title stringlengths 1 1.19k | keywords stringlengths 0 668 | concept stringlengths 0 909 | paragraph stringlengths 0 61.8k | PMID stringlengths 10 11 |
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Skin area visit 1 | Click here for additional data file. | PMC10734405 | ||
Skin area visit 2 | Click here for additional data file. | PMC10734405 | ||
DET Score | Click here for additional data file. | PMC10734405 | ||
Case Report Form (annotated) | Click here for additional data file. | PMC10734405 | ||
Baseplate Change scoring | Click here for additional data file. | PMC10734405 | ||
Randomisation | SKIN | Click here for additional data file.The authors wish to extend a special thanks to the patients with PSCs and health care professionals who participated in the study and provided valuable insight into their experience of living with/managing patients with PSCs. Moreover, the authors would like to thank the members of the Skin Expert Panel and the Skin group project team at Coloplast for valuable inputs to the content and fruitful discussions throughout the development of the tool. Finally, the authors would also like to acknowledge Louise O’Hara for helping to conduct, analyse, and report findings from the CD interviews, and to Katie Tinsley who helped with reporting and interpretation of the psychometric evaluation findings. | PMC10734405 | |
Additional Information and Declarations | PMC10734405 | |||
Competing Interests | HANSEN | During the investigation, Nana O. Herschend, Zenia Størling and Helle Doré Hansen were employed by Coloplast A/S, and Amy Findley, Abi Williams and Kate Sully were employed by Adelphi Values. | PMC10734405 | |
Human Ethics | The following information was supplied relating to ethical approvals (i.e., approving body and any reference numbers):The study was approved by the local ethics committee in each country (UK: 20/LO/0220, Germany: 19-363 and 00012177, the Netherlands: NL71653.068.19, Italy: NP 3841, and Norway: 65025). | PMC10734405 | ||
Data Availability | The following information was supplied regarding data availability:The raw measurements and an annotated Case Report Form are available in the | PMC10734405 | ||
References | PMC10734405 | |||
Abstract | PMC9804082 | |||
Aim | schizophrenia | The aim of this study was to explore the effectiveness and safety of pentoxifylline as an adjuvant to risperidone in mitigating the negative symptoms in patients with chronic schizophrenia. | PMC9804082 | |
Methods | schizophrenia | SYNDROME | In this randomized, placebo‐controlled study, eighty outpatients with chronic schizophrenia were given risperidone for 8 weeks along with either pentoxifylline or a placebo. The positive and negative syndrome scale (PANSS) was used to assess patients at the start of the trial, as well as at 2, 4, 6, and 8 weeks. Pre‐ and posttreatment serum levels of cAMP, TNF‐α‐, and IL‐6 were measured. | PMC9804082 |
Results | The pentoxifylline group revealed a significant effect for time‐treatment interaction on PANSS‐negative subscale scores ( | PMC9804082 | ||
Conclusion | inflammation, schizophrenia, TNF‐α | INFLAMMATION, PATHOPHYSIOLOGY | Pentoxifylline adjunctive therapy with risperidone for 8 weeks was found to be promising in mitigating the negative symptoms in patients with chronic schizophrenia. Trial registration number: NCT04094207.Phosphodiesterases and inflammation play a role in the pathophysiology of schizophrenia negative symptoms. Treatment with the PDE inhibitor pentoxifylline improve the expression of cAMP and decreases the expression of inflammatory cytokines including TNF‐α and IL‐6. Upregulation of cAMP/PKA signaling triggers the synthesis of dopamine at dopaminergic synapse, blocks the dopamine D2‐receptor, and activates dopamine D1‐receptor in striatonigral neurons. Pentoxifylline adjunctive therapy with risperidone for 8‐weeks demonstrated a favorable efficacy and safety profile in improving the negative symptoms in patients with chronic schizophrenia.
