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American Journal of Kidney Diseases :... Jul 2015Calciphylaxis is a rare but devastating condition that has continued to challenge the medical community since its early descriptions in the scientific literature many... (Review)
Review
Calciphylaxis is a rare but devastating condition that has continued to challenge the medical community since its early descriptions in the scientific literature many decades ago. It is predominantly seen in patients with chronic kidney failure treated with dialysis (uremic calciphylaxis) but is also described in patients with earlier stages of chronic kidney disease and with normal kidney function. In this review, we discuss the available medical literature regarding risk factors, diagnosis, and treatment of both uremic and nonuremic calciphylaxis. High-quality evidence for the evaluation and management of calciphylaxis is lacking at this time due to its rare incidence and poorly understood pathogenesis and the relative paucity of collaborative research efforts. We hereby provide a summary of recommendations developed by a multidisciplinary team for patients with calciphylaxis.
Topics: Animals; Arterioles; Biopsy; Calciphylaxis; Case-Control Studies; Chronic Kidney Disease-Mineral and Bone Disorder; Combined Modality Therapy; Comorbidity; Diabetic Nephropathies; Disease Models, Animal; Electrolytes; Fatal Outcome; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Malnutrition; Middle Aged; Obesity; Pain Management; Rats; Risk Factors; Shock, Septic; Skin; Thiosulfates; Uremia; Vitamin D Deficiency; Wound Healing
PubMed: 25960299
DOI: 10.1053/j.ajkd.2015.01.034 -
The New England Journal of Medicine Jun 2018Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk hepatoblastoma but may cause considerable and irreversible hearing loss. This... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival.
METHODS
We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (≤3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years.
RESULTS
A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P=0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively.
CONCLUSIONS
The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132 ; EudraCT number, 2007-002402-21 .).
Topics: Adolescent; Child; Child, Preschool; Cisplatin; Doxorubicin; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Hearing Loss; Hepatoblastoma; Humans; Incidence; Infant; Liver Neoplasms; Male; Single-Blind Method; Survival Analysis; Thiosulfates
PubMed: 29924955
DOI: 10.1056/NEJMoa1801109 -
The Lancet. Child & Adolescent Health Feb 2020Despite ototoxicity being a prevalent consequence of cisplatin chemotherapy, little guidance exists on interventions to prevent this permanent and progressive adverse... (Review)
Review
Despite ototoxicity being a prevalent consequence of cisplatin chemotherapy, little guidance exists on interventions to prevent this permanent and progressive adverse event. To develop a clinical practice guideline for the prevention of cisplatin-induced ototoxicity in children and adolescents with cancer, we convened an international, multidisciplinary panel of experts and patient advocates to update a systematic review of randomised trials for the prevention of cisplatin-induced ototoxicity. The systematic review identified 27 eligible adult and paediatric trials that evaluated amifostine, sodium diethyldithiocarbamate or disulfiram, systemic sodium thiosulfate, intratympanic therapies, and cisplatin infusion duration. Regarding systemic sodium thiosulfate, the panel made a strong recommendation for administration in non-metastatic hepatoblastoma, a weak recommendation for administration in other non-metastatic cancers, and a weak recommendation against its routine use in metastatic cancers. Amifostine, sodium diethyldithiocarbamate, and intratympanic therapy should not be routinely used. Cisplatin infusion duration should not be altered as a means to reduce ototoxicity. Further research to determine the safety of sodium thiosulfate in patients with metastatic cancer is encouraged.
Topics: Adolescent; Antineoplastic Agents; Child; Cisplatin; Female; Hearing Loss; Humans; Male; Neoplasms; Ototoxicity; Prognosis; Randomized Controlled Trials as Topic; Survival Rate; Thiosulfates
PubMed: 31866182
DOI: 10.1016/S2352-4642(19)30336-0 -
The Lancet. Oncology Jan 2017Sodium thiosulfate is an antioxidant shown in preclinical studies in animals to prevent cisplatin-induced hearing loss with timed administration after cisplatin without... (Comparative Study)
Comparative Study Observational Study Randomized Controlled Trial
Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial.
