Fibroblast growth factor receptor 2 (FGFR2) inhibitors are now being included in the treatment guidelines of multiple countries for patients with advanced cholangiocarcinoma (CCA). Activation of the FGF-FGFR pathway is related to proliferation and tumor progression. Targeting the FGF-FGFR pathway is effective and can yield durable responses in patients with CCA harboring FGFR2 fusions or rearrangements. In this review article, we address molecules and clinical trials evaluating FGFR inhibitors in advanced CCA. We will further discuss identified mechanisms of resistance and the strategies to overcome it. The incorporation of next-generation sequencing in advanced CCA and circulating tumor DNA on disease progression will unveil mechanisms of resistance and improve the development of future clinical trials and more selective drugs and combinations.

Targeting Fibroblast Growth Factor Receptor Pathway: Precision Medicine for Biliary Cancer and Beyond.

Seminars in Liver Disease

The International Society on Thrombosis and Haemostasis (ISTH) released overt disseminated intravascular coagulation (DIC) diagnostic criteria in 2001. Since then, DIC has been understood as the end-stage consumptive coagulopathy and not the therapeutic target. However, DIC is not merely a decompensated coagulation disorder, but also includes early stages with systemic activation in coagulation. Thus, the ISTH has recently released sepsis-induced coagulopathy (SIC) criteria that can diagnose compensated-phase of coagulopathy with readily available biomarkers.

DIC is a laboratory-based diagnosis due to various critical conditions, although sepsis is the most common underlying disease. The pathophysiology of sepsis-associated DIC is multifactorial, and in addition to coagulation activation with suppressed fibrinolysis, multiple inflammatory responses are initiated by activated leukocytes, platelets, and vascular endothelial cells as part of thromboinflammation. Although overt DIC diagnostic criteria were established by ISTH to diagnose the advanced stage of DIC, additional criteria that can detect an earlier stage of DIC were needed for potential therapeutic considerations. Accordingly, the ISTH introduced SIC criteria in 2019 that are easy to use and require only platelet count, prothrombin time-international normalized ratio, and Sequential Organ Failure Assessment Score. SIC score can be used to evaluate disease severity and determine the timing of potential therapeutic interventions. One of the major disadvantages in treating sepsis-associated DIC is the lack of availability of specific therapeutic approaches beyond treating the underlying infection. Clinical trials to date have failed because included patients who were not coagulopathic. Nevertheless, in addition to infection control, anticoagulant therapy will be the choice for sepsis-associated DIC. Therefore, the efficacy of heparin, antithrombin, and recombinant thrombomodulin has to be proven in future clinical studies.

It is necessary to develop a novel therapeutic strategy against sepsis-associated DIC and improve the outcomes. Consequently, we recommend screening and monitoring DIC using SIC scoring system.

The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation.

Journal of Intensive Care

Abdominal wall closure.

British Journal of Surgery

This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and&#xa0;aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.

Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement.

Nature Reviews. Endocrinology

To investigate brain MRI abnormalities in a cohort of patients with rapidly progressive dementia (RPD) with and without a diagnosis of Creutzfeldt-Jakob disease (CJD).

One hundred and seven patients with diagnosis of prion disease (60 with definite sCJD, 33 with probable sCJD and 14 with genetic prion disease) and 40 non-prion related RPD patients (npRPD) underwent brain MRI including DWI and FLAIR. MRIs were evaluated with a semiquantitative rating score, which separately considered abnormal signal extent and intensity in 22 brain regions. Clinical findings at onset, disease duration, cerebrospinal-fluid 14-3-3 and t-tau protein levels, and EEG data were recorded.

Among patients with definite/probable diagnosis of CJD or genetic prion disease, 2/107 had normal DWI-MRI: in one patient a 2-months follow-up DWI-MRI showed CJD-related changes while the other had autopsy-proven CJD despite no DWI abnormalities 282&#xa0;days after clinical onset. CJD-related cortical changes were detected in all lobes and involvement of thalamus was common. In the npRPD groups, 6/40 patients showed DWI alterations that clustered in three different patterns: (1) minimal/doubtful signal alterations (limbic encephalitis, dementia with Lewy bodies); (2) clearly suggestive of alternative diagnoses (status epilepticus, Wernicke or metabolic encephalopathy); (3) highly suggestive of CJD (mitochondrial disease), though cortical swelling let exclude CJD.

In the diagnostic work-up of RPD, negative/doubtful DWI makes CJD diagnosis rather unlikely, while specific DWI patterns help differentiating CJD from alternative diagnoses. The pulvinar sign is not exclusive of the variant form.

MRI abnormalities in Creutzfeldt-Jakob disease and other rapidly progressive dementia.

Journal of Neurology

Patients with bacteremia caused by gram positive bacteria are at risk for infective endocarditis (IE). Since IE needs long antibiotic treatment and sometimes heart valve surgery, it is very important to identify patients with IE.

In this narrative review we present and discuss how to determine which investigations to detect IE that are needed in individual patients with gram positive bacteremia.

Published original studies and previous reviews in English, within the relevant field are used.

First, the different qualities of the bacteremia in relation to IE-risk are discussed. The risk for IE in bacteremia is related to the species of the bacterium but also to monomicrobial bacteremia and the number of positive cultures. Secondly, patient-related factors for IE risk in bacteremia are presented. Next, the risk stratification systems to determine the risk for IE in gram positive bacteremia caused by Staphylococcus aureus, viridans streptococci and Enterococcus faecalis are presented and their use is discussed. In the last part of the review, an account for the different modalities of IE-investigations is given. The main focus is on echocardiography which is the cornerstone of IE-investigations. Furthermore, 18 F-FDG PET/CT and cardiac CT are presented and their use is also discussed. A brief account for investigations used to identify embolic phenomena in IE is also given. Finally, we present a flow-chart suggesting which investigations to perform in relation to IE in patients with gram positive bacteremia.

For the individual patient as well as the healthcare system, it is important both to diagnose IE and to decide when to stop looking for IE. This review might be helpful in finding that balance.

Bacteremia with gram positive bacteria - when and how do I need to look for endocarditis?

Clinical Microbiology and Infection

Dilated cardiomyopathy is conventionally defined as the presence of left ventricular or biventricular dilatation or systolic dysfunction in the absence of abnormal loading conditions (eg, primary valve disease) or significant coronary artery disease sufficient to cause ventricular remodelling. This definition has been recognised as overly restrictive, as left ventricular hypokinesis without dilation could be the initial presentation of dilated cardiomyopathy. The causes of dilated cardiomyopathy comprise genetic (primary dilated cardiomyopathy) or acquired factors (secondary dilated cardiomyopathy). Acquired factors include infections, toxins, cancer treatment, endocrinopathies, pregnancy, tachyarrhythmias, and immune-mediated diseases. 5-15% of patients with acquired dilated cardiomyopathy harbour a likely pathogenic or pathogenic gene variant (ie, gene mutation). Therefore, the diagnostic tests and therapeutic approach should always consider both genetic and acquired factors. This Seminar will focus on the current multidimensional diagnostic and therapeutic approach and discuss the underlying pathophysiology that could drive future treatments aiming to repair or replace the existing gene mutation, or target the specific inflammatory, metabolic, or pro-fibrotic drivers of genetic or acquired dilated cardiomyopathy.

Targeting Fibroblast Growth Factor Receptor Pathway: Precision Medicine for Biliary Cancer and Beyond.

Full text links

For the best experience, use the Read mobile app

Targeting Fibroblast Growth Factor Receptor Pathway: Precision Medicine for Biliary Cancer and Beyond.

Full text links

Trending Papers

For the best experience, use the Read mobile app