| PMC9804082 |
INTRODUCTION | motivational deficits, Schizophrenia, neuropsychiatric diseases, claudication symptoms | DISORDER, DISEASE, PATHOGENESIS | Schizophrenia is a chronic psychiatric disorder that contributes significantly to the burden of mental disease worldwide.Several attempts have been made to define the distinctive mechanisms responsible for these negative symptoms to introduce new therapeutic agents that could target those mechanisms.Studies over the past two decades have provided important data about the effects of inflammatory cytokines, involving TNF‐α, interleukin‐1beta (IL‐1β), and IL‐6, on the basal ganglia, which contributes to the pathogenesis of all neuropsychiatric diseases including negative symptoms and motivational deficits.Pentoxifylline is a methylated xanthine derivative and works as a phosphodiesterase inhibitor that is commonly used for the management of claudication symptoms by inhibition thrombocytes aggregation, boosting erythrocyte flexibility or deformity, and decrease blood viscosity. | PMC9804082 |
METHODS | PMC9804082 | |||
Study design | This study was a prospective, parallel‐group, randomized, double‐blind, 8‐week trial. The Menoufia University Faculty of Medicine's ethical committee granted approval for this study (4/2021NEUR1), and it was carried out in accordance with the Declaration of Helsinki and its subsequent amendments. The study was registered at | PMC9804082 | ||
Participants | mental disorders, depression, schizophrenia, intellectual disability | DISORDERS, SYNDROME | From September 2019 to January 2022, patients between the ages of 20 and 40 were recruited from the neuropsychiatric department of Menoufia University Hospital. Patients with a confirmed diagnosis of schizophrenia using a structured interview conducted in accordance the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision,Exclusion criteria included abusing alcohol or other drugs, having intellectual disability, having undergone electroconvulsive therapy within the previous 12 weeks, having any other mental disorders, scoring ≥4 on the depression item of the positive and negative syndrome scale (PANSS) | PMC9804082 |
Sample size | With an effect size (Cohen's | PMC9804082 | ||
Randomization and blinding | Randomization was performed by impartial person using electronic random number generator. (Assignment ratio was 1:1, blocks of two). Blinding of the assignment was achieved by using serially numbered, solid, and stapled wrappers. Placebo tablets were manufactured in Zeta Pharma Company, and they were indistinguishable from pentoxifylline tablets in their appearance. The assignment was concealed from the participant, the doctor who referred the patient, the healthcare provider, the statistician, and the evaluator. | PMC9804082 | ||
Intervention | Pentoxifylline 400 mg SR tablets twice day, or a placebo, were given to participants for 8 weeks. Pentoxifylline dose selection was based on our previous study | PMC9804082 | ||
Outcomes | schizophrenia | The PANSS validated 30‐item rating scale, which comprises positive (seven items), negative (seven items), psychopathological symptoms in general (16 items), and PANSS total scores, was used to assess the drug efficacy and severity of symptoms in patients with schizophrenia. | PMC9804082 | |
Safety | ADVERSE EFFECTS | Patients were advised to notify the study team if they experienced any unusual symptoms during the trial. At each appointment, adverse effects (AEs) were meticulously recorded using a checklist. Physical examinations were also performed, and the participants' vital signs and body weight were listed during the screening session. Patients or their representatives were called once a week to assess their adherence to the medications. | PMC9804082 | |
Measurements | Fasting morning blood samples | Fasting morning blood samples (10 a.m.) were collected at the same time for all patients in vacutainers. The samples were then centrifuged at 4500 | PMC9804082 | |
