钙和维生素D补充剂对结直肠肿瘤的预防效应

对近年来结直肠癌的病因学研究及钙和维生素D作为其潜在的化学性预防剂的干预研究资料加以综述，并提出需进一步研究的方向。     

Management of Metastatic Colorectal Cancer

Colorectal cancer (CRC), one of the most common cancers, is associated with significant morbidity, mortality, and medical costs. Treatment options in metastatic CRC are largely palliative, and aim to provide symptom relief, improve health-related quality of life, and prolong survival. Chemotherapy is the mainstay of treatment for metastatic disease. Fluorouracil/leucovorin with or without oxaliplatin or irinotecan is the most widely used regimen. These agents are administered intravenously (by bolus or infusion), thereby causing significant inconvenience to patients.Capecitabine (Xeloda®), an oral fluoropyrimidine, is currently recommended as single-agent first-line treatment in patients with metastatic CRC in whom fluoropyrimidine monotherapy is the preferred option. As first-line monotherapy, capecitabine is as least as clinically effective as bolus fluorouracil/leucovorin in terms of time to disease progression, time to treatment failure, and overall survival, but achieves significantly higher response rates and has the added advantage of oral administration. In addition, capecitabine has improved tolerability with a significantly lower incidence of diarrhea, stomatitis, nausea, and alopecia than fluorouracil/leucovorin. The lower incidence of grade 3 or 4 neutropenia with capecitabine results in significantly less neutropenic fever/sepsis and, consequently, fewer hospitalizations. The significantly higher incidence of hand-and-foot syndrome with capecitabine rarely necessitates hospitalization.Measures of resource utilization found patients treated with capecitabine had fewer hospital visits for drug administration, fewer days in hospital for management of treatment-related adverse events, and required less expensive drug therapy for the management of adverse events than fluorouracil/leucovorin recipients. In cost-minimization studies in various countries, these benefits translated into cost savings with capecitabine relative to fluorouracil/leucovorin.Clinical trials have shown combination therapy with capecitabine and either irinotecan or oxaliplatin to be effective and well tolerated. Capecitabine appears to be an acceptable alternative to fluorouracil/leucovorin in combination therapy. Moreover, one economic analysis predicted that capecitabine plus oxaliplatin will result in cost savings compared with fluorouracil/leucovorin plus oxaliplatin.In conclusion, oral capecitabine offers an effective, but more convenient, alternative to bolus fluorouracil/leucovorin in the first-line treatment of patients with metastatic CRC. The improved tolerability and cost savings of capecitabine relative to fluorouracil/leucovorin support the use of capecitabine when treatment with fluoropyrimidine therapy alone is the preferred option. Results of further phase III trials of capectabine plus either irinotecan or oxaliplatin are eagerly awaited to determine if replacing fluorouracil/leucovorin with capecitabine in combination therapy will result in further improvements in convenience, tolerability, and, ultimately, cost savings for patients and payors in the metastatic CRC setting.     

Hepatic Vitamin A Preloading Reduces Colorectal Cancer Metastatic Multiplicity in a Mouse Xenograft Model

Previous research in our laboratory showed that retinol inhibited all-trans retinoic acid (ATRA)-resistant human colon cancer cell invasion via a retinoic acid receptor-independent mechanism in vitro. The objective of the current study was to determine if dietary vitamin A supplementation inhibited metastasis of ATRA-resistant colon cancer cells in a nude mouse xenograft model. Female nude mice (BALB/cAnNCr-nu/nu, n = 14 per group) consumed a control diet (2,400 IU retinyl palmitate/kg diet) or a vitamin A supplemented diet (200,000 IU retinyl palmitate/kg diet) for 1 mo prior to tumor cell injection to preload the liver with vitamin A. HCT-116, ATRA-resistant, human colon cancer cells were intrasplenically injected. Mice continued to consume their respective diets for 5 wk following surgery. Consumption of supplemental vitamin A decreased hepatic metastatic multiplicity to 17% of control. Hepatic and splenic retinol and retinyl ester concentrations were significantly higher in the mice supplemented with vitamin A when compared to mice consuming the control diet. Supplemental vitamin A did not decrease body weight, feed intake, or cause toxicity. Thus, supplemental dietary vitamin A may decrease the overall number of hepatic metastasis resulting from colon cancer.     

Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial

Patients with newly resected stage II melanoma (n = 104) were randomized to receive adjuvant vitamin D3 (100,000 IU every 50 days) or placebo for 3 years to investigate vitamin D3 protective effects on developing a recurrent disease. Median age at diagnosis was 50 years, and 43% of the patients were female. Median serum 25-hydroxy vitamin D (25OHD) level at baseline was 18 ng/mL, interquartile range (IQ) was 13–24 ng/mL, and 80% of the patients had insufficient vitamin D levels. We observed pronounced increases in 25OHD levels after 4 months in the active arm (median 32.9 ng/mL; IQ range 25.9–38.4) against placebo (median 19.05 ng/mL; IQ range 13.0–25.9), constantly rising during treatment. Remarkably, patients with low Breslow score (<3 mm) had a double increase in 25OHD levels from baseline, whereas patients with Breslow score ≥3 mm had a significantly lower increase over time. After 12 months, subjects with low 25OHD levels and Breslow score ≥3 mm had shorter disease-free survival (p = 0.02) compared to those with Breslow score <3 mm and/or high levels of 25OHD. Adjusting for age and treatment arm, the hazard ratio for relapse was 4.81 (95% CI: 1.44–16.09, p = 0.011). Despite the evidence of a role of 25OHD in melanoma prognosis, larger trials with vitamin D supplementation involving subjects with melanoma are needed.     

Vitamin D and Vitamin D3 Supplementation during Photodynamic Therapy: A Review

Photodynamic therapy is an unconventional yet increasingly common method of treating dermatological diseases and cancer that is implemented more often in adults than in children. Current clinical uses include treatment of actinic keratosis, superficial basal cell carcinomas, and acne. Despite its high efficiency, photodynamic therapy support supplements have recently been reported in the literature, including calcitriol (1,25-dihydroxycholecalciferol), the active form of vitamin D, and vitamin D3 cholecalciferol. In clinical trials, photodynamic therapy enhanced with vitamin D or D3 supplementation has been reported for treatment of squamous cell skin cancers, actinic keratosis, and psoriasis. Experimental research on the effect of photodynamic therapy with vitamin D or D3 has also been carried out in breast cancer cell lines and in animal models. The aim of this review is to evaluate the usefulness and effectiveness of vitamin D and D3 as supports for photodynamic therapy. For this purpose, the Pubmed and Scopus literature databases were searched. The search keyword was: “vitamin D in photodynamic therapy”. In the analyzed articles (1979–2022), the authors found experimental evidence of a positive effect of vitamin D and D3 when used in conjunction with photodynamic therapy. An average of 6–30% (in one case, up to 10 times) increased response to photodynamic therapy was reported in combination with vitamin D and D3 as compared to photodynamic therapy alone. Implementing vitamin D and D3 as a supplement to photodynamic therapy is promising and may lead to further clinical trials and new clinical methodologies.     

