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Targeted Oncology Jan 2024Pemigatinib (Pemazyre), a selective, potent, reversible, oral inhibitor of fibroblast growth factor receptor (FGFR) 1-3, has received conditional (in the EU) or... (Review)
Review
Pemigatinib (Pemazyre), a selective, potent, reversible, oral inhibitor of fibroblast growth factor receptor (FGFR) 1-3, has received conditional (in the EU) or accelerated (in the USA) approval for the treatment of adults with previously treated, unresectable locally-advanced or metastatic cholangiocarcinoma (CCA) with an FGFR2 gene fusion or rearrangement. Over the course of a single-arm, phase 2 study (FIGHT-202), just over a third of patients with pretreated, advanced CCA [almost exclusively intrahepatic CCA (iCCA)] harbouring an FGFR2 fusion or rearrangement who received pemigatinib once daily (2 weeks on, 1 week off) had an objective response; nearly half had stable disease. Median progression-free survival and overall survival at the time of the final analysis were 7.0 months and 17.5 months, respectively. Pemigatinib was generally well tolerated and had a manageable safety profile. The most common treatment-related adverse event, hyperphosphataemia, was exclusively grade 1-2 in severity and, similarly, observed ocular and nail toxicities were rarely grade ≥ 3 in severity. Pending confirmation of its clinical benefits in an ongoing cisplatin plus gemcitabine-controlled, phase 3 study (FIGHT-302), pemigatinib provides a valuable targeted therapy for pretreated patients with advanced (i)CCA harbouring a FGFR2 fusion or rearrangement.
Topics: Adult; Humans; Cholangiocarcinoma; Pyrimidines; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Morpholines; Pyrroles
PubMed: 38206555
DOI: 10.1007/s11523-023-01024-x -
Nephrology, Dialysis, Transplantation :... Oct 2023Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a common complication of CKD; it is associated with higher mortality in dialysis patients, while its impact...
BACKGROUND
Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a common complication of CKD; it is associated with higher mortality in dialysis patients, while its impact in non-dialysis patients remains mostly unknown. We investigated the associations between parathyroid hormone (PTH), phosphate and calcium (and their interactions), and all-cause, cardiovascular (CV) and non-CV mortality in older non-dialysis patients with advanced CKD.
METHODS
We used data from the European Quality study, which includes patients aged ≥65 years with estimated glomerular filtration rate ≤20 mL/min/1.73 m2 from six European countries. Sequentially adjusted Cox models were used to assess the association between baseline and time-dependent CKD-MBD biomarkers and all-cause, CV and non-CV mortality. Effect modification between biomarkers was also assessed.
RESULTS
In 1294 patients, the prevalence of CKD-MBD at baseline was 94%. Both PTH [adjusted hazard ratio (aHR) 1.12, 95% confidence interval (CI) 1.03-1.23, P = .01] and phosphate (aHR 1.35, 95% CI 1.00-1.84, P = .05), but not calcium (aHR 1.11, 95% CI 0.57-2.17, P = .76), were associated with all-cause mortality. Calcium was not independently associated with mortality, but modified the effect of phosphate, with the highest mortality risk found in patients with both hypercalcemia and hyperphosphatemia. PTH level was associated with CV mortality, but not with non-CV mortality, whereas phosphate was associated with both CV and non-CV mortality in most models.
CONCLUSIONS
CKD-MBD is very common in older non-dialysis patients with advanced CKD. PTH and phosphate are independently associated with all-cause mortality in this population. While PTH level is only associated with CV mortality, phosphate seems to be associated with both CV and non-CV mortality.
Topics: Humans; Aged; Chronic Kidney Disease-Mineral and Bone Disorder; Calcium; Parathyroid Hormone; Phosphates; Calcium, Dietary; Biomarkers; Renal Insufficiency, Chronic; Renal Dialysis
PubMed: 37230954
DOI: 10.1093/ndt/gfad100 -
Clinical Ophthalmology (Auckland, N.Z.) 2023Sclerochoroidal calcification (SCC) is a rare disease which is characterized by calcium deposition in the sclera. The choroid is secondarily involved. Typical... (Review)
Review
Sclerochoroidal calcification (SCC) is a rare disease which is characterized by calcium deposition in the sclera. The choroid is secondarily involved. Typical localization is in the midperipheral region, outside the vascular arcades. SCC is mostly located in the superotemporal quadrant. Often times, the patients are referred with the diagnosis of an amelanotic tumor. SCC may be dystrophic or metastatic. Metastatic SCC lesions are associated with conditions altering calcium and phosphate metabolism including primary and secondary hyperparathyroidism, vitamin D intoxication, renal failure, hyperphosphatemia, and destructive bony lesions. SCC lesions have a characteristic appearance and appear as distinct, ill-defined, yellow-white, elevated scleral/choroidal masses funduscopically. The purpose of this literature review is to review the current knowledge on SCC, highlight the imaging features, and discuss the differential diagnosis as well as management options.
