Introduction One-third of adults in the United States and United Kingdom suffer from varicose veins.n-butyl-2-cyanoacrylate (NBCA) glue is a novel endovascular, nontumescent, nonthermal ablation technique for treatment of this condition. It has proved effective in multiple studies since its first use in 2013. The aim of this systematic review is to assess the efficacy of NBCA in ablating primary truncal varicose veins and eliminating reflux compared with existing endovascular techniques. Secondary outcomes include complications and quality of life.Methods PRISMA was used as a guide and studies were screened for risk of bias and methodological quality. Subjects had to be ≥18 years of age and followed-up posttreatment with color Duplex ultrasound (DUS). Eligibility criteria included saphenofemoral junction (SFJ) or saphenopopliteal junction (SPJ) incompetence with reflux down truncal veins lasting >0.5 seconds on DUS interrogation and a Clinical, Etiological, Anatomical, and Pathophysiological classification of venous disorders ranging between C1 and C6.Results Out of 2,910 patients  in 17 studies, 1,981 were administered NBCA, 445 radiofrequency ablation (RFA), and 484 endovenous laser ablation (EVLA) with mean procedure times of 25.7, 23.2, and 28.7 minutes, respectively. Mean recruitment period was 9 months (1–36 months) and followed-up for an average of 12.3 months (1–36 months). The majority were C2 to C3. Two-year occlusion rates were 93.7, 90.9, and 91.5% for NBCA, RFA, and EVLA, respectively. NBCA-treated patients experienced the least complications, with bruising, phlebitis, and pain being the most prevalent. Quality of life improved equally in all three modalities.Conclusion NBCA is simple to administer, safe, and effective even without compression stockings. Further studies are required to assess longer-term benefit and the effect of anticoagulation on vein obliteration. Second-line is ultrasound-guided foam sclerotherapy. Open surgery is indicated only if the other methods are unsuitable. Any incompetent tributaries are preferentially treated in the same session. Compression hosiery should not be used longer than 7 days after intervention, and is first choice only in pregnancy or if the previously mentioned interventions are unsuitable.The aim of this systematic review is to assess the efficacy of NBCA in ablating primary truncal varicose veins and eliminating reflux compared with existing endovascular techniques in the immediate, medium, and long-term settings. Secondary outcomes include complications, patient acceptability, and quality of life.n-butyl cyanoacrylate,” and “n-butyl 2 cyanoacrylate.” References and article suggestions by search engines were assessed to identify more relevant studies. Duplicates were removed and further exclusions performed after reviewing abstracts. The chosen manuscripts were then scrutinized while applying inclusion and exclusion criteria.This review is registered in PROSPERO database (registration code: CRD42018106323) and followed the PRISMA checklist.Human randomized controlled trials (RCTs), cohort studies, and case reports in English language involving the use of NBCA to treat primary truncal varicose veins  were included. If more than one modality was used, the said manuscript was only included if the data for NBCA could be fully extracted. Studies excluding NBCA glue or comparing NBCA with treatments other than RFA, EVLA, or foam sclerotherapy were excluded.Primary outcome was successful obliteration of lumen of target vein, defined as occlusion of the entire treated vein segment with no discrete segments of patency exceeding 5 cm, confirmed on color Duplex ultrasound (DUS) after the procedure.Influence of vein length, diameter, NBCA device, and postoperative compression stockings on early (3 months) and intermediate term  occlusion rate was taken as secondary outcomes. Vein length was taken as a mean value incorporating GSVs, SSVs, and AASVs with no distinction between the three. Where a particular vein diameter was taken at different levels, the mean of these values was calculated.Clinical, Etiological, Anatomical, and Pathophysiological classification and Varicose Clinical Severity Score (VCSS) were used to measure severity of varicose veins at baseline and postintervention. Quality of life was primarily investigated using the Aberdeen Varicose Vein Questionnaire (AVVQ).Any uncertainties in the literature were discussed with the second author and the authors of the original manuscripts where applicable. Risk of methodological bias was explored using the Cochrane Risk of Bias tool for RCTs.p < 0.05.Continuous variables were represented by means, standard deviations, and ranges. Categorical variables were shown in actual numbers and percentages. Scatter plots were created using Python version 3.7 . Statistical analysis was done using IBM SPSS Statistics software . Spearman's correlation and Mann-Whitney U-test were performed on