Vitamin D Reduces Colitis- and Inflammation-Associated Colorectal Cancer in Mice Independent of NOD2

Inflammatory bowel disease (IBD) patients are at increased risk of developing colorectal cancer (CRC). Vitamin D (vD) induces NOD2 gene expression, enhancing immunity, while deficiency impairs intestinal epithelial integrity, increasing inflammation. This study investigated the effect of vD on CRC in colitis, and if preventive benefits are mediated via NOD2. Inflammation-associated CRC was induced by treating C57BL/6J and Nod2^?/? mice with azoxymethane (AOM) and dextran sodium sulfate (DSS) cycles (×3). vD-deficient mice displayed more severe colitis compared to vD-supplemented mice, with greater weight loss, higher colitis activity index, increased colonic weight/length ratios, and lower survival rates. Increased histological inflammation score and increased IL-6 were observed in the mucosa of vD-deficient mice. Overall incidence of colonic tumors was not significantly different between vD-deficient and vD-supplemented mice. Higher tumor multiplicity was observed in vD-deficient vs vD-supplemented groups (both mouse strains). After AOM/DSS treatment, decreased plasma 25(OH)D₃ levels and downregulation of vD target genes Cyp24 and Vdr were observed in both mice strains (vD-deficient or vD-supplemented diet), compared to saline-treated controls on the vD-deficient diet. In conclusion, vD supplementation reduced colitis severity and decreased the number of inflammation-associated colorectal tumors in both C57BL/6J and Nod2^?/? mice, independent of NOD2.     

Vitamin E Supplementation in Chemical Colorectal Carcinogenesis: A Two-Edged Knife

This work investigated the effects of Vitamin E (VE) on aberrant crypt foci (ACF) incidence, oxidative stress parameters (serum and hepatic VE concentration, and homocysteine, glutathione (GSH), and malondialdehyde (MDA) levels), and expression of both cyclooxygenase-2 (COX2) and proliferating cellular nuclear antigen (PCNA) in experimental colorectal carcinogenesis. Male Wistar rats received subcutaneous injections of 1,2-dimethylhydrazine (DMH) twice a week, for two weeks (40 mg/kg), except for the Control group. Animals were separated into groups that received different amounts of VE in the diet: 0 IU (0×), 75 IU (recommended daily intake, RDI), 225 IU (3× RDI), or 1500 IU (20× RDI), during (dDMH) or after (aDMH) administration of carcinogen. The 0×dDMH and 3×dDMH groups showed decreased serum VE levels. Hepatic VE concentration was higher in 3×aDMH as compared with the other groups. All the groups, except the Control and the 0×aDMH groups, had reduced GSH levels. The 0×dDMH, 0×aDMH, and 20×aDMH groups exhibited increased MDA levels. The aDMH groups had higher ACF incidence and PCNA expression. The 0×aDMH group presented higher ACF rate, followed by 20×aDMH. Moreover, the 3×aDMH group displayed reduced ACF incidence and COX2 expression. Multivariate analysis revealed that GSH modulated homocysteine levels and COX2. These results suggested that 1500 IU of VE is hazardous, whereas 225 IU of VE has beneficial effects on chemical colorectal carcinogenesis.     

Vitamin D Supplementation and Cancer Mortality: Narrative Review of Observational Studies and Clinical Trials

Several studies have investigated the beneficial effects of vitamin D on survival of cancer patients. Overall evidence has been accumulating with contrasting results. This paper aims at narratively reviewing the existing articles examining the link between vitamin D supplementation and cancer mortality. We performed two distinct searches to identify observational (ObS) studies and randomized clinical trials (RCTs) of vitamin D supplementation (VDS) in cancer patients and cohorts of general population, which included cancer mortality as an outcome. Published reports were gathered until March 2021. We identified 25 papers published between 2003 and 2020, including n. 8 RCTs on cancer patients, n. 8 population RCTs and n. 9 ObS studies. There was some evidence that the use of VDS in cancer patients could improve cancer survival, but no significant effect was found in population RCTs. Some ObS studies reported evidence that VDS was associated with a longer survival among cancer patients, and only one study found an opposite effect. The findings do not allow conclusive answers. VDS may have the potential as treatment to improve survival in cancer patients, but further investigations are warranted. We strongly support investment in well-designed and sufficiently powered RCTs to fully evaluate this association.     