PubMed: 37720010
DOI: 10.2147/OPTH.S399058 -
Journal of Molecular Endocrinology Jan 2024Several human disorders are caused by genetic or epigenetic changes involving the GNAS locus on chromosome 20q13.3 that encodes the alpha-subunit of the stimulatory G... (Review)
Review
Several human disorders are caused by genetic or epigenetic changes involving the GNAS locus on chromosome 20q13.3 that encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. Thus, pseudohypoparathyroidism type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal GNAS exons 1-13 resulting in characteristic abnormalities referred to as Albright's hereditary osteodystrophy (AHO) that are associated with resistance to several agonist ligands, particularly to parathyroid hormone (PTH), thereby leading to hypocalcemia and hyperphosphatemia. GNAS mutations involving the paternal Gsα exons also cause most of these AHO features, but without evidence for hormonal resistance, hence the term pseudopseudohypoparathyroidism (PPHP). Autosomal dominant pseudohypoparathyroidism type Ib (PHP1B) due to maternal GNAS or STX16 mutations (deletions, duplications, insertions, and inversions) is associated with epigenetic changes at one or several differentially methylated regions (DMRs) within GNAS. Unlike the inactivating Gsα mutations that cause PHP1A and PPHP, hormonal resistance is caused in all PHP1B variants by impaired Gsα expression due to loss of methylation at GNAS exon A/B, which can be associated in some familial cases with epigenetic changes at the other maternal GNAS DMRs. The genetic defect(s) responsible for sporadic PHP1B, the most frequent variant of this disorder, remain(s) unknown for the majority of patients. However, characteristic epigenetic GNAS changes can be readily detected that include a gain of methylation at the neuroendocrine secretory protein (NESP) DMR. Multiple genetic or epigenetic GNAS abnormalities can thus impair Gsα function or expression, consequently leading to inadequate cAMP-dependent signaling events downstream of various Gsα-coupled receptors.
Topics: Humans; Chromogranins; Pseudohypoparathyroidism; GTP-Binding Protein alpha Subunits, Gs; Epigenesis, Genetic; DNA Methylation
PubMed: 37965945
DOI: 10.1530/JME-23-0104 -
Journal of Applied Toxicology : JAT Jan 2024Alcohol consumption is associated with an increased risk of breast cancer, even at low alcohol intake levels, but public awareness of the breast cancer risk associated... (Review)
Review
Alcohol consumption is associated with an increased risk of breast cancer, even at low alcohol intake levels, but public awareness of the breast cancer risk associated with alcohol intake is low. Furthermore, the causative mechanisms underlying alcohol's association with breast cancer are unknown. The present theoretical paper uses a modified grounded theory method to review the research literature and propose that alcohol's association with breast cancer is mediated by phosphate toxicity, the accumulation of excess inorganic phosphate in body tissue. Serum levels of inorganic phosphate are regulated through a network of hormones released from the bone, kidneys, parathyroid glands, and intestines. Alcohol burdens renal function, which may disturb the regulation of inorganic phosphate, impair phosphate excretion, and increase phosphate toxicity. In addition to causing cellular dehydration, alcohol is an etiologic factor in nontraumatic rhabdomyolysis, which ruptures cell membranes and releases inorganic phosphate into the serum, leading to hyperphosphatemia. Phosphate toxicity is also associated with tumorigenesis, as high levels of inorganic phosphate within the tumor microenvironment activate cell signaling pathways and promote cancer cell growth. Furthermore, phosphate toxicity potentially links cancer and kidney disease in onco-nephrology. Insights into the mediating role of phosphate toxicity may lead to future research and interventions that raise public health awareness of breast cancer risk and alcohol consumption.
