Hepatic resection for metastatic melanoma in the era of targeted therapy: A case report.

INTRODUCTION: While prognosis in metastatic melanoma has traditionally been poor, novel systemic therapies such as immunotherapy and targeted agents have improved overall survival (Steininger et al., 2021). These medications are generally well tolerated but can be associated with immune related adverse events (Remash et al., 2021). Hepatic metastatectomy is an important component of management, conferring a survival benefit over systemic therapy alone in appropriately selected patients (Medina et al., 2020). Gadoxetic acid-enhanced magnetic resonance imaging (GA-MRI) has been demonstrated to have enhanced diagnostic accuracy compared with other imaging modalities for hepatic metastases (Freitas et al., 2021). The risk of tumour seeding associated fine-needle aspiration biopsy (FNAB) of hepatic lesions varies, with most studies reporting a low incidence (Maturen et al., 2006). PRESENTATION OF CASE: In February 2020, a 75-year-old male underwent wide local excision and sentinel lymph node biopsy for stage IIA (T2B, N0, M0) melanoma. Routine surveillance without adjuvant systemic treatment was commenced. In July 2022, he presented with haemoptysis and was subsequently diagnosed with widespread metastatic disease on positive emission tomography (PET). After combination ipilimumab and nivolumab, PET scans in August 2023 revealed new liver lesions with disease response at all other metastatic sites. Following a multi-disciplinary team (MDT) discussion, the patient proceeded to hepatic metastatectomy. Histopathology demonstrated chronic necrotising granulomatous hepatitis. DISCUSSION: This case reflects the challenges involved in investigation and management of hepatic metastases in melanoma. CONCLUSION: Despite the accuracy of modern imaging, this case demonstrates the need for MDT consideration of liver biopsy in patients on anti-CTL4 treatment or with response to systemic treatment at extrahepatic sites.

An ultrasound-based femoral artery calcification score.

Objective: Duplex ultrasound (US) of the lower extremities is commonly used to assess patients with lower extremity atherosclerosis. Arterial calcification can often be visualized in these images; however, efforts to quantify its extent have been limited. We, thus, sought to develop a new scoring system to measure calcification on duplex US studies of the femoral artery and correlate it with standard computed tomography (CT)-based methods. We then made preliminary attempts to correlate US-based femoral artery calcification scores with limb-specific outcomes in patients with peripheral arterial disease. Methods: Patients who underwent CT evaluation of the lower extremities and arterial duplex US of either lower extremity within 6 months of each examination were included in the study. CT-based calcium scores of the femoral artery were generated using calcium scoring software. To determine the US score, five standard arterial segments (ie, common femoral artery, proximal superficial femoral artery [SFA], mid-SFA, distal SFA, and above the knee popliteal artery) were scored using a scale of 0 to 2 (0, a completely normal vessel segment; 1, a vessel with hyperechoic irregularities of the vessel wall; and 2, clear anechoic shadowing). The available scores were then averaged to yield a single femoral calcium score for each leg. Predictors of femoral calcification scores were then assessed and compared with the CT-based methods. The correlation between the US- and CT-based femoral calcification was assessed, and then the association between the US-based femoral calcification score and limb outcomes was evaluated. Results: A total of 113 patients met the inclusion criteria and were included in the final analysis. US-based calcification scores were increased in patients with diabetes, renal failure, and the presence of chronic limb threatening ischemia similar to CT-based femoral calcification. The US- and CT-based calcification scores showed a moderate to strong correlation (r = 0.64). An elevated US-based femoral artery calcification score was associated with decreased amputation-free survival. Conclusions: A novel US-based method shows promise as a simple method for quantifying the extent of femoral artery calcification in patients with peripheral arterial disease. The US-based method correlates with standard CT-based methods. Preliminary studies show that it could be useful for predicating outcomes for patients with peripheral arterial disease.

Multicolor Photoluminescent Carbon Dots à La Carte for Biomedical Applications.