BACKGROUND
Sodium thiosulfate is an antioxidant shown in preclinical studies in animals to prevent cisplatin-induced hearing loss with timed administration after cisplatin without compromising the antitumour efficacy of cisplatin. The primary aim of this study was to assess sodium thiosulfate for prevention of cisplatin-induced hearing loss in children and adolescents.
METHODS
ACCL0431 was a multicentre, randomised, open-label, phase 3 trial that enrolled participants at 38 participating Children's Oncology Group hospitals in the USA and Canada. Eligible participants aged 1-18 years with newly diagnosed cancer and normal audiometry were randomly assigned (1:1) to receive sodium thiosulfate or observation (control group) in addition to their planned cisplatin-containing chemotherapy regimen, using permuted blocks of four. Randomisation was initially stratified by age and duration of cisplatin infusion. Stratification by previous cranial irradiation was added later as a protocol amendment. The allocation sequence was computer-generated centrally and concealed to all personnel. Participants received sodium thiosulfate 16 g/m intravenously 6 h after each cisplatin dose or observation. The primary endpoint was incidence of hearing loss 4 weeks after final cisplatin dose. Hearing was measured using standard audiometry and reviewed centrally by audiologists masked to allocation using American Speech-Language-Hearing Association criteria but treatment was not masked for participants or clinicians. Analysis of the primary endpoint was by modified intention to treat, which included all randomly assigned patients irrespective of treatment received but restricted to those assessable for hearing loss. Enrolment is complete and this report represents the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00716976.
FINDINGS
Between June 23, 2008, and Sept 28, 2012, 125 eligible participants were randomly assigned to either sodium thiosulfate (n=61) or observation (n=64). Of these, 104 participants were assessable for the primary endpoint (sodium thiosulfate, n=49; control, n=55). Hearing loss was identified in 14 (28·6%; 95% CI 16·6-43·3) participants in the sodium thiosulfate group compared with 31 (56·4%; 42·3-69·7) in the control group (p=0·00022). Adjusted for stratification variables, the likelihood of hearing loss was significantly lower in the sodium thiosulfate group compared with the control group (odds ratio 0·31, 95% CI 0·13-0·73; p=0·0036). The most common grade 3-4 haematological adverse events reported, irrespective of attribution, were neutropenia (117 [66%] of 177 participant cycles in the sodium thiosulfate group vs 145 [65%] of 223 in the control group), whereas the most common non-haematological adverse event was hypokalaemia (25 [17%] of 147 vs 22 [12%] of 187). Of 194 serious adverse events reported in 26 participants who had received sodium thiosulfate, none were deemed probably or definitely related to sodium thiosulfate; the most common serious adverse event was decreased neutrophil count: 26 episodes in 14 participants.
INTERPRETATION
Sodium thiosulfate protects against cisplatin-induced hearing loss in children and is not associated with serious adverse events attributed to its use. Further research is needed to define the appropriate role for sodium thiosulfate among emerging otoprotection strategies.
FUNDING
US National Cancer Institute.
Topics: Adolescent; Antineoplastic Agents; Antioxidants; Child; Child, Preschool; Cisplatin; Drug Therapy, Combination; Female; Follow-Up Studies; Hearing Loss; Humans; Incidence; Infant; Male; Neoplasm Staging; Neoplasms; Prognosis; Survival Rate; Thiosulfates; United States
PubMed: 27914822
DOI: 10.1016/S1470-2045(16)30625-8 -
Molecules (Basel, Switzerland) Oct 2022Molybdenum cofactor (Moco) deficiency (MoCD) is characterized by neonatal-onset myoclonic epileptic encephalopathy and dystonia with cerebral MRI changes similar to... (Review)
Review
Molybdenum cofactor (Moco) deficiency (MoCD) is characterized by neonatal-onset myoclonic epileptic encephalopathy and dystonia with cerebral MRI changes similar to hypoxic-ischemic lesions. The molecular cause of the disease is the loss of sulfite oxidase (SOX) activity, one of four Moco-dependent enzymes in men. Accumulating toxic sulfite causes a secondary increase of metabolites such as S-sulfocysteine and thiosulfate as well as a decrease in cysteine and its oxidized form, cystine. Moco is synthesized by a three-step biosynthetic pathway that involves the gene products of , and . Depending on which synthetic step is impaired, MoCD is classified as type A, B, or C. This distinction is relevant for patient management because the metabolic block in MoCD type A can be circumvented by administering cyclic pyranopterin monophosphate (cPMP). Substitution therapy with cPMP is highly effective in reducing sulfite toxicity and restoring biochemical homeostasis, while the clinical outcome critically depends on the degree of brain injury prior to the start of treatment. In the absence of a specific treatment for MoCD type B/C and SOX deficiency, we summarize recent progress in our understanding of the underlying metabolic changes in cysteine homeostasis and propose novel therapeutic interventions to circumvent those pathological changes.
