A Systematised Literature Review of Real-World Treatment Patterns and Outcomes in Unresectable Advanced or Metastatic Biliary Tract Cancer.

BACKGROUND: Biliary tract cancers are rare aggressive malignancies typically diagnosed when the disease is metastatic or unresectable, precluding curative treatment. OBJECTIVE: We aimed to identify treatment guidelines, real-world treatment patterns, and outcomes for unresectable advanced or metastatic biliary tract cancers in adult patients. METHODS: Databases (MEDLINE, Embase, Cochrane Database of Systematic Reviews) were systematically searched between 1 January, 2000 and 25 November, 2021, and supplemented by hand searches. Eligible records were (1) treatment guidelines and (2) observational studies reporting real-world treatment outcomes, for unresectable advanced or metastatic biliary tract cancers. Only studies performed in the UK, Germany, France, Australia, Canada and South Korea were extracted, to moderate the number of records for synthesis while maintaining representation of a wide range of biliary tract cancer incidences. RESULTS: A total of 66 relevant unique full-text records were extracted, including 16 treatment guidelines and 50 observational studies. Among guidelines, chemotherapies were most strongly recommended at first line (1L); the combination of gemcitabine and cisplatin (GEMCIS) was recommended as the standard of care in 1L. Recommendations for systemic chemotherapy in the second line (2L) conflicted because of uncertainties around survival benefit. Guidelines on further lines of treatment included a range of locoregional modalities and stenting or best supportive care without providing clear recommendations because of data paucity. Fifty observational studies reporting real-world treatment outcomes were extracted, of which 25 (50%) and 9 (18%) reported outcomes in 1L and 2L, respectively; 22 (44%) reported outcomes for treatments described as 'palliative'. In 1L, outcomes for systemic chemotherapy were most frequently described (23/25 studies), and GEMCIS was the most common systemic chemotherapy used (10/23 studies) in line with guidelines. Median overall survival with 1L systemic chemotherapy was < 12 months in most studies (16/23; range 4.7-22.3 months). Most 2L studies (10/11) described outcomes for systemic chemotherapy, most commonly for fluoropyrimidine-based regimen (5/10 studies). Median overall survival with 2L systemic chemotherapy was < 12 months in 5/10 studies (range 4.9-21.5 months). Median progression-free survival was reported more rarely than median overall survival. Some studies with small sample sizes or specifically selected patient populations (e.g. higher performance status, or patients who had already responded to treatment) achieved higher median overall survival. CONCLUSIONS: At the time of this review, treatment options for unresectable advanced or metastatic biliary tract cancers confer poor real-world survival. For over a decade, GEMCIS remained the 1L standard of care, highlighting the lack of therapeutic innovation in this indication and the urgent unmet need for novel treatments with improved outcomes in this aggressive condition. Additional observational studies are needed to further understand the effectiveness of currently available treatments, as well as newly available therapies including the addition of immunotherapy in the evolving treatment landscape.

Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis.

The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.

Evaluation of the National Institute for Health and Care Excellence Diagnostics Assessment Program Decisions: Incremental Cost-Effectiveness Ratio Thresholds and Decision-Modifying Factors.

OBJECTIVES: The National Institute for Health and Care Excellence (NICE) Diagnostics Assessment Programme (DAP) evaluates the cost-effectiveness of diagnostic technologies. A decision-making process benchmarking the incremental cost-effectiveness ratio (ICER) against a threshold while considering decision-modifying factors is common to NICE evaluations. This study investigated whether DAP decisions are consistent with the ICER thresholds described in the DAP manual, and to assess the impact of decision-modifying factors. METHODS: DAP evaluations published before March 2018 were reviewed, and the following items were extracted: diagnostic technologies evaluated, decision problems assessed, Diagnostics Advisory Committee (DAC) decisions, incremental quality-adjusted life years (QALYs), incremental costs, ICERs considered to be most plausible by the DAC, and decision justifications. RESULTS: All 30 evaluations were reviewed; 8 were excluded because the DAC concluded there was "insufficient evidence" for decision making. In the remaining 22 evaluations, 91 decision problems were identified for further analysis, of which 52, 15, and 24 received "recommended," "not recommended," and "not recommended-only in research" guidance, respectively. The overall consistency rate of the DAC decisions with the £20 000/QALY threshold was 73.6%. Diagnostic technologies that were not recommended, despite an ICER less than £20 000/QALY, were associated with a larger number of decision-modifying factors favoring the comparator, versus recommended diagnostic technologies with ICERs less than £20 000/QALY. For technologies with ICERs greater than £20 000/QALY, the number of decision-modifying factors was comparable for positive and negative recommendations. CONCLUSIONS: Most DAP decisions were consistent with the ICER threshold. However, cost-effectiveness was not the only determining factor in decision making; recommendations also considered patient- and healthcare-centric factors and uncertainty.

Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is characterized by lipotoxicity, inflammation and fibrosis, ultimately leading to end-stage liver disease. The molecular mechanisms promoting NASH are poorly understood, and treatment options are limited. Here, we demonstrate that hepatic expression of bone morphogenetic protein 8B (BMP8B), a member of the transforming growth factor beta (TGFß)-BMP superfamily, increases proportionally to disease stage in people and animal models with NASH. BMP8B signals via both SMAD2/3 and SMAD1/5/9 branches of the TGFß-BMP pathway in hepatic stellate cells (HSCs), promoting their proinflammatory phenotype. In vivo, the absence of BMP8B prevents HSC activation, reduces inflammation and affects the wound-healing responses, thereby limiting NASH progression. Evidence is featured in primary human 3D microtissues modelling NASH, when challenged with recombinant BMP8. Our data show that BMP8B is a major contributor to NASH progression. Owing to the near absence of BMP8B in healthy livers, inhibition of BMP8B may represent a promising new therapeutic avenue for NASH treatment.

Cost-minimisation model of magnetic resonance-guided focussed ultrasound therapy compared to unilateral deep brain stimulation for essential tremor treatment in Japan.

OBJECTIVE: To investigate the cost differences between magnetic resonance-guided focussed ultrasound (MRgFUS) and unilateral deep brain stimulation (DBS) for the treatment of medication-refractory essential tremor (ET) in Japan using a cost-minimisation model. METHODS: A cost-minimisation model estimated total costs for MRgFUS and unilateral DBS by summing the pre-procedure, procedure, and post-procedure costs over a 12-month time horizon, using data from published sources and expert clinical opinion. The model base case considered medical costs from fee-for-service tariffs. Scenario analyses investigated the use of Diagnosis Procedure Combination tariffs, a diagnosis-related group-based fixed-payment system, and the addition of healthcare professional labour costs healthcare professionals using tariffs from the Japanese Health Insurance Federation for Surgery. One-way sensitivity analyses altered costs associated with tremor recurrence after MRgFUS, the extraction rate following unilateral DBS, the length of hospitalisation for unilateral DBS and the procedure duration for MRgFUS. The impact of uncertainty in model parameters on the model results was further explored using probabilistic sensitivity analysis. RESULTS: Compared to unilateral DBS, MRgFUS was cost saving in the base case and Diagnosis Procedure Combination cost scenario, with total savings of JPY400,380 and JPY414,691, respectively. The majority of savings were accrued at the procedural stage. Including labour costs further increased the cost differences between MRgFUS and unilateral DBS. Cost savings were maintained in each sensitivity analysis and the probabilistic sensitivity analysis, demonstrating that the model results are highly robust. CONCLUSIONS: In the Japanese healthcare setting, MRgFUS could be a cost saving option versus unilateral DBS for treating medication-refractory ET. The model results may even be conservative, as the cost of multiple follow-ups for unilateral DBS and treatment costs for adverse events associated with each procedure were not included. This model is also consistent with the results of other economic analyses of MRgFUS versus DBS in various settings worldwide.

Adipocyte-secreted BMP8b mediates adrenergic-induced remodeling of the neuro-vascular network in adipose tissue.

Activation of brown adipose tissue-mediated thermogenesis is a strategy for tackling obesity and promoting metabolic health. BMP8b is secreted by brown/beige adipocytes and enhances energy dissipation. Here we show that adipocyte-secreted BMP8b contributes to adrenergic-induced remodeling of the neuro-vascular network in adipose tissue (AT). Overexpression of bmp8b in AT enhances browning of the subcutaneous depot and maximal thermogenic capacity. Moreover, BMP8b-induced browning, increased sympathetic innervation and vascularization of AT were maintained at 28 °C, a condition of low adrenergic output. This reinforces the local trophic effect of BMP8b. Innervation and vascular remodeling effects required BMP8b signaling through the adipocytes to 1) secrete neuregulin-4 (NRG4), which promotes sympathetic axon growth and branching in vitro, and 2) induce a pro-angiogenic transcriptional and secretory profile that promotes vascular sprouting. Thus, BMP8b and NRG4 can be considered as interconnected regulators of neuro-vascular remodeling in AT and are potential therapeutic targets in obesity.

Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans.

Thermogenesis in brown adipose tissue (BAT) is an important component of energy expenditure in mammals. Recent studies have confirmed its presence and metabolic role in humans. Defining the physiological regulation of BAT is therefore of great importance for developing strategies to treat metabolic diseases. Here we show that the soluble form of the low-density lipoprotein receptor relative, LR11/SorLA (sLR11), suppresses thermogenesis in adipose tissue in a cell-autonomous manner. Mice lacking LR11 are protected from diet-induced obesity associated with an increased browning of white adipose tissue and hypermetabolism. Treatment of adipocytes with sLR11 inhibits thermogenesis via the bone morphogenetic protein/TGFß signalling pathway and reduces Smad phosphorylation. In addition, sLR11 levels in humans are shown to positively correlate with body mass index and adiposity. Given the need for tight regulation of a tissue with a high capacity for energy wastage, we propose that LR11 plays an energy conserving role that is exaggerated in states of obesity.

Transcription factor Nrf1 negatively regulates the cystine/glutamate transporter and lipid-metabolizing enzymes.

Liver-specific Nrf1 (NF-E2-p45-related factor 1) knockout mice develop nonalcoholic steatohepatitis. To identify postnatal mechanisms responsible for this phenotype, we generated an inducible liver-specific Nrf1 knockout mouse line using animals harboring an Nrf1(flox) allele and a rat CYP1A1-Cre transgene (Nrf1(flox/flox)::CYP1A1-Cre mice). Administration of 3-methylcholanthrene (3-MC) to these mice (Nrf1(flox/flox)::CYP1A1-Cre+3MC mice) resulted in loss of hepatic Nrf1 expression. The livers of mice lacking Nrf1 accumulated lipid, and the hepatic fatty acid (FA) composition in such animals differed significantly from that in the Nrf1(flox/flox)::CYP1A1-Cre control. This change was provoked by upregulation of several FA metabolism genes. Unexpectedly, we also found that the level of glutathione was increased dramatically in livers of Nrf1(flox/flox)::CYP1A1-Cre+3MC mice. While expression of glutathione biosynthetic enzymes was unchanged, xCT, a component of the cystine/glutamate antiporter system x(c)(-), was significantly upregulated in livers of Nrf1(flox/flox)::CYP1A1-Cre+3MC mice, suggesting that Nrf1 normally suppresses xCT. Thus, stress-inducible expression of xCT is a two-step process: under homeostatic conditions, Nrf1 effectively suppresses nonspecific transactivation of xCT, but when cells encounter severe oxidative/electrophilic stress, Nrf1 is displaced from an antioxidant response element (ARE) in the gene promoter while Nrf2 is recruited to the ARE. Thus, Nrf1 controls both the FA and the cystine/cysteine content of hepatocytes by participating in an elaborate regulatory network.

The different shades of fat.

Our understanding of adipose tissue biology has progressed rapidly since the turn of the century. White adipose tissue has emerged as a key determinant of healthy metabolism and metabolic dysfunction. This realization is paralleled only by the confirmation that adult humans have heat-dissipating brown adipose tissue, an important contributor to energy balance and a possible therapeutic target for the treatment of metabolic disease. We propose that the development of successful strategies to target brown and white adipose tissues will depend on investigations that elucidate their developmental origins and cell-type-specific functional regulators.

Regulation of glucose homoeostasis by brown adipose tissue.

Brown adipose tissue (BAT) has emerged as a therapeutic target for the treatment of obesity. Activation of BAT in human beings could also have beneficial metabolic effects that might resolve common complications of obesity, such as type 2 diabetes, by ameliorating the glucolipotoxic pathological changes that underlie the development of peripheral insulin resistance and impaired insulin secretion due to pancreatic ß-cell failure. Evidence from rodent models suggests that BAT activation improves glucose homoeostasis through several mechanisms, which could point to new strategies to optimise stimulation of BAT in human beings and reverse insulin resistance in peripheral tissues.