Dual-emission fluorescence probes that provide high sensitivity are key for biomedical diagnostic applications. Nontoxic carbon dots (CDs) are an emerging alternative to traditional fluorescent probes; however, robust and reproducible synthetic strategies are still needed to access materials with controlled emission profiles and improved fluorescence quantum yields (FQYs). Herein, we report a practical and general synthetic strategy to access dual-emission CDs with FQYs as high as 0.67 and green/blue, yellow/blue, or red/blue excitation-dependent emission profiles using common starting materials such as citric acid, cysteine, and co-dopants to bias the synthetic pathway. Structural and physicochemical analysis using nuclear magnetic resonance, absorbance and fluorescence spectroscopy, Fourier-transform infrared spectroscopy, and X-ray photoelectron spectroscopy in addition to transmission electron and atomic force microscopy (TEM and AFM) is used to elucidate the material's composition which is responsible for the unique observed photoluminescence properties. Moreover, the utility of the probes is demonstrated in the clinical setting by the synthesis of green/blue emitting antibody-CD conjugates which are used for the immunohistochemical staining of human brain tissues of glioblastoma patients, showing detection under two different emission channels.

bamSliceR: cross-cohort variant and allelic bias analysis for rare variants and rare diseases.

Rare diseases and conditions create unique challenges for genetic epidemiologists precisely because cases and samples are scarce. In recent years, whole-genome and whole-transcriptome sequencing (WGS/WTS) have eased the study of rare genetic variants. Paired WGS and WTS data are ideal, but logistical and financial constraints often preclude generating paired WGS and WTS data. Thus, many databases contain a patchwork of specimens with either WGS or WTS data, but only a minority of samples have both. The NCI Genomic Data Commons facilitates controlled access to genomic and transcriptomic data for thousands of subjects, many with unpaired sequencing results. Local reanalysis of expressed variants across whole transcriptomes requires significant data storage, compute, and expertise. We developed the bamSliceR package to facilitate swift transition from aligned sequence reads to expressed variant characterization. bamSliceR leverages the NCI Genomic Data Commons API to query genomic sub-regions of aligned sequence reads from specimens identified through the robust Bioconductor ecosystem. We demonstrate how population-scale targeted genomic analysis can be completed using orders of magnitude fewer resources in this fashion, with minimal compute burden. We demonstrate pilot results from bamSliceR for the TARGET pediatric AML and BEAT-AML projects, where identification of rare but recurrent somatic variants directly yields biologically testable hypotheses. bamSliceR and its documentation are freely available on GitHub at https://github.com/trichelab/bamSliceR.

Biomimetic Nacre-like Hydroxyapatite/Polymer Composites for Bone Implants.

One of the most ambitious goals for bone implants is to improve bioactivity, incapability, and mechanical properties; to reduce the need for further surgery; and increase efficiency. Hydroxyapatite (HA), the main inorganic component of bones and teeth, has high biocompatibility but is weak and brittle material. Cortical bone is composed of 70% calcium phosphate (CaP) and 30% collagen and forms a complex hierarchical structure with anisotropic and lamellar microstructure (osteons) which makes bone a light, strong, tough, and durable material that can support large loads. However, imitation of concentric lamellar structure of osteons is difficult to achieve in fabrication. Nacre from mollusk shells with layered structures has now become the archetype of the natural "model" for bio-inspired materials. Incorporating a nacre-like layered structure into bone implants can enhance their mechanical strength, toughness, and durability, reducing the risk of implant catastrophic failure or fracture. The layered structure of nacre-like HA/polymer composites possess high strength, toughness, and tunable stiffness which matches that of bone. The nacre-like HA/polymer composites should also possess excellent biocompatibility and bioactivity which facilitate the bonding of the implant with the surrounding bone, leading to improved implant stability and long-term success. To achieve this, a bi-directional freeze-casting technique was used to produce elongated lamellar HA were further densified and infiltrated with polymer to produce nacre-like HA/polymer composites with high strength and fracture toughness. Mechanical characterization shows that increasing the ceramic fractions in the composite increases the density of the mineral bridges, resulting in higher flexural and compressive strength. The nacre-like HA/(methyl methacrylate (MMA) + 5 wt.% acrylic acid (AA)) composites with a ceramic fraction of 80 vol.% showed a flexural strength of 158 ± 7.02 MPa and a Young's modulus of 24 ± 4.34 GPa, compared with 130 ± 5.82 MPa and 19.75 ± 2.38 GPa, in the composite of HA/PMMA, due to the higher strength of the polymer and the interface of the composite. The fracture toughness in the composition of 5 wt.% PAA to PMMA improves from 3.023 ± 0.98 MPa·m1/2 to 5.27 ± 1.033 MPa·m1/2 by increasing the ceramic fraction from 70 vol.% to 80 vol.%, respectively.