Vitamin D Receptor (VDR) Gene Polymorphism in Patients Diagnosed with Colorectal Cancer

Colorectal cancer (CRC) is one of the most commonly occurring neoplasias in humans. The prevalence of CRC rates is still rising. Although the exact background of the disease still remains unknown, it is believed that CRC may not only be a result of environmental factors, but also genetic ones. One of the mechanisms underlying CRC might be the vitamin D pathway, as CRC is the most closely linked neoplasia to vitamin D deficiency. This study shows a possible association of the vitamin D receptor (VDR) polymorphisms FokI, BsmI, ApaI, and TaqI with CRC susceptibility. A total of 103 patients diagnosed with CRC (61 men and 42 women, aged 57–82 years) and 109 healthy people (50 men and 59 women, aged 47–68 years) were genotyped using PCR-RFLP for FokI, BsmI, ApaI, and TaqI. None of the single nucleotide polymorphisms (SNPs) individually increased or decreased the risk of CRC. The evaluation of haplotypes revealed two that might enhance the likelihood of CRC development: taB (OR = 30.22; 95% CI 2.81–325.31; p = 0.01) and tAb (OR = 3.84; 95% CI 1.29–11.38; p = 0.01). In conclusion, genotyping is an easy and robust procedure that needs to be performed only once in a lifetime. A creation of a relevant SNP’s panel might contribute to the identification of the groups that are at the greatest risk of CRC.     

Vitamin D Supplementation in Patients with Juvenile Idiopathic Arthritis

Vitamin D has been implicated in the pathogenesis of skeletal disorders and various autoimmune disorders. Vitamin D can be consumed from the diet or synthesized in the skin upon ultraviolet exposure and hydroxylation in the liver and kidneys. In its bioactive form, vitamin D exerts a potent immunomodulatory effect and is important for bone health. Juvenile idiopathic arthritis (JIA) is a collection of inflammatory joint diseases in children that share the manifestation of inflamed synovium, which can result in growth arrest, articular deformity, bone density loss, and disability. To evaluate the potential effect of vitamin D on JIA disease manifestations and outcomes, we review the role of vitamin D in bone metabolism, discuss the mechanism of vitamin D in modulating the innate and adaptive immune systems, evaluate the clinical significance of vitamin D in patients with JIA, and summarize the supplementation studies.     

Vitamin D Supplementation for Extraskeletal Indications in Older Persons

Low levels of vitamin D have been implicated in a wide variety of conditions highly prevalent in the geriatric population, including fractures, functional limitations, cancer, cardiovascular disease, and depression. Vitamin D supplementation is often considered integral to the prevention of falls and fractures in the setting of osteoporosis. For other conditions, however, consensus is lacking, and the clinician may struggle to balance competing recommendations around screening, supplementation, and monitoring. This review seeks to provide an overview of the available evidence on the use of vitamin D supplementation to ameliorate sarcopenia, enhance cognition, treat depression, prevent cancer, and reduce mortality—outcomes that are common concerns in the geriatric population for which the merits of treatment are not always certain.Evidence suggests vitamin D supplementation may decrease mortality. Therefore, it may be reasonable to prescribe routine supplementation with oral cholecalciferol 800 to 1000 IU daily to all patients aged ≥65 years who do not have a contraindication. No screening or monitoring would be recommended for this population. We additionally recommend the use of oral cholecalciferol over ergocalciferol for any routine supplementation as this benefit was only observed with cholecalciferol. For patients with depression or cognitive disorders, we recommend screening for vitamin D deficiency, treating with oral cholecalciferol if present, and monitoring periodically to target a level of >30 ng/mL as an adjunct to usual care. The level of evidence certainly would not justify the use of vitamin D in place of more evidence-based therapies, but given the burden of these conditions in the geriatric population, we believe the potential benefit justifies the minimal risk.     