Statistical analysis | ® | Data analysis was done using IBM® SPSS® Statistics version 22 software (USA). Shapiro–Wilk and Kolmogorov–Smirnov tests were used to examine the normal distribution of continuous variables. Student's | PMC9804082 | |
RESULTS | Depression, Extrapyramidal Symptoms | SYNDROME, POSITIVE | According to the inclusion and exclusion criteria, 116 patients were assessed for their eligibility. Eighty outpatients were randomized to receive either pentoxifylline or placebo (Flow chart of the study participantsParticipants' demographics and baseline characteristics
Abbreviations: BMI, body mass index; CRP, C‐Reactive Protein; ESRS, Extrapyramidal Symptoms Rating Scale; HDRS, Hamilton Depression Rating Scale score; PANSS, Positive and negative syndrome scale score. | PMC9804082 |
Outcomes | PMC9804082 | |||
SD | SYNDROME, SYNDROME, POSITIVE | No significant differences were found between the two groups' baseline PANSS‐negative subscale scores (The two therapies' effects on the Positive and Negative Syndrome Scale (PANSS). Data presented as means ± SD: (A) Negative, (B) Positive, (C) General psychopathology, and (D) Total scores. NS, non‐significantBaseline‐to‐endpoint decline in PANSS scoresAbbreviation: PANSS, Positive and negative syndrome scale score. | PMC9804082 | |
When comparing the two groups, the baseline PANSS‐positive subscale scores were not substantially different ( | PMC9804082 | |||
When the two groups' baseline PANSS general psychopathology subscale scores were compared, there was no significant difference ( | PMC9804082 | |||
When the two groups' baseline PANSS total scores were compared, there was no significant difference ( | PMC9804082 | |||
Hamilton depression rating scale | The baseline HDRS total score in the pentoxifylline group was 7.35 ± 0.95, whereas in the placebo group it was 7.55 ± 0.85, with no statistically significant difference between the two groups ( | PMC9804082 | ||
Extrapyramidal symptoms rating scale | The baseline ESRS total score in pentoxifylline group was 1.78 ± 0.42 and 1.73 ± 0.45 in the placebo group, with no statistically significant difference between the two groups ( | PMC9804082 | ||
Effect on | There was no statistically significant difference in baseline cAMP, TNF‐α, and IL‐6 serum levels between the pentoxifylline and placebo groups. (Changes in cAMP and inflammatory markers
Baseline and 8‐week comparisons between groups.Within group comparison.Furthermore, cAMP serum level in the pentoxifylline group was significantly higher after 8 weeks compared with their baseline data (Notably, the pentoxifylline group's PANSS‐negative subscale scores and cAMP serum levels revealed a statistically significant negative correlation ( | PMC9804082 | ||
Clinical side effects | diarrhea, heartburn, abdominal pain, extrapyramidal symptoms, dizziness, sexual dysfunction, insomnia, headache | The frequency of side effects was not substantially different between the two groups. In pentoxifylline group, five patients suffered from headache, three from dizziness, five from insomnia, six from abdominal pain, five from heartburn, seven from diarrhea, six from decrease appetite, two from increase appetite, and five from sexual dysfunction. In placebo group, four patients suffered from headache, three from dizziness, four from insomnia, seven from abdominal pain, four from heartburn, six from diarrhea, five from decrease appetite, three from increase appetite, and four from sexual dysfunction. In both groups, no extrapyramidal symptoms were reported. | PMC9804082 | |
DISCUSSION | deficit syndrome, schizophrenia, cognitive dysfunction | DISEASES, CORTEX | As far as we know, our study is the first randomized, double‐blind, placebo‐controlled trial that assessing the efficacy and safety of pentoxifylline as PDE inhibitor in alleviating the negative symptoms in chronic schizophrenia. Patients received pentoxifylline showed significant enhancement in PANSS negative, general psychopathology, and total subscale scores relatively to placebo group, but regarding the PANSS positive, the results were non‐significant. Our results could be clinically significant since negative symptoms are principal