Evaluation of a modified emergency surgical acuity score in predicting operative and non-operative mortality and morbidity in an acute surgical unit.

BACKGROUND: Emergency general surgery (EGS) patients have an increased risk of mortality and morbidity compared to other surgical patients. Limited risk assessment tools exist for use in both operative and non-operative EGS patients. We assessed the accuracy of a modified Emergency Surgical Acuity Score (mESAS) in EGS patients at our institution. METHODS: A retrospective cohort study from an acute surgical unit at a tertiary referral hospital was performed. Primary endpoints assessed included death before discharge, length of stay (LOS) >5 days and unplanned readmission within 28 days. Operative and non-operative patients were analysed separately. Validation was performed using the area under the receiver operating characteristic (AUROC), Brier score and Hosmer-Lemeshow test. RESULTS: A total of 1763 admissions between March 2018 and June 2021 were included for analysis. The mESAS was an accurate predictor of both death before discharge (AUROC 0.979, Brier score 0.007, Hosmer-Lemeshow P = 0.981) and LOS >5 days (0.787, 0.104, and 0.253, respectively). The mESAS was less accurate in predicting readmission within 28 days (0.639, 0.040, and 0.887, respectively). The mESAS retained its predictive ability for death before discharge and LOS >5 days in the split cohort analysis. CONCLUSION: This study is the first to validate a modified ESAS in a non-operatively managed EGS population internationally and the first to validate the mESAS in Australia. The mESAS accurately predicts death before discharge and prolonged LOS for all EGS patients, providing a highly useful tool for surgeons and EGS units worldwide.

Persistent low rates of same-day umbilical hernia repair in Australia over the past 20 years: is there a need to change?

BACKGROUND: Several recent reports have identified significant variations in discharge practices following umbilical hernia repair (UHR). The primary aim of this paper is to determine Australian UHR same day discharge (SDD) rates over the past two decades. Secondary aims are to analyse factors which may contribute to variation in discharge practices, compare Australian UHR SDD rates internationally and determine LOS trends. METHODS: A retrospective, population-based cohort study was conducted using de-identified data from the Australian Institute of Health and Welfare (1 July 1998 to 30 June 2019). SDD rates and LOS were calculated for age, gender and complexity. Negative binomial models were used to investigate associations between characteristics. RESULTS: The overall mean UHR SDD rate was 41.2% with a modest improvement over the study period (36.5% to 44.4%, P < 0.0001). The mean LOS was 3.4 days, and this decreased over the study period (P = 0.01). Males had a higher rate of SDD (42.1% vs. 39.4%, P < 0.0001) and shorter LOS (3.0 vs. 3.7 days, P < 0.0001) compared with females. Increased age was associated with decreased SDD (P < 0.0001) and increased LOS (P < 0.0001). Australia's SDD rate was lower than in both New Zealand and the United Kingdom. CONCLUSION: While SDD and LOS following UHR improved across the study period, SDD rates remain below the RACS recommendation and compare unfavourably internationally. Advancing age and female gender were associated with decreased SDD and increased LOS demonstrating potential areas for improvement. Multiple strategies are discussed to address the persistently low rates of SDD after UHR.

Gastrectomy mortality in Australia.