Topics: Humans; Female; Breast Neoplasms; Hyperphosphatemia; Phosphates; Kidney; Ethanol; Tumor Microenvironment
PubMed: 37332052
DOI: 10.1002/jat.4504 -
Annals of Translational Medicine Oct 2023Vascular calcification (VC) is common in chronic kidney disease (CKD) patients and is associated with poor cardiovascular outcomes. This study aims to review nutritive... (Review)
Review
BACKGROUND AND OBJECTIVE
Vascular calcification (VC) is common in chronic kidney disease (CKD) patients and is associated with poor cardiovascular outcomes. This study aims to review nutritive pro-calcifying factors of CKD.
METHODS
Electronic databases (PubMed, Embase, and the Cochrane Central Register of Controlled Trials) were searched from 2001 as at July 26, 2022, to select and summarize the basic and clinical studies reporting the effects of malnutrition or metabolic disorders on VC in CKD and the evolving treatments for these nutrient metabolic disorders.
KEY CONTENT AND FINDINGS
Hyperphosphatemia, calcium load, hypomagnesemia, iron deficiency, lipoprotein(a) abnormalities, protein malnutrition, and vitamin K deficiency secondary to CKD were closely associated with the occurrence and development of VC. Elevated phosphate and calcium levels were essential contributors to VC, yet current phosphate binders with good phosphate-lowering effects had not been shown to delay VC progression in CKD, and it remained challenging on how to identify and prevent calcium overload. Magnesium supplementation was the most promising treatment for mitigating VC, as supported by and studies and clinical trials. Correction of iron and vitamin K deficiency might contribute to VC attenuation, yet there was a lack of clinical evidence on CKD patients.
CONCLUSIONS
This review highlighted the effects of nutrient metabolism disorders on CKD-VC, and additional studies are needed to further address optimal nutrition strategies for mitigating VC in CKD.
PubMed: 37970595
DOI: 10.21037/atm-22-5358 -
Journal of Gastroenterology Nov 2023Abnormal phosphate levels are associated with adverse outcomes in critical illness. However, there is scarce evidence on phosphate's impact on acute pancreatitis...
BACKGROUND
Abnormal phosphate levels are associated with adverse outcomes in critical illness. However, there is scarce evidence on phosphate's impact on acute pancreatitis outcomes, and the few studies examining this subject are relatively small and show conflicting data. We sought to determine the association between phosphate level at admission and the clinical course and outcomes of acute pancreatitis.
METHODS
In this retrospective single-center observational study, we included all adult patients admitted with a primary diagnosis of acute pancreatitis between January 2008 and June 2021. Phosphate levels at admission were classified as normal (2.8-4.5 mg/dl), low (below 2.8 mg/dl), or high (above 4.5 mg/dl).
RESULTS
Out of 2308 cases, 1868 patients had documented phosphate levels at admission and were thus included in our final analysis. 1096 (59%) had normal phosphate levels, 686 (37%) had hypophosphatemia, and 86 (4.6%) had hyperphosphatemia on admission. 30-day mortality rates were 3.4%, 3.8%, and 19% in normal, low, and high phosphate levels, respectively. In univariate analysis, hyperphosphatemia was significantly associated with 30-day mortality, with an OR of 6.54 (95% CI 3.39-12.2, p < 0.001; AUC = 0.58). In a multivariate analysis adjusting for age, MAP, GFR, BUN, and pH, hyperphosphatemia remained a statistically significant independent predictor of early mortality (OR-2.93, 95% CI 1.28-6.51, p = 0.009). Hypophosphatemia was not significantly associated with 30-day mortality in univariate analysis, OR of 1.13 (95% CI 0.67-1.87, p = 0.6).
CONCLUSION
Hyperphosphatemia at admission was independently associated with increased 30-day mortality in patients with acute pancreatitis. Hypophosphatemia at admission was not significantly associated with 30-day mortality.