predictors for further functional impairment in patients suffering from schizophrenia and the current antipsychotics alone do not satisfactorily alleviate these symptoms.A Previous report proved that PDEs are highly expressed in the brain particularly in the striatum, hippocampus, caudate‐putamen, and cortex, which are known to be involved in neuropsychiatric diseases including cognitive dysfunction and negative symptoms in schizophrenia.Additionally, the pentoxifylline group's improvement may be attributed to the drug's anti‐inflammatory properties, which led to a significant drop in TNF‐α, and IL‐6 serum levels compared to baseline and patients taking a placebo. Pentoxifylline can also inhibit the production of cytokines and other biomolecules that are responsible for inflammatory cascade, decrease the neutrophil to lymphocyte ratio and thereby reinstating regulatory T cells/T helper‐17 (Treg/Th17) lymphocytes.The inflammatory activation of astrocytes can increase kynurenic acid production that results in a decrease in the levels of dopamine, acetylcholine, gamma‐aminobutyric acid, and glutamate.Although these encouraging outcomes of our study regarding the safety and efficacy of pentoxifylline in management of negative symptoms of schizophrenia, it had some limitations. We had no guide to make an unambiguous conclusion about the best dosage because this was the first clinical research of pentoxifylline in patients with schizophrenia. Furthermore, the small sample size and the short duration are considered probable limitations of this study. Even yet, PANSS is the “gold standard measure of treatment efficacy” since it offers objective evaluation of clinical response to pharmacological therapy. It still has the flaw of not specifically covering all deficit syndrome, cognitive function, and negative symptom domains. | PMC9804082 |
CONCLUSION | inflammation, schizophrenia | INFLAMMATION, PATHOPHYSIOLOGY | Pentoxifylline adjuvant to risperidone enhanced the negative symptoms in chronic schizophrenia patients without remarkable side effects. These effects could be attributed to inhibition of PDEs and inflammatory cytokines. Our findings could indirectly support the role of PDEs and inflammation in the schizophrenia‐negative symptoms pathophysiology. Nevertheless, further trials with larger scale and longer durations are recommended to test the long‐term safety, effectiveness, and optimum dose of pentoxifylline. | PMC9804082 |
CONFLICT OF INTEREST | The authors state they have no competing or financial interests. | PMC9804082 | ||
ACKNOWLEDGMENTS | Zeta Pharma is acknowledged by the authors for producing the placebo. | PMC9804082 | ||
DATA AVAILABILITY STATEMENT | On reasonable request, the corresponding author will provide the data that underpin the study's conclusions. | PMC9804082 | ||
REFERENCES | PMC9804082 | |||
Aims/hypothesis | hyperglycaemia, glucometabolic | HYPERGLYCAEMIA, TYPE 2 DIABETES | Hyperbaric oxygen (HBO) therapy may improve hyperglycaemia in humans with type 2 diabetes, but underlying mechanisms are unclear. Our objective was to examine the glucometabolic effects of HBO on whole-body glucose disposal in humans with type 2 diabetes. | PMC9729133 |
Methods | Diabetes | TYPE 2 DIABETES, DIABETES | In a randomised placebo-controlled crossover trial located at the German Diabetes Center, 12 male individuals with type 2 diabetes (age 18–75 years, BMI <35 kg/m | PMC9729133 |
Results | INSULIN SENSITIVITY | HBO decreased fasting blood glucose by 19% and increased whole-body, hepatic and WAT insulin sensitivity about one-third ( | PMC9729133 | |
Conclusions/interpretation | TYPE 2 DIABETES, INSULIN SENSITIVITY | HBO-mediated improvement of insulin sensitivity likely results from decreased endoplasmic reticulum stress and increased mitochondrial capacity, possibly leading to low-dose reactive oxygen species-mediated mitohormesis in humans with type 2 diabetes. | PMC9729133 | |
Funding | German Federal Ministry of Health, German Federal Ministry of Education and Research, North-Rhine Westfalia Ministry of Culture and Science, European-Regional-Development-Fund, German-Research-Foundation (DFG), Schmutzler Stiftung | PMC9729133 | ||