Topics: Male; Infant, Newborn; Humans; Cysteine; Thiosulfates; Cystine; Coenzymes; Metalloproteins; Sulfite Oxidase; Brain Diseases; Sulfites; Molybdenum Cofactors; Molybdenum
PubMed: 36296488
DOI: 10.3390/molecules27206896 -
Cell Host & Microbe Feb 2023Rapid advances in synthetic biology have fueled interest in engineered microorganisms that can diagnose and treat disease. However, designing bacteria that detect...
Rapid advances in synthetic biology have fueled interest in engineered microorganisms that can diagnose and treat disease. However, designing bacteria that detect dynamic disease-associated biomarkers that then drive treatment remains difficult. Here, we have developed an engineered probiotic that noninvasively monitors and records inflammatory bowel disease (IBD) occurrence and progression in real time and can release treatments via a self-tunable mechanism in response to these biomarkers. These intelligent responsive bacteria for diagnosis and therapy (i-ROBOT) consists of E. coli Nissle 1917 that responds to levels of the inflammatory marker thiosulfate by activating a base-editing system to generate a heritable genomic DNA sequence as well as producing a colorimetric signal. Fluctuations in thiosulfate also drive the tunable release of the immunomodulator AvCystatin. Orally administering i-ROBOT to mice with colitis generated molecular recording signals in processed fecal and colon samples and effectively ameliorated disease. i-ROBOT provides a promising paradigm for gastrointestinal and other metabolic disorders.
Topics: Animals; Mice; Escherichia coli; Thiosulfates; Inflammatory Bowel Diseases; Colitis; Bacteria; Probiotics
PubMed: 36758520
DOI: 10.1016/j.chom.2022.12.004 -
Medicina 2017Calciphylaxis is vasculopathy characterized by ischemia and painful skin necrosis due to calcification and intimal fibroplasia of thrombosis of the panicular arterioles....
Calciphylaxis is vasculopathy characterized by ischemia and painful skin necrosis due to calcification and intimal fibroplasia of thrombosis of the panicular arterioles. It most frequently compromises patients with terminal chronic renal failure and has a high mortality rate. Biopsy of skin lesions is used as a diagnostic method. No specific laboratory findings have been recorded. Skin lesions usually begin in the extremities like a painful purplish mottling similar to "livedo reticularis". The natural evolution is to ulcers and bedsores. The first line of treatment involves the care of skin lesions and antibiotic therapy. Sodium thiosulfate is used as treatment due to its antioxidant activity and as a chelating. Two clinical cases are here reported.
Topics: Adult; Calciphylaxis; Combined Modality Therapy; Debridement; Female; Humans; Kidney Failure, Chronic; Middle Aged
PubMed: 28825580
DOI: No ID Found -
JAMA Network Open Apr 2023Calciphylaxis is a rare disease with high mortality mainly involving patients with chronic kidney disease (CKD). Sodium thiosulphate (STS) has been used as an off-label... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Calciphylaxis is a rare disease with high mortality mainly involving patients with chronic kidney disease (CKD). Sodium thiosulphate (STS) has been used as an off-label therapeutic in calciphylaxis, but there is a lack of clinical trials and studies that demonstrate its effect compared with those without STS treatment.
