib, an FDA-approved PARP inhibitor, is used as a single agent in maintenance therapy to provide promising treatment efficacy with an acceptable safety profile in various types of BRCA-mutated cancers. However, not all patients receive the same benefit from rucaparib-maintenance therapy. A predictive biomarker to help with patient selection for rucaparib treatment and predict clinical benefit is therefore warranted. With this aim, we developed [18F]rucaparib, an 18F-labelled isotopologue of rucaparib, and employed it as a PARP-targeting agent for cancer imaging with PET. Here, we report the in vitro and in vivo evaluation of [18F]rucaparib in human pancreatic cancer models. METHOD: We incorporated the positron-emitting 18F isotope into rucaparib, enabling its use as a PET imaging agent. [18F]rucaparib binds to the DNA damage repair enzyme, PARP, allowing direct visualisation and measurement of PARP in cancerous models before and after PARP inhibition or other genotoxic cancer therapies, providing critical information for cancer diagnosis and therapy. Proof-of-concept evaluations were determined in pancreatic cancer models. RESULTS: Uptake of [18F]rucaparib was found to be mainly dependent on PARP1 expression. Induction of DNA damage increased PARP expression, thereby increasing uptake of [18F]rucaparib. In vivo studies revealed relatively fast blood clearance of [18F]rucaparib in PSN1 tumour-bearing mice, with a tumour uptake of 5.5 \u00b1 0.5%ID/g (1 h after i.v. administration). In vitro and in vivo studies showed significant reduction of [18F]rucaparib uptake by addition of different PARP inhibitors, indicating PARP-selective binding. CONCLUSION: Taken together, we demonstrate the potential of [18F]rucaparib as a non-invasive PARP-targeting imaging agent for pancreatic cancers.
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