Graphical abstract | PMC9729133 | |||
Supplementary Information | The online version of this article (10.1007/s00125-022-05797-0) contains peer-reviewed but unedited supplementary material.. | PMC9729133 | ||
Keywords | PMC9729133 | |||
Introduction | type 2 diabetes | OXIDATIVE STRESS, TYPE 2 DIABETES | Various studies have suggested a causal relationship between oxidative stress and insulin resistance [Hyperbaric oxygen (HBO) treatment provides for 100% oxygen (OThis study compared the acute effects of one single session of 100% OStudy design. Participants with type 2 diabetes ( | PMC9729133 |
Methods | PMC9729133 | |||
Volunteers | TYPE 2 DIABETES | Fifteen male volunteers with type 2 diabetes were enrolled in this randomised, placebo-controlled, crossover clinical trial ( | PMC9729133 | |
Randomisation | Diabetes | DIABETES | The random allocation sequence (1:1) was generated by an experienced statistician at the German Diabetes Center (DDZ) (PB) using SAS software, version 9.3 (SAS Institute, Cary, NC, USA). Participants were randomly assigned to their treatment sequence by a person at the DDZ who was not involved in the conduct of the study. The randomisation list was kept by this person and was not accessible to the study personnel. Study participants, medical staff and researchers were blinded until completion of the study. | PMC9729133 |
Experimental protocol | The visits took place at an interval of 3 weeks. Each visit covered a period of 31 h, divided into four time periods (Fig. | PMC9729133 | ||
Indirect calorimetry | Indirect calorimetry was performed in the canopy mode with Vmax Encore 29n (CareFusion, Höchberg, Germany) during the last 30 min of the basal, pre-clamp and clamp periods [ | PMC9729133 | ||
Skeletal muscle and WAT biopsy | Skeletal muscle and WAT biopsy samples were taken from the vastus lateralis muscle and subcutaneous adipose tissue of the lower abdomen, respectively, as described before [ | PMC9729133 | ||
MRI and MRS | BEST | All MRI/MRS measurements were conducted on a 3.0-T MR scanner (Achieva X-series; Philips Healthcare, Best, the Netherlands). Intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) contents were quantified by | PMC9729133 | |
High-resolution respirometry | Ex vivo analysis of mitochondrial respiration was performed in permeabilised muscle fibres and WAT using high-resolution respirometry (Oxygraph-2k; Oroboros, Innsbruck, Austria), as previously described [ | PMC9729133 | ||
Analyses of lipid peroxidation, antioxidative capacity and oxidative stress | In skeletal muscle | Concentrations of thiobarbituric acid reactive substances (TBARS) were assessed fluorometrically in serum and biopsy samples from subcutaneous fat and skeletal muscle according to the manufacturer’s instructions (BioTek, Bad Friedrichshall, Germany) [In skeletal muscle and WAT samples, total glutathione and oxidised glutathione (GSSG) contents were quantified colorimetrically and normalised to protein concentration (Thermo Fisher Scientific, Dreieich, Germany), based on the method of Griffith [ | PMC9729133 | |
GC-MS | Determination of atom per cent enrichment of blood [ | PMC9729133 | ||
Western blotting | Expression levels of proteins of interest were assessed by western blot analysis, as described before [ | PMC9729133 | ||
Measurement of circulating metabolites and hormones | Plasma concentrations of insulin, glycerol, NEFA, alanine aminotransferase, aspartate aminotransferase, triacylglycerol and chylomicrons, as well as whole-blood measurements of glucose and HbA | PMC9729133 | ||
Calculations | During pre-clamp and clamp periods, whole-body glucose disposal rate ( | PMC9729133 | ||
Statistics | The power calculation was based on a previous study on HBO-induced glucose lowering, using two simultaneous two-sided paired | PMC9729133 | ||
Results | PMC9729133 | |||
HBO raises tissue oxygen pressure | During HBO treatment, tissue oxygen pressure as measured by tcpO | PMC9729133 | ||