BACKGROUND: Despite advances in medical management and endoscopic therapy, gastrectomy remains an important yet high-risk procedure for a range of benign and malignant upper gastrointestinal pathologies. No study has previously analysed Australian gastrectomy perioperative mortality rate (POMR). This retrospective, population-based cohort study was conducted to determine the Australian national gastrectomy POMR, allowing state-based and regional trends and outcomes to be assessed. METHODS: Logistic regression models were compared using de-identified procedural data between 1 July 2005 and 30 June 2017 from the Australian Institute of Health and Welfare. Codes relating to total and subtotal gastrectomy contained in the Australian Classification of Health Interventions were used to extract patient data. Mortality rates were risk adjusted for age and gender. Temporal trends and differences between states/territories and regions were investigated. RESULTS: The national average POMR throughout the study period was 2.1%. For subtotal gastrectomy, the national mean POMR was 1.1%, decreasing from 2.7% (2005) to 1.3% (2017). For total gastrectomy, the national mean POMR was 2.8%, decreasing from 3.3% (2005) to 1.7% (2017). POMR significantly reduced over time without variation between states or regions. Procedure volume steadily reduced in rural centres with a concomitant increase in metropolitan centres over time. CONCLUSION: Pleasingly, the Australian gastrectomy POMR is favourable when compared to international cohorts. Improved outcomes were consistent between states and territories, and metropolitan and regional centres. Progressive metropolitan centralization of gastrectomy was demonstrated without evidence of improved outcomes.

Biopolymeric Coacervate Microvectors for the Delivery of Functional Proteins to Cells.

The extent to which biologic payloads can be effectively delivered to cells is a limiting factor in the development of new therapies. Limitations arise from the lack of pharmacokinetic stability of biologics in vivo. Encapsulating biologics in a protective delivery vector has the potential to improve delivery profile and enhance performance. Coacervate microdroplets are developed as cell-mimetic materials with established potential for the stabilization of biological molecules, such as proteins and nucleic acids. Here, the development of biodegradable coacervate microvectors (comprising synthetically modified amylose polymers) is presented, for the delivery of biologic payloads to cells. Amylose-based coacervate microdroplets are stable under physiological conditions (e.g., temperature and ionic strength), are noncytotoxic owing to their biopolymeric structure, spontaneously interacted with the cell membrane, and are able to deliver and release proteinaceous payloads beyond the plasma membrane. In particular, myoglobin, an oxygen storage and antioxidant protein, is successfully delivered into human mesenchymal stem cells (hMSCs) within 24 h. Furthermore, coacervate microvectors are implemented for the delivery of human bone morphogenetic protein 2 growth factor, inducing differentiation of hMSCs into osteoprogenitor cells. This study demonstrates the potential of coacervate microdroplets as delivery microvectors for biomedical research and the development of new therapies.

From Patient Engagement to Precision Oncology: Leveraging Informatics to Advance Cancer Care.

OBJECTIVES: Conduct a survey of the literature for advancements in cancer informatics over the last three years in three specific areas where there has been unprecedented growth: 1) digital health; 2) machine learning; and 3) precision oncology. We also highlight the ethical implications and future opportunities within each area. METHODS: A search was conducted over a three-year period in two electronic databases (PubMed, Google Scholar) to identify peer-reviewed articles and conference proceedings. Search terms included variations of the following: neoplasms[MeSH], informatics[MeSH], cancer, oncology, clinical cancer informatics, medical cancer informatics. The search returned too many articles for practical review (23,994 from PubMed and 23,100 from Google Scholar). Thus, we conducted searches of key PubMed-indexed informatics journals and proceedings. We further limited our search to manuscripts that demonstrated a clear focus on clinical or translational cancer informatics. Manuscripts were then selected based on their methodological rigor, scientific impact, innovation, and contribution towards cancer informatics as a field or on their impact on cancer care and research. RESULTS: Key developments and opportunities in cancer informatics research in the areas of digital health, machine learning, and precision oncology were summarized. CONCLUSION: While there are numerous innovations in the field of cancer informatics to advance prevention and clinical care, considerable challenges remain related to data sharing and privacy, digital accessibility, and algorithm biases and interpretation. The implementation and application of these findings in cancer care necessitates further consideration and research.