Supplementation of Vitamin D Deficiency in Patients with Neuroendocrine Tumors Using Over-the-Counter Vitamin D3 Preparations

Vitamin D (vit-D) deficiency is highly prevalent in patients with gastro-entero-pancreatic neuroendocrine tumors (GEP-NET) and has been linked to reduced overall survival. We here assessed the vit-D status in 183 patients with GEP-NET at the time of their first presentation in the ARDEN NET Centre. We further examined the effect of simple advice to increase vit-D intake using over-the-counter vit-D preparations [colecalciferol (Vit-D3), 1,000–2,000 units/day], over a prospective observation period of 24 mo. At baseline, only 33.3% of patients showed vit-D sufficiency (25-OH-vit-D; >50 nmol/L), the remainder was insufficient (31.3%; 25-OH-vit-D; 25–50 nmol/L) or deficient (35.5%; 25-OH-vit-D; <25 nmol/L). Repeated advice to increase vit-D intake at routine 6-monthly follow-up appointments was associated with increased 25-OH-vit-D from 37.8 ± 3.5 nmol/L at baseline to 60.4 ± 5.6 nmol/L (P < 0.0001) and 56.8 ± 7.0 nmol/L (P = 0.039) after 12 and 24 mo. Percentage of vit-D insufficiency decreased from 66.6% at baseline to 44.9% and 46.2% after 12 and 24 months, respectively. Previous abdominal surgery, but not treatment with somatostatin analogues predicted 25-OH-vit-D levels in bootstrapped linear regression analyses (P = 0.037). In summary, simple advice to increase vit-D intake using over-the-counter preparations was associated with significant improvement of vit-D deficiency/insufficiency, although, 15% of GEP-NET patients remained deficient and may benefit from additional measures of vit-D replacement.     

Factors Affecting 25-Hydroxyvitamin D Concentration in Response to Vitamin D Supplementation

Sun exposure is the main source of vitamin D. Due to many lifestyle risk factors vitamin D deficiency/insufficiency is becoming a worldwide health problem. Low 25(OH)D concentration is associated with adverse musculoskeletal and non-musculoskeletal health outcomes. Vitamin D supplementation is currently the best approach to treat deficiency and to maintain adequacy. In response to a given dose of vitamin D, the effect on 25(OH)D concentration differs between individuals, and it is imperative that factors affecting this response be identified. For this review, a comprehensive literature search was conducted to identify those factors and to explore their significance in relation to circulating 25(OH)D response to vitamin D supplementation. The effect of several demographic/biological factors such as baseline 25(OH)D, aging, body mass index(BMI)/body fat percentage, ethnicity, calcium intake, genetics, oestrogen use, dietary fat content and composition, and some diseases and medications has been addressed. Furthermore, strategies employed by researchers or health care providers (type, dose and duration of vitamin D supplementation) and environment (season) are other contributing factors. With the exception of baseline 25(OH)D, BMI/body fat percentage, dose and type of vitamin D, the relative importance of other factors and the mechanisms by which these factors may affect the response remains to be determined.     

Vitamin D Supplementation on Carotid Remodeling and Stiffness in Obese Adolescents

Obesity is associated with vitamin D (VD) deficiency and arterial stiffness. This randomized control trial assessed the effects of VD supplementation during a weight-loss program on carotid intima-media thickness (IMT) and carotid compliance in obese adolescents. Participants were randomly assigned to receive either a 12-week lifestyle program with VD supplementation (n = 13), a lifestyle program without VD supplementation (n = 13) or a control group composed of normal-weight adolescents (n = 18). Serum total and free 25-hydroxyvitamin D (25(OH)D), IMT and carotid compliance were measured before and after the trial. Insufficiency in 25(OH)D concentration was found in 73% of obese participants compared to 22% among controls. Obese adolescents had lower free 25(OH)D and displayed higher IMT but lower carotid compliance than controls. Free 25(OH)D and IMT were negatively correlated in adolescents displaying VD insufficiency at baseline. After three months, total and free 25(OH)D increased in both groups. The changes of IMT and carotid compliance were similar between groups. The changes in IMT were correlated with the changes in total 25(OH)D in obese adolescents with VD insufficiency at baseline (r = −0.59, p = 0.03). While the lifestyle program with VD supplementation did not affect carotid compliance, IMT reduction was improved in obese adolescents.     