HBO rapidly improves hyperglycaemia | fasting blood glucose | TYPE 2 DIABETES | After HBO treatment, blood glucose decreased by 19% from baseline compared with CON (iAUC Time course of circulating metabolites and hormones in humans with type 2 diabetes before and after HBO or CON treatment. Concentrations (means ± SEM) of fasting blood glucose ( | PMC9729133 |
HBO leads to improvement of hepatic, skeletal muscle and WAT insulin sensitivity | TYPE 2 DIABETES | During the pre-clamp period, REE (Whole-body and tissue-specific glucose and lipid metabolism after HBO or CON treatment in humans with type 2 diabetes. ( | PMC9729133 | |
HBO acutely stimulates energy metabolism but also increases oxidative stress and antioxidative defence | TYPE 2 DIABETES | Changes were analysed by comparing the difference (Δ) between pre-clamp and basal periods for each intervention. Non-invasive Variables of tissue-specific energy metabolism and antioxidative capacity after HBO or CON treatment in humans with type 2 diabetes. Difference (Δ) between pre-clamp and basal periods for hepatic ATP concentration (Changes in skeletal muscle mitochondrial CSA were comparable between HBO and CON (ΔCSA, 5.9±1.1 and 3.5±1.3 CON [nmol minIn WAT, the change in CSA did not differ between the interventions (ΔCSA, 4.8±1.6 HBO vs 3.1±1.4 CON [nmol min | PMC9729133 | |
HBO acutely improves myocellular insulin signalling while reducing endoplasmic reticulum stress | TYPE 2 DIABETES | First, changes were analysed by comparing the difference (Δ) between pre-clamp and basal periods. During the pre-clamp period, expression of biomarkers of endoplasmic reticulum (ER) stress was measured in skeletal muscle. Expression levels of eIF2α were comparable between the interventions (ΔeIF2α, Myocellular ER stress and insulin signalling after HBO or CON in humans with type 2 diabetes. (For the clamp period, changes were analysed by comparing the difference (Δ) between clamp and basal periods. Skeletal muscle Akt was not different between the groups (ΔAkt, | PMC9729133 | |
HBO does not immediately affect biomarkers of systemic low-grade inflammation | Serum IL-6, IL-1ra, TNF-α, FGF-21, MPO, SOD3, and total and high-molecular-weight adiponectin were not different between interventions (iAUCs | PMC9729133 | ||
Discussion | generalised, skeletal muscle, inflammation, beta cell loss, diabetes endotypes, hyperglycaemia, normoglycaemia, mitochondrial damage | INFLAMMATION, DISEASE, IMPAIRED GLUCOSE TOLERANCE, INSULIN RESISTANCE, HYPERGLYCAEMIA, TYPE 2 DIABETES, PATHOGENESIS, INSULIN SENSITIVITY | This study demonstrates that a single HBO treatment with 100% OThe observation of a clinically meaningful reduction in fasting hyperglycaemia in humans with type 2 diabetes extends previous data [The novelty resides in the investigation of the initial tissue-specific cellular mechanisms underlying the beneficial metabolic effects of HBO treatment. In general, improvements in tissue-specific insulin sensitivity in type 2 diabetes may result from reductions in lipotoxic insulin signalling, low-grade inflammation, and oxidative and/or ER stress [We also found that short-term HBO leads to higher production of ROS as well as antioxidative defence markers in both skeletal muscle and WAT of humans with type 2 diabetes. While chronic ROS overproduction can cause mitochondrial damage and reduced function in type 2 diabetes [This study also provides evidence for a substantial decrease in biomarkers of ER stress after a single session of HBO in humans with type 2 diabetes. ER stress has been shown to be involved in the pathogenesis of type 2 diabetes by leading to pancreatic beta cell loss and insulin resistance [Interestingly, the present study failed to detect any changes in circulating biomarkers of subclinical inflammation in humans with type 2 diabetes after HBO. While this is in line with a previous study [The limitations of this study include the use of a single dose of HBO, which does not allow extrapolation to long-term metabolic effects. Second, the applied study design neither clarifies how long the glucose-lowering effect persists after one session of HBO nor allows for detailed insights into changes in lipid metabolism upon HBO. Third, the study comprised male volunteers with type 2 diabetes, so findings cannot be generalised to women or to people with normoglycaemia or impaired glucose tolerance. In addition, the results may not be generalisable to all individuals with type 2 diabetes because of the short known disease duration as well as the rather narrow range of age and of insulin resistance, given the different diabetes endotypes [In conclusion, one single treatment of HBO with 100% O | PMC9729133 |