Safe surgery during the coronavirus disease 2019 crisis.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created a global pandemic. Surgical care has been impacted, with concerns raised around surgical safety, especially in terms of laparoscopic versus open surgery. Due to potential aerosol transmission of SARS-CoV-2, precautions during aerosol-generating procedures and production of surgical plume are paramount for the safety of surgical teams. METHODS: A rapid review methodology was used with evidence sourced from PubMed, Departments of Health, surgical colleges and other health authorities. From this, a working group of expert surgeons developed recommendations for surgical safety in the current environment. RESULTS: Pre-operative testing of surgical patients with reverse transcription-polymerase chain reaction does not guarantee lack of infectivity due to a demonstrated false-negative rate of up to 30%. All bodily tissues and fluids should therefore be treated as a potential source of COVID-19 infection during operative management. Caution must be taken, especially when using an energy source that produces surgical plumes, and an appropriate capture device should also be used. Limiting the use of such devices or using lower energy devices is desirable. To reduce perceived risks association with desufflation of pneumoperitoneum during laparoscopic surgery, an appropriate suction irrigator system, attached to a high-efficiency particulate air filter, should be used. Additionally, appropriate use of personal protective equipment by the surgical team is necessary during high-risk aerosol-generating procedures. CONCLUSIONS: As a result of the rapid review, evidence-based guidance has been produced to support safe surgical practice.

Melanoblast transcriptome analysis reveals pathways promoting melanoma metastasis.

Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posit that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover metastatic melanoma biology. Using a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, we identify melanoblast-specific genes whose expression contribute to metastatic competence and derive a 43-gene signature that predicts patient survival. We identify a melanoblast gene, KDELR3, whose loss impairs experimental metastasis. In contrast, KDELR1 deficiency enhances metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover targetable pathways for melanoma therapy.

Size-dependent melting point depression of nickel nanoparticles.

We investigate the phase-transition behaviour of nickel nanoparticles (3-6 nm) via dynamic TEM. The nanoparticles were synthesized within a reverse microemulsion and then monitored via dynamic TEM simultaneously while undergoing controlled heating. The size-dependent melting point depression experimentally observed is compared with, and is in good agreement with existing thermodynamic and molecular dynamic predictions.

Regional versus metropolitan pancreaticoduodenectomy mortality in Australia.

BACKGROUND: This retrospective, population-based cohort study aims to determine if differences in the regional distribution of procedures or variation in regional mortality contributes to the variable pancreaticoduodenectomy (PD) mortality between Australian states and territories. METHODS: De-identified procedural data from public hospitals between 1 July 2005 and 30 June 2015 from the Australian Institute of Health and Welfare were analysed. The regional distribution of procedures and variation in perioperative mortality rate (POMR) were investigated in New South Wales (NSW), Victoria and Queensland (QLD) using logistic regression analysis. RESULTS: NSW performed the highest proportion of city-based procedures (93.8%) while QLD performed the highest proportion of regional procedures (15.3%). QLD demonstrated the lowest city mortality (1.9%) and lowest POMR overall (2.0%). City, regional and state-wide mortality was highest in NSW (5.0%, 8.4% and 5.3%). No significant difference in POMR was demonstrated between regional and city hospitals in each of the states (P = 0.46) or across all states (P = 0.50). CONCLUSION: This study demonstrates comparable regional PD distribution across Australia. The difference in PD POMR between city and regional areas was not found to be statistically significant. NSW exhibited the highest city, regional and overall PD POMR, potentially warranting further investigation.

restfulSE: A semantically rich interface for cloud-scale genomics with Bioconductor.

Bioconductor's SummarizedExperiment class unites numerical assay quantifications with sample- and experiment-level metadata.  SummarizedExperiment is the standard Bioconductor class for assays that produce matrix-like data, used by over 200 packages.  We describe the restfulSE package, a deployment of  this data model that supports remote storage.  We illustrate use of SummarizedExperiment with remote HDF5 and Google BigQuery back ends, with two applications in cancer genomics.  Our intent is to allow the use of familiar and semantically meaningful programmatic idioms to query genomic data, while abstracting the remote interface from end users and developers.

Selective photothermal killing of cancer cells using LED-activated nucleus targeting fluorescent carbon dots.