groups of subjects at 3, 6, and 12-month intervals following NBCA treatment. These tests were chosen because continuous variables were not normally distributed. Level of statistical significance was taken asThe PRISMA flowchart  depictsRisk of bias for RCTs is illustrated inProspective studies were of a higher methodological quality .For VenaSeal, two initial 0.09-mL glue aliquots were injected 1 cm apart, followed by 3 cm pullbacks between each trigger pull. Pressure with Ultrasound (US) probe was applied to occlude the SFJ/SPJ before dispensing the first two aliquots to prevent glue from entering the deep venous system. The first two injections were followed by 3 minutes of compression. US probe pressure was applied for 30 seconds after subsequent injections.The VariClose system used a similar technique in terms of initial pressure to occlude the SFJ or SPJ before first injection. The trigger was pressed for 5 seconds while withdrawing the catheter by 10 cm (giving 0.06 mL of glue at 2 cm/s). Pressure over each 10-cm segment of treated vein was applied for 30 seconds. Once the entire vein was treated, a further 30 seconds of pressure over the entire target vein was applied. VenaBlock used a similar method.Recording of duration of NBCA procedures was not standardized. Two prospective studies calculated duration from the time of insertion of NBCA delivery catheter to the time of withdrawal (mean 19.3 minutes).p < 0.01).p < 0.001).Three studies compared NBCA with RFA.p < 0.001).EVLA was performed on 246 females (50.8%). Mean age was 44.4 years. Evlas Circular fiber EVLA kit  was used in all three studies. It operates at a wavelength of 1,470 nm and uses tumescent anesthesia. Peak temperature reaches 1200°C (compared with 120°C for RFA). One retrospective analysis mentioned the application of manual pressure over the treated vein during laser fiber withdrawal but its benefit in terms of promoting vein closure was not investigated.There were no pulmonary embolic events. Nine cases of postablation DVT were observed in the NBCA group .2125p < 0.001).p < 0.001 and 0.024).All endovenous ablation modalities exhibited a statistically significant decline in VCSS scores over time.The AVVQ was the main reporting modality for quality of life. Its downward decline from baseline was significant, consistent, and similar in all groups. Few manuscripts utilized other quality of life scores including EQ-5D, EQ-5D TTO, CIVIQ, and SF-36. All except SF-36 exhibited a significant improvement from baseline.Occlusion rate after cyanoacrylate glue treatment is not influenced by vein length, diameter, dispensing device, or use of postoperative compression stockings .Monomeric cyanoacrylate compounds polymerize upon contact with anionic components of plasma, a process consisting of three distinct phases: initial rapid polymerization with linear increase in tensile forces lasting approximately 10 seconds (phase 1), stable tensile forces lasting approximately 60 seconds (phase 2) followed by a more rapid rise of tensile forces (phase 3).There were outliers that skewed the NBCA occlusion data at 6 months and 1 year, leading to a dip in success rate at these intervals.Recanalization does not necessarily signify return of symptoms as many maintain a good quality of life and anticoagulation does not appear to be a predisposing factor.There is no officially reported incidence of DVT for NBCA but it is understood to be very low especially if tip of catheter is positioned 5 cm away from the superficial-to-deep vein junction. RFA carries a risk of 0 to 16% and EVLA 0 to 7.7%. Routine postoperative DUS may pick up asymptomatic thrombi.This systematic review has some limitations. The comprehensive literature search and data extraction were performed by one author. It excluded mechanochemical ablation and the period of follow-up was short. A meta-analysis would have been ideal but as highlighted in a recent article, the scarcity and heterogeneity of RCTs made this difficult.In terms of patient characteristics, one study included more smokers in the NBCA group and another deviated its protocol to include a patient with higher BMI.This systematic review shows the potential benefits of cyanoacrylate glue over RFA and EVLA. Due to its immediate action, occlusion is retained even without postoperative elastic bandages or compression stockings. Patients experienced less pain as there was no tumescent anesthesia, multiple injection sites, or heat involved. Phlebitis is often mild, self-limiting, and attributed to localized skin reaction to the glue. It can be managed conservatively. Procedure times are generally short and patients typically resume work on day 1 or 2. Failure rates are less but longer-term data are required to affirm this. Cyanoacrylate ablation carries less risk of paresthesia, ecchymosis, and eliminates burn injuries. The two most readily available NBCA kits can be used on various lengths and diameters of veins .