Supplementary information |
(PDF 531 kb) | PMC9729133 | ||
Acknowledgements | A. Shokouhmehr, Diabetes | DIABETES | We would like to thank F. Ziehve, M. Eßer, D. Höhn, D. F. Markgraf, U. Partke, A. Shokouhmehr, J. Leonhard and A. Sparla, all co-workers at the German Diabetes Center (DDZ), for their excellent support. | PMC9729133 |
Authors’ relationships and activities | MR | MR received personal fees from Allergan, Eli Lilly, Fishawack Group, Gilead Sciences, Novo Nordisk, Pfizer, Prosciento and Target RWE and investigator-initiated research support from Boehringer-Ingelheim, Nutricia/Danone and Sanofi-Aventis. CH received research support from Sanofi-Aventis and is a member of the Editorial Board of Diabetologia. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. | PMC9729133 | |
Contribution statement | MR | MR initiated the study, led the clinical experiments, and wrote, reviewed and edited the manuscript. TS led the clinical experiments, obtained and analysed the data, and wrote, edited and reviewed the manuscript. SK, HK, GB, SD, RG, SGM, PB, LM, CH and MW made significant contributions to data collection or analysis and interpretation of the data. All authors were involved in critically revising the article and have given final approval of the version to be published. MR is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and data analysis. | PMC9729133 | |
Funding | Diabetes | DIABETES | Open Access funding enabled and organized by Projekt DEAL. This study was supported by grants to the German Diabetes Center, which is funded by the German Federal Ministry of Health and Ministry of Culture and Science of the State North Rhine-Westphalia, and to the German Center for Diabetes Research by the German Federal Ministry of Education and Research, as well as by grants from the European Funds for Regional Development (EFRE-0400191), EUREKA Eurostars-2 (E! 113230 DIA-PEP), the German Research Foundation (DFG; CRC/SFB 1116/2 B12 and RTG/GRK 2576) and the Schmutzler Stiftung. | PMC9729133 |
Data availability | All data generated or analysed during this study are included in the published article (and its | PMC9729133 | ||
References | PMC9729133 | |||
Key Points | PMC10445201 | |||
Question | digestive tract cancer, cancer, death | CANCER | Can vitamin D supplementation reduce the risk of relapse or death in a subgroup of patients with digestive tract cancer who were p53 immunoreactive, defined by positivity for anti-p53 antibodies in serum and p53 protein in more than 99% of cancer cells? | PMC10445201 |
Findings | digestive tract cancer | In this post hoc analysis of a randomized clinical trial including 392 patients with digestive tract cancer, 5-year relapse-free survival was significantly higher in the vitamin D group (80.9%) than the placebo group (30.6%) among patients in the p53-immunoreactive subgroup but not in the non–p53-immunoreactive subgroup. | PMC10445201 | |
Meaning | death | These findings suggest that vitamin D supplementation may reduce the risk of relapse or death in this subgroup of patients. | PMC10445201 | |
Importance | cancer | CANCER | Recent meta-analyses of randomized clinical trials found that daily vitamin D3 supplementation had beneficial effects on cancer mortality, although the results are still controversial. | PMC10445201 |
Objective | digestive tract cancer, death | To examine whether vitamin D supplementation reduces the risk of relapse or death in a supgroup of patients with digestive tract cancer who were p53 immunoreactive. | PMC10445201 | |