OBJECTIVE
To perform a meta-analysis of the cohort studies that provided data comparing outcomes among patients with calciphylaxis treated with and without intravenous STS.
DATA SOURCES
PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched using relevant terms and synonyms including sodium thiosulphate and calci* without language restriction.
STUDY SELECTION
The initial search was for cohort studies published before August 31, 2021, that included adult patients diagnosed with CKD experiencing calciphylaxis and could provide a comparison between patients treated with and without intravenous STS. Studies were excluded if they reported outcomes only from nonintravenous administration of STS or if the outcomes for CKD patients were not provided.
DATA EXTRACTION AND SYNTHESIS
Random-effects models were performed. The Egger test was used to measure publication bias. Heterogeneity was assessed using the I2 test.
MAIN OUTCOMES AND MEASURES
Skin lesion improvement and survival, synthesized as ratio data by a random-effects empirical Bayes model.
RESULTS
Among the 5601 publications retrieved from the targeted databases, 19 retrospective cohort studies including 422 patients (mean age, 57 years; 37.3% male) met the eligibility criteria. No difference was observed in skin lesion improvement (12 studies with 110 patients; risk ratio, 1.23; 95% CI, 0.85-1.78) between the STS and the comparator groups. No difference was noted for the risk of death (15 studies with 158 patients; risk ratio, 0.88; 95% CI, 0.70-1.10) and overall survival using time-to-event data (3 studies with 269 participants; hazard ratio, 0.82; 95% CI, 0.57-1.18). In meta-regression, lesion improvement associated with STS negatively correlated with publication year, implying that recent studies are more likely to report a null association compared with past studies (coefficient = -0.14; P = .008).
CONCLUSIONS AND RELEVANCE
Intravenous STS was not associated with skin lesion improvement or survival benefit in patients with CKD experiencing calciphylaxis. Future investigations are warranted to examine the efficacy and safety of therapies for patients with calciphylaxis.
Topics: Adult; Humans; Male; Middle Aged; Female; Calciphylaxis; Retrospective Studies; Bayes Theorem; Renal Insufficiency, Chronic
PubMed: 37099293
DOI: 10.1001/jamanetworkopen.2023.10068 -
Microbiology (Reading, England) Dec 2018The principal mechanism of reducing sulfur into organic compounds is via the synthesis of l-cysteine. Cysteine is used for protein and glutathione synthesis, as well as... (Review)
Review
The principal mechanism of reducing sulfur into organic compounds is via the synthesis of l-cysteine. Cysteine is used for protein and glutathione synthesis, as well as being the primary sulfur source for a variety of other molecules, such as biotin, coenzyme A, lipoic acid and more. Glutathione and other cysteine derivatives are important for protection against the oxidative stress that pathogenic bacteria such as Neisseria gonorrhoeae and Neisseria meningitidis encounter during infection. With the alarming rise of antibiotic-resistant strains of N. gonorrhoeae, the development of inhibitors for the future treatment of this disease is critical, and targeting cysteine biosynthesis enzymes could be a promising approach for this. Little is known about the transport of sulfate and thiosulfate and subsequent sulfate reduction and incorporation into cysteine in Neisseria species. In this review we investigate cysteine biosynthesis within Neisseria species and examine the differences between species and with other bacteria. Neisseria species exhibit different arrangements of cysteine biosynthesis genes and have slight differences in how they assimilate sulfate and synthesize cysteine, while, most interestingly, N. gonorrhoeae by virtue of a genome deletion, lacks the ability to reduce sulfate to bisulfide for incorporation into cysteine, and as such uses the thiosulfate uptake pathway for the synthesis of cysteine.
Topics: Biological Transport; Cysteine; Cysteine Synthase; Enzyme Inhibitors; Gene Expression Regulation, Bacterial; Neisseria; Oxidation-Reduction; Oxidative Stress; Sulfates; Thiosulfates
PubMed: 30307392
DOI: 10.1099/mic.0.000728