The vast majority of hospital admitted patients with traumatic brain injury (TBI) will have intracranial injury identified by neuroimaging, requiring qualified staff and hospital beds. Moreover, increased pressure in health care services is expected because of an aging population. Thus, a regular evaluation of characteristics of hospital admitted patients with TBI is needed. Oslo TBI Registry – Neurosurgery prospectively register all patients with TBI identified by neuroimaging admitted to a trauma center for southeast part of Norway. The purpose of this study is to describe this patient population with respect to case load, time of admission, age, comorbidity, injury mechanism, injury characteristics, length of stay, and 30-days survival.Data for 5 years was extracted from Oslo TBI Registry – Neurosurgery. Case load, time of admission, age, sex, comorbidity, injury mechanism, injury characteristics, length of stay, and 30-days survival was compiled and compared.From January 1st, 2015 to December 31st, 2019, 2153 consecutive patients with TBI identified by neuroimaging were registered. The admission rate of TBI of all severities has been stable year-round since 2015. Mean age was 52 years , and 68% were males. Comorbidities were common; 28% with pre-injury ASA score of ≥3 and 25% used antithrombotic medication. The dominating cause of injury in all ages was falls (55%) but increased with age. Upon admission, the head injury was classified as mild TBI in 46%, moderate in 28%, and severe (Glasgow coma score ≤ 8) in 26%. Case load was stable without seasonal variation. Majority of patients (68%) were admitted during evening, night or weekend. 68% was admitted to intensive care unit. Length of hospital stay was 4 days . 30-day survival for mild, moderate and severe TBI was 98, 94 and 69%, respectively.The typical TBI patients admitted to hospital with abnormal neuroimaging were aged 50–79 years, often with significant comorbidity, and admitted outside ordinary working hours. This suggests the necessity for all-hour presence of competent health care professionals. Traumatic Brain Injury (TBI) is globally recognized as a major health and socioeconomic issue  established in 2015 the Oslo TBI Registry – Neurosurgery for admitted patients with TBI identified by neuroimaging  in the time period January 1st, 2015 to December 31st, 2019.2, and is divided into four geographical healthcare regions. The South-East region is the largest with a population of 3,032,670 in 2019 . Data is retrieved from electronic medical records and stored in Medinsight (version 2.12.4.0), a database approved by the OUH data protection officer. Medinsight is linked to the National Population Register and date of death is automatically updated. Inclusion criteria are: (a) traumatic brain injury; (b) cerebral-CT/CTA or cerebral-MRI/MRA with findings of acute trauma ; (c) admitted to OUH within 7 days post-injury; (d) having a Norwegian social security number. Data for this study was retrieved from the Oslo TBI Registry – Neurosurgery on February 17th, 2020.Age was retrieved as a continuous variable and categorized into five-year intervals. Sex was registered as male or female. Living status at time of injury is registered into home – independent, home – with assistance, or institutionalized.Pre-injury health status was assessed using three different categories: (i) American Society of Anesthesiologists ASA Physical Status Classification System  (American Society of Anesthesiologists Trauma mechanism was grouped into (i) falls; (ii) motor vehicle crashes (MVC) ; (iii) pedestrian hit by a motor vehicle; (iv) bicycle (including electric bicycles and scooters) (v) sports; (vi) violence; (vii) self-harm; (viii) other or unknown. High energy as yes/no . Alcohol influence at time of injury as yes/no .Cerebral-CT was done as part of the primary assessment and an additional cerebral-MRI was only performed on clinical indication. The following traumatic imaging findings were registered (yes/no); cranial fracture, epidural hematoma (EDH), acute subdural hematoma (SDH), traumatic subarachnoid hemorrhage (tSAH), intraventricular hemorrhage (IVH), brain contusion, traumatic axonal injury (TAI), and penetrating injury. The Rotterdam CT score was used to classify CT findings and was assessed on the initial cerebral-CT with a range from 1 to 6 (worst score = 6). The score is based on (i) status of basal cisterns ; (ii) midline shift (0–5 mm or > 5 mm); (iii) epidural hematoma (present or absent); (iv) traumatic subarachnoid hemorrhage/intraventricular hemorrhage (present or absent). Increased Rotterdam CT score correlates with increased mortality in patients with severe and moderate TBI  recorded was the lowest score documented in the time window between injury and arrival at the OUH emergency room (ER) or intubation. TBI was categorized according to Head Injury Severity Score (HISS) into minimal (GCS 15 and no loss of consciousness or amnesia), mild  loss of consciousness, or impaired alertness or memory), moderate  or severe (Severe: GCS ≤ 8)  and registered with “no”, “yes, conservative treatment” or “yes, surgical treatment”. Skin injuries were not registered.Time and date of admission to OUH was registered and from what location (i) scene of accident; (ii) local hospital; (iii) Oslo Emergency Department ; (iv) other. The presence of OUH trauma team (yes/no), which consists of specialty trained physicians and nurses in