Design, Setting, and Participants | digestive tract cancers | This was a post hoc subgroup analysis of the AMATERASU randomized, double-blind, placebo-controlled clinical trial. This trial included patients at a single university hospital in Japan with digestive tract cancers between January 2010 and February 2018 followed up for a median (IQR) of 3.5 (2.5-5.3) years to compare the effects of vitamin D supplementation with placebo and was reported in 2019. Patients from among 417 participants in the AMATERASU trial whose residual serum samples were available were included. Data were analyzed from October 20 to November 24, 2022. | PMC10445201 | |
Interventions | Vitamin D3 (2000 IU/d) supplementation or placebo. | PMC10445201 | ||
Main Outcomes and Measures | cancer, death | CANCER | The primary outcome was 5-year relapse or death. The subgroup of patients who were p53 immunoreactive was defined by positivity for anti-p53 antibodies in serum and nuclear accumulation of p53 oncosuppressor protein in more than 99% of cancer cells, which is considered a biomarker for | PMC10445201 |
Results | esophageal cancer, colorectal cancer, small bowel cancer, digestive tract cancer, gastric cancer | SMALL BOWEL CANCER, COLORECTAL CANCER, OESOPHAGEAL CANCER, GASTRIC CANCER | Among 392 patients with digestive tract cancer (mean [SD] age, 66 [10.7] years; 260 males [66.3%]), there were 37 patients with esophageal cancer (9.4%), 170 patients with gastric cancer (43.4%), 2 patients with small bowel cancer (0.5%), and 183 patients with colorectal cancer (46.7%). Serum anti-p53 antibody was detectable in 142 patients (36.2%), and p53-immunohistochemistry grade showed a positive association with serum anti-p53 antibody levels (coefficient = 0.19; | PMC10445201 |
Conclusions and Relevance | digestive tract cancer, death | This study found that vitamin D supplementation reduced the risk of relapse or death in the subgroup of patients with digestive tract cancer who were p53 immunoreactive. | PMC10445201 | |
Trial Registration | Identifier: | PMC10445201 | ||
Introduction | cancer deaths | Worldwide, an estimated 10.0 million cancer deaths occurred in 2020,Vitamin D was previously demonstrated to upregulate innate and adaptive immunity. | PMC10445201 | |
Methods | The trial protocol ( | PMC10445201 | ||
Trial Design | This was a post hoc analysis of parent trial participants from the AMATERASU RCT | PMC10445201 | ||
Participants | digestive tract cancers | Of 417 patients with digestive tract cancers who were randomly assigned to receive vitamin D supplements (251 patients [60.2%]) or placebo (166 patients [39.8%]) and who were followed up for a median (IQR; maximum) period of 3.5 (2.5-5.3; 7.6) years, 392 participants (94.0%) had available serum samples and were eligible for this post hoc analysis. Serum samples were not obtained for 25 patients (6.0%). Details of inclusion and exclusion criteria are described in the original report. | PMC10445201 | |
Outcome | death | The outcome was prespecified as relapse or all-cause death. Elapsed time was defined as the time from starting the supplement to the date the outcome occurred or the patient was censored. | PMC10445201 | |
Detection of p53 Protein in Pathological Specimens | cancer | CANCER, PATHOLOGY | Immunohistochemical staining data of p53 in cancer tissue in pathology specimens was obtained from our previous study. | PMC10445201 |
Serum Anti-p53 Antibody Level Measurement | Patient serum p53-Ab levels at approximately 2 weeks after operation and just before starting trial vitamin D supplementation (ie, at randomization), were measured by SRL, Inc (Shinjuku, Tokyo, Japan) using chemiluminescent enzyme immune assay (CLEIA). The lowest measurable serum p53-Ab level is 0.4 U/mL. The study population was divided into 2 subgroups based on serum p53-Ab levels, with patients having levels of 0.4 U/mL or higher designated as p53-Ab (+) and those having levels less than 0.4 U/mL designated as p53-Ab (−). | PMC10445201 |
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