PubMed: 37594581
DOI: 10.1007/s00535-023-02034-2 -
Advances in Kidney Disease and Health Nov 2023The Mediterranean diet is a plant-based healthy diet similar to the vegetarian and the Dietary Approaches to Stop Hypertension diets. Unlike vegetarian and Dietary... (Review)
Review
The Mediterranean diet is a plant-based healthy diet similar to the vegetarian and the Dietary Approaches to Stop Hypertension diets. Unlike vegetarian and Dietary Approaches to Stop Hypertension diets, the Mediterranean diet encourages a lifestyle associated with physical activity, and social connections. In addition, the Mediterranean diet is not based on restriction of nutrients but does limit intake of processed foods. Prospective studies have confirmed that the Mediterranean diet confers primary and secondary cardiovascular disease prevention in the general population. The benefits of the Mediterranean diet lifestyle include reducing the risk of diabetes mellitus, dyslipidemia, and lowers blood pressure. In adults with CKD, adherence to the Mediterranean diet is associated with a lower risk of CKD progression and its complications such as hyperphosphatemia and metabolic acidosis, and reduces production of uremic toxins and inflammatory mediators when compared to omnivore dietary patterns. Nevertheless, prospective studies are needed to confirm the cardiovascular disease prevention with the Mediterranean diet in adults with CKD. Medical nutrition therapy remains a cornerstone of CKD management, and the Mediterranean diet could be utilized to slow CKD progression and complications.
Topics: Adult; Humans; Diet, Mediterranean; Cardiovascular Diseases; Prospective Studies; Risk Factors; Renal Insufficiency, Chronic; Hypertension; Heart Disease Risk Factors
PubMed: 38453265
DOI: 10.1053/j.akdh.2023.07.007 -
Expert Review of Clinical Pharmacology 2023Biliary tract carcinoma (BTC) is a heterogenous group of aggressive hepatic malignancies, second to hepatocellular carcinoma per prevalence. Despite clinical research... (Review)
Review
INTRODUCTION
Biliary tract carcinoma (BTC) is a heterogenous group of aggressive hepatic malignancies, second to hepatocellular carcinoma per prevalence. Despite clinical research advancement, the overall 5-year survival rate is just above 2%. With the identification of somatic core mutations in half of cholangiocarcinomas. In the intrahepatic subtype (iCCA), it is possible to target mutational pathways of pharmacological interest.
AREAS COVERED
Major attention has been drawn to fibroblast growth factor receptor (FGFR), especially the type 2 (FGFR2), found mutated in 10-15% of iCCAs. FGFR2 fusions became the target of novel tyrosine-kinase inhibitors investigated in clinical studies, showing promising results so as to gain regulatory approval by American and European committees in recent years. Such drugs demonstrated a better impact on the quality of life compared to standard chemotherapy; however, side effects including hyperphosphatemia, gastrointestinal, eye, and nail disorders are common although mostly manageable.
EXPERT OPINION
As FGFR inhibitors may soon become the new alternative to standard chemotherapy in FGFR-mutated cholangiocarcinoma, accurate molecular testing and monitoring of acquired resistance mechanisms will be essential. The possible application of FGFR inhibitors in first-line treatment, as well as in combination with current standard treatments, remains the next step to be taken.
Topics: Humans; Quality of Life; Cholangiocarcinoma; Mutation; Protein Kinase Inhibitors; Bile Ducts, Intrahepatic; Bile Duct Neoplasms
PubMed: 37387533
DOI: 10.1080/17512433.2023.2232302 -
Nutrients Jul 2023Hyperphosphatemia is a common complication in advanced chronic kidney disease and contributes to cardiovascular morbidity and mortality. The present narrative review... (Review)
Review
Hyperphosphatemia is a common complication in advanced chronic kidney disease and contributes to cardiovascular morbidity and mortality. The present narrative review focuses on the management of phosphatemia in uremic patients receiving peritoneal dialysis. These patients frequently develop hyperphosphatemia since phosphate anion behaves as a middle-size molecule despite its low molecular weight. Accordingly, patient transporter characteristics and peritoneal dialysis modalities and prescriptions remarkably influence serum phosphate control. Given that phosphate peritoneal removal is often insufficient, especially in lower transporters, patients are often prescribed phosphate binders whose use in peritoneal dialysis is primarily based on clinical trials conducted in hemodialysis because very few studies have been performed solely in peritoneal dialysis populations. A crucial role in phosphate control among peritoneal dialysis patients is played by diet, which must help in reducing phosphorous intake while preventing malnutrition. Moreover, residual renal function, which is preserved in most peritoneal dialysis patients, significantly contributes to maintaining phosphate balance. The inadequate serum phosphate control observed in many patients on peritoneal dialysis highlights the need for large and well-designed clinical trials including exclusively peritoneal dialysis patients to evaluate the effects of a multiple therapeutic approach on serum phosphate control and on hard clinical outcomes in this high-risk population.
Topics: Humans; Phosphates; Hyperphosphatemia; Peritoneal Dialysis; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 37513579
DOI: 10.3390/nu15143161