anesthesia and surgery, radiologist, radiographer and bioengineer. Monday to Friday between 07:00 and 17:00 the hospital is staffed to manage elective and emergency patients, and critically ill inpatients. Beyond these hours, the hospital is mainly staffed for emergencies and care of critically ill inpatients.LOS = date of discharge – date of admission + 1. Stay at rehabilitation unit was not included in calculation of LOS.All patients admitted to an intensive care unit (ICU) were registered as admitted to ICU regardless of medical condition. In addition, patients admitted to an intermediate unit and in need of any organ-supportive interventions/medication or sedatives, or requiring observation > 24 h, was registered as ICU admitted. Length of stay (LOS) was calculated with formula 2 test for categorical variables, and independent t-test or Mann-Whitney U Test for continuous variables. 30-days survival was estimated using Kaplan-Meier and log-rank test for group comparison. Two-sided p-values of 0.05 were considered for statistical significance. Data were analyzed using IBM SPSS© version 25.Descriptive statistics summarize the characteristics of patients, injuries and treatment. Categorical data is presented with frequencies and percentages. Continuous variables are presented with mean  or median  depending on distribution. To compare group differences, we used Pearson χAnonymized data was retrieved from the Oslo TBI Registry. The Registry was approved by OUH data protection officer . This study qualifies as a quality control study, hence application to the regional ethical committee was waived , During the five-year study period 2153 consecutive patients with TBI identified by neuroimaging were admitted to OUH and included in this study.U Test, p = <.001). The majority lived independently at home (88%)  Table b.Fig. 2Description of comorbidity measured by ASA-PS score, use of antithrombotic medication and substance dependency are given in Table p = <.001). At time of injury 579/2153 (27%) were under influence of alcohol with a mean age of 49 years (SD 18), patients not influenced by alcohol had mean age 53 years (SD 27) . The percentage of patients influenced by alcohol was > 30% in age group 20–75 years. No patients < 15 years was influenced by alcohol .Trauma mechanism is presented in Table p = <.001). There was no difference in HISS between male/female (χ2 (2) =4, p = .1).Severity of TBI and TBI pathology is presented in Table p = <.001), tSAH (p = <.001) and cranial fracture (p = <.001). Younger age was associated with EDH (p = <.001). Penetrating injury rarely occurred (1.6%). MRIs were done in 626/2153 (29%) and accounted for younger patients, mean age 39 (SD 23) compared to those without MRI, mean age 58 years (SD 23) . MRI revealed TAI lesions in 322 patients of MRIs performed (51%).Rotterdam CT score ≥ 4 was seen in 362/2153 (17%). Compressed/absent basal cisterns were seen in 352 (16%) and midline shift ≥5 mm and 353/2153 (17%). The most frequent pathologies in this series were SDH, tSAH, brain contusion and cranial fracture. Multiple pathologies were seen in the majority (70%), e.g. simultaneous cranial fracture, SDH, tSAH and brain contusion. Higher age was significantly associated with SDH (p = .03). The most frequent body regions affected in multitraumas were face (24%), thoracic (21%), extremities (14%) and cervical spine (12%), presented in Table Multiple traumas were diagnosed in 1016/2153 (47%) with a mean age of 51 years (SD 22), compared to a mean age of 53 (SD 26) in those with isolated TBI .800/2153 (37%) were transported directly from scene of accident to OUH. Before transfer to OUH 816/2153 (38%) had primary assessment at local hospital, and 256/2153 (24%) had primary assessment at the Oslo Emergency Department. The OUH trauma team was activated in 1656/2153 (77%) patients with a mean age of 49 years (SD 24) compared to patients admitted without the trauma team who had a mean age of 61 years (SD 25) . Of patients with severe TBI; 96% were admitted to ICU, with ICU-LOS median 3 days (IQR 2–8).LOS in hospital and ICU are presented in Table p = .08), distribution of TBI severity according to HISS per month (χ2 (22) =23, p = .4) or HISS per day of the week (χ2 (12) =9, p = .7). There was no significant variation of multitrauma between days of the week (χ2 (6) =9, p = .2).Patient load according to year, month, day of the week and time of day is presented in Fig. p = .02). In weekends, significantly more patients were admitted during night, especially from midnight to 06:00 Saturday and Sunday (χ2 (3) =59, p = <.001)  Fig. e. Overalp = <.001) . For patients with severe TBI and < 60 years, most deaths occurred within 1 week after injury and 30-day survival was between 78 and 79%, except patients 10–19 years who had highest 30-days survival; 90%. There was a decline in survival from 60 year olds (66%), down to 11% in 90 year olds  Fig. a. Figurelds Fig. c. The suThis is one of very few large-sample size studies that describes the TBI population admitted to trauma hospital from 2015 to 2019, in order to provide additional information and guide the hospital administration to adequately distribute its resources. The admission rate of TBI of all severities has been stable year-round since 2015. The largest patient group is from the late middle ages. Many of the patients are elderly with comorbidities and use of antithrombotic drugs is common. The majority of TBI