The development of effective theranostic probes in cancer therapy is hampered due to issues with selectivity and off-target toxicity. We report the selective LED-photothermal ablation of cervical (HeLa) cancer cells over human dermal fibroblasts (HDF) using a new class of green-emissive fluorescent carbon dots (FCDs). The FCDs can be easily prepared in one pot using cheap and commercial starting materials. Physico-chemical characterization revealed that a surface coating of 2,5-deoxyfructosazine on a robust amorphous core gives rise to the nanomaterial's unique properties. We show that intracellular uptake mostly involves passive mechanisms in combination with intracellular DNA interactions to target the nucleus and that cancer cell selective killing is likely due to an increase in intracellular temperature in combination with ATP depletion, which is not observed upon exposure to either the "naked" core FCDs or the surface components individually. The selectivity of these nanoprobes and the lack of apparent production of toxic metabolic byproducts make these new nanomaterials promising agents in cancer therapy.

Fatal flaws in clinical decision making.

BACKGROUND: Clinical decision making is a core competency of surgical practice, involving a continuous and evolving process of data interpretation and evaluation. The aim of this article is twofold. First, to recognize patient deaths where a clinical incident arose following unsatisfactory clinical decision making, determining where in the clinical decision-making process each failure occurred. Second, to discuss and explore individual incidents to provide lessons from which the surgical community can learn. METHODS: Using the Australian and New Zealand Audit of Surgical Mortality database, all deaths from 1 January 2015 to 31 December 2015 were analysed. All deaths in which the surgeon or assessor identified an aspect of patient management that was inadequate were recognized. Clinical incidents deemed by the assessor to be an area of concern or an adverse event were individually reviewed to determine if a clinical decision-making incident (CDMI) occurred. CDMIs were categorized into various themes depending on the nature of the incident. RESULTS: A total of 3422 fully audited deaths occurred throughout the study period; from these cases, 226 individual CDMIs were identified. Decision to operate was the most commonly identified CDMI (n = 99, 43.8%), followed by diagnostic error (n = 49, 21.7%). The least common CDMI identified was inadequate post-operative assessment (n = 14, 6.2%). CONCLUSION: This paper demonstrates thought-provoking examples of clinical decision-making failure implicated in patient death. Clinical decision-making failures most commonly occur around the decision to operate with increased discussion of complex cases possibly required. Further CDMI evaluation should be considered to complement more traditional methods of surgical mortality evaluation.

Practical Three-Minute Synthesis of Acid-Coated Fluorescent Carbon Dots with Tuneable Core Structure.

We report a one-pot, three-minute synthesis of carboxylic acid-decorated fluorescent carbon dots (COOH-FCDs) with tuneable core morphology dependent on the surface passivating agent. Mechanism investigations highlighted the presence of key pyrazine and polyhydroxyl aromatic motifs, which are formed from the degradation of glucosamine in the presence of a bifunctional linker bearing acid and amine groups. The novel COOH-FCDs are selective Fe3+ and hemin sensors. Furthermore, the FCDs are shown to be non-toxic, fluorescent bioimaging agents for cancer cells.

Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours.

Analysis of molecular aberrations across multiple cancer types, known as pan-cancer analysis, identifies commonalities and differences in key biological processes that are dysregulated in cancer cells from diverse lineages. Pan-cancer analyses have been performed for adult but not paediatric cancers, which commonly occur in developing mesodermic rather than adult epithelial tissues. Here we present a pan-cancer study of somatic alterations, including single nucleotide variants, small insertions or deletions, structural variations, copy number alterations, gene fusions and internal tandem duplications in 1,699 paediatric leukaemias and solid tumours across six histotypes, with whole-genome, whole-exome and transcriptome sequencing data processed under a uniform analytical framework. We report 142 driver genes in paediatric cancers, of which only 45% match those found in adult pan-cancer studies; copy number alterations and structural variants constituted the majority (62%) of events. Eleven genome-wide mutational signatures were identified, including one attributed to ultraviolet-light exposure in eight aneuploid leukaemias. Transcription of the mutant allele was detectable for 34% of protein-coding mutations, and 20% exhibited allele-specific expression. These data provide a comprehensive genomic architecture for paediatric cancers and emphasize the need for paediatric cancer-specific development of precision therapies.