Vitamin D and COVID-19 Severity in Hospitalized Older Patients: Potential Benefit of Prehospital Vitamin D Supplementation

Studies involving the associations between vitamin D supplementation taken before the onset of COVID-19 infection and the clinical outcomes are still scarce and this issue remains controversial. This study aimed to assess the relationships between vitamin D (VitD) status and supplementation and coronavirus disease 2019 (COVID-19) severity in older adults (average age of 78 years) hospitalized for COVID-19. We conducted an observational retrospective cohort study with 228 older hospitalized patients during the first wave of the COVID-19 pandemic. The outcomes were in-hospital mortality secondary to COVID-19 or critically severe COVID-19. A logistic regression analysis was conducted to test whether pre-hospital VitD supplementation was independently associated with severity. In this study, 46% of patients developed a severe form and the overall in-hospital mortality was 15%. Sixty-six (29%) patients received a VitD supplement during the 3 months preceding the infection onset. Additionally, a VitD supplement was associated with fewer severe COVID-19 forms (OR = 0.426, p = 0.0135) and intensive care unit (ICU) admissions (OR = 0.341, p = 0.0076). As expected, age > 70 years, male gender and BMI ≥ 35 kg/m² were independent risk factors for severe forms of COVID-19. No relationship between serum 25(OH)D levels and the severity of the COVID-19 was identified. VitD supplementation taken during the 3 months preceding the infection onset may have a protective effect on the development of severe COVID-19 forms in older adults. Randomized controlled trials and large-scale cohort studies are necessary to strengthen this observation.     

Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study

Background. The objective of this quasi-experimental study was to determine whether bolus vitamin D supplementation taken either regularly over the preceding year or after the diagnosis of COVID-19 was effective in improving survival among hospitalized frail elderly COVID-19 patients. Methods. Seventy-seven patients consecutively hospitalized for COVID-19 in a geriatric unit were included. Intervention groups were participants regularly supplemented with vitamin D over the preceding year (Group 1), and those supplemented with vitamin D after COVID-19 diagnosis (Group 2). The comparator group involved participants having received no vitamin D supplements (Group 3). Outcomes were 14-day mortality and highest (worst) score on the ordinal scale for clinical improvement (OSCI) measured during COVID-19 acute phase. Potential confounders were age, gender, functional abilities, undernutrition, cancer, hypertension, cardiomyopathy, glycated hemoglobin, number of acute health issues at admission, hospital use of antibiotics, corticosteroids, and pharmacological treatments of respiratory disorders. Results. The three groups (n = 77; mean ± SD, 88 ± 5 years; 49% women) were similar at baseline (except for woman proportion, p = 0.02), as were the treatments used for COVID-19. In Group 1 (n = 29), 93.1% of COVID-19 participants survived at day 14, compared to 81.2% survivors in Group 2 (n = 16) (p = 0.33) and 68.7% survivors in Group 3 (n = 32) (p = 0.02). While considering Group 3 as reference (hazard ratio (HR) = 1), the fully-adjusted HR for 14-day mortality was HR = 0.07 (p = 0.017) for Group 1 and HR = 0.37 (p = 0.28) for Group 2. Group 1 had longer survival time than Group 3 (log-rank p = 0.015), although there was no difference between Groups 2 and 3 (log-rank p = 0.32). Group 1, but not Group 2 (p = 0.40), was associated with lower risk of OSCI score ≥5 compared to Group 3 (odds ratio = 0.08, p = 0.03). Conclusions. Regular bolus vitamin D supplementation was associated with less severe COVID-19 and better survival in frail elderly.