Molecular biology of cholangiocarcinoma and its implications for targeted therapy in patient management.

Cholangiocarcinoma (CCA) remains a devastating malignancy and a significant challenge to treat. The majority of CCA patients are diagnosed at an advanced stage, making the disease incurable in most cases. The advent of high-throughput genetic sequencing has significantly improved our understanding of the molecular biology underpinning cancer. The identification of 'druggable' genetic aberrations and the development of novel targeted therapies against them is opening up new treatment strategies. Currently, 3 targeted therapies are approved for use in CCA; Ivosidenib in patients with IDH1 mutations and Infigratinib/Pemigatinib in those with FGFR2 fusions. As our understanding of the biology underpinning CCA continues to improve it is highly likely that additional targeted therapies will become available in the near future. This is important, as it is thought up to 40 % of CCA patients harbour a potentially actionable mutation. In this review we provide an overview of the molecular pathogenesis of CCA and highlight currently available and potential future targeted treatments.

Peptide receptor radionuclide therapy with (90)Y-DOTATATE/(90)Y-DOTATOC in patients with progressive metastatic neuroendocrine tumours: assessment of response, survival and toxicity.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is an established treatment for patients with metastatic neuroendocrine tumours (NETs), although which factors are associated with an improved overall survival (OS) remains unclear. The primary aim of this study is to determine to what extent a radiological response to (90)Y-DOTATOC/(90)Y-DOTATATE PRRT is associated with an improved OS. The association of biochemical and clinical response to OS were assessed as secondary outcome measures. METHODS: A retrospective analysis was conducted on 57 patients: radiological response was classified using RECIST criteria, biochemical response was classified using WHO criteria and clinical response was assessed subjectively. Responses were recorded as positive response (PR), stable disease (SD) or progressive disease (PD), and survival analysed. RESULTS: Radiological response was achieved in 71.5% (24.5% PR, 47% SD) and was associated with a greater OS (51 and 56 months, respectively), compared with PD (18 months). A biochemical or clinical response post PRRT were not associated with a statistically significant improvement in OS. However, when combined with radiological response a survival benefit was observed according to the number of outcomes (radiological, biochemical, clinical), in which a response was observed. Mild haematological toxicity was common, renal toxicity was rare. CONCLUSION: In patients with progressive metastatic NETs receiving (90)Y-DOTATOC/(90)Y-DOTATATE PRRT, a radiological response with either a PR or a SD post therapy confers a significant OS benefit.

Doppler echocardiography in cardiac transplant patients: allograft rejection and its relationship to diastolic function.

Right ventricular endomyocardial biopsy has been the traditional gold standard for determining cardiac transplant rejection. Although endomyocardial biopsy has proved useful in guiding rejection therapy, this procedure is not without risk. The objective of the present study was to determine whether a noninvasive method for assessing cardiac diastolic function would be of value in predicting biopsy scores. Doppler echocardiographic indices of left ventricular function were compared with biopsy scores in 43 studies from 23 patients (age 50 +/- 8 years). The average time from transplant to echocardiographic study was 1.5 years. Standard clinical indices of diastolic function failed to predict biopsy results. The A-Ar interval, evaluated in 36 studies, was found to significantly decrease (p < 0.003) with increasing biopsy scores. Preliminary results suggest that this echocardiographic parameter may prove useful in predicting biopsy results.

Response of pulpal blood flow to intra-arterial infusion of endothelin.

Laser Doppler flowmetry was used to determine the effect of the vasoconstrictor endothelin 1 (ET-1) on the pulpal blood flow of intact dogs' teeth during mandibular arterial infusion. ET-1 produced a profound decrease in pulpal blood flow of a relatively long duration at lower doses than similar infusions of norepinephrine. The decrease in pulpal blood flow in response to ET-1 was partially attenuated by the calcium channel blocker nifedipine. These findings demonstrate the presence of receptors for ET-1 in the microvasculature of the dental pulp and suggests that ET-1 may function in the local control of the pulpal microcirculation.

Prostaglandin E levels in third ventricular cerebrospinal fluid of rabbits during fever and changes in body temperature.

1. A method was devised to sample cerebrospinal fluid (c.s.f.) from the third ventricle of conscious rabbits.2. Levels of PGE were measured in c.s.f. withdrawn from the third ventricle of rabbits exposed to a variety of manipulations of both brain and body core temperatures which mimicked various facets of fever in these animals. These results were compared to the levels of PGE in the c.s.f. of the same rabbits made febrile by I.V. injections of endogenous pyrogen.3. Levels of PGE in ventricular c.s.f. remained unaltered at 2-3 ng/ml. during exposure to cold, hyperthermia due to heat exposure, hypothalamic cooling or hypothalamic heating, whereas during fever produced by endogenous pyrogen, they rose to an average of 11-12 ng/ml. Furthermore, a significant positive correlation was established between the level of PGE measured in the c.s.f. and the subsequent height of the fever produced by the pyrogen.4. Since production of PGE within the brain is not caused by changes in the brain or body temperatures which are comparable to those observed during fever, and yet greater than fivefold increases in the PGE levels in c.s.f. are produced by I.V. injections of endogenous pyrogen, it is concluded that PGE production in the brain is involved in the pathogenesis of fever.

Hypothalamic thermoregulatory pathways in the rat.

The cutaneous blood flow (mbl), rate of oxygen consumption (Vo2), rectal (Tre) and cutaneous (Tsk) temperatures, and shivering activity were measured in unanthetized male rats during a 2-h exposure to 26, 33, or 5 degrees C 2 wk after selective bilateral hypothalamic microknife cuts. Animals with preoptic-anterior hypothalamic (PO/AH) junction cuts 1.5 or 3.0 mm lateral to the midline, as well as parasagittal cuts which separated connections between the PO/AH and medial forebrain bundle exhibited a higher mbl at 26 degrees C than did sham-operated rats. At 5 degrees C the extended (3.0 mm) PO/AH cuts as well as the parasagittal cuts prevented cutaneous vasoconstriction but had no effect on shivering activity; hence Tre was not maintained. None of the cuts demonstrably impaired thermoregulation in the 33 degrees C environment. These results suggest that different sites in the hypothalamus may separately control cold-induced skin vasoconstriction and shivering activity, as well as heat-induced skin vasodilation. It would seem therefore that the integrity of the PO/AH is indispensable in rats for cold-induced cutaneous vasoconstriction but not for cold thermogenesis, and also not for heat-induced cutaneous vasodilation.