patients were admitted when the hospital was outside ordinary working hours (Monday to Friday between 07.00 and 17:00), and 60% of the hospital stay was spent in the ICU. The TBI patients pose a significant burden to trauma hospitals due to high numbers, injury severity and complexity, need for ICU admittance, and need for all-hour presence of competent personnel.Oslo TBI Registry – Neurosurgery had a higher mean age compared to previous epidemiological TBI studies  compared to CENTER-TBI which was 11%  was in line with other European and local studies reporting proportions from 24 to 36%  with a marked increase from age group 50 years in line with recent studies  (Kieffer et al. We found a higher rate of admissions during the weekend, in accordance with other studies on trauma admissions (Kieffer et al. Our results show that trauma activity is high when the hospital is mainly staffed for emergency care; particularly weekends are vulnerable in the execution of daily activities such as bedside visits. Knowing the high likelihood of interruptions and conflicts caused by new trauma; most of the planning and execution of elective inpatient treatment should be performed Monday to Friday between 07:00 and 17:00.In the years after 2002, the trauma system at OUH was upgraded. As part of this process, neurosurgeons increased their all-hour presence and involvement in trauma patients. The result was increased survival in trauma patients, especially for patients with severe head/neck injury (Sovik et al. In high-income countries, observed short term survival for severe TBI have varied between 70 and 55% (Haller and Walder Some study limitations need to be addressed. The study was performed at a single Level 1 trauma center with neurosurgical service in southeast region of Norway. We did not calculate the incidence of hospital-admitted intracranial injuries in the region, as we did not have an overview of patients with minor intracranial injuries who were admitted and treated in general hospitals. Thus, the generalizability to patients treated in general hospitals, other geographical areas and countries with different health care organization is limited. Further, a well-known limitation of studies based on hospital medical records is missing data. Database coding errors can also be a limitation, but we have continuously searched and adjusted the database for inconsistency and coding errors. However, a large sample size, and prospective registration with no exclusion based on age, preinjury conditions or treatment are strengths of the study.In TBI patients admitted to OUH with abnormal neuroimaging, the largest group is the late middle-aged and pre-injury comorbidities are common. Fall is the major trauma mechanism. Patients are being admitted throughout the year, without seasonal differences. The case load is greatest when the hospital is mainly staffed for emergencies and care of critically ill inpatients, thus demanding an all-hour presence of competent personnel. Overall burden for the trauma hospital is considerable, shown by high numbers and high admission rates to the ICU. Given the national population composition by an aging population, we have no reason to believe the number of patients will decrease in near future.


Great progress in the treatment of patients with multiple myeloma (MM) has been made due to the development of novel drugs. Patients with relapsed/refractory MM (RRMM) can be enrolled in early-phase clinical trials, but their performance across the last decade is unknown. We conducted a meta-analysis on the overall response rate (ORR) and toxicity. PubMed, Embase, and Cochrane Library were systematically searched for phase I and phase II trials investigating an experimental compound as a single agent or in combination with dexamethasone, published from January 1, 2010 to July 1, 2020. Eighty-eight articles were included, describing 61 phase I trials involving 1835 patients and 37 phase II trials involving 2644 patients. There was a high degree of heterogeneity. Using a random-effects model, the 95% CIs of the estimated ORR were 8–17% for phase I trials and 18–28% for phase II trials. There were significant subgroup differences in ORR between the years of publication in phase I trials and between drug classes in both phase I and phase II trials. The ORR in early-phase clinical trials in RRMM is substantial, especially in phase II trials, but due to high heterogeneity a general assessment of clinical benefit before participation is difficult to offer to patients. Phase I trials often represent the first-in-human use and are primarily used to assess toxicities, dosing schedule, and maximum tolerated dose (MTD). Historically, there was no or only very limited therapeutic intent in phase I trials. Phase II trials test the selected dosing regimen in a larger sample to acquire insight into the effectiveness of experimental drugs. In oncology, participants in early-phase clinical trials typically have the advanced-stage disease and have exhausted one or more lines of approved therapeutic regimens. Participants are to expect a higher risk of toxicities, while the activity of the experimental drug is uncertain5. However, rates of therapeutic success have improved since, with estimated responses of 5–10% in the 1990s and estimates for the past two decades varying from 5 to 20%9. The American Society of Clinical Oncology, among others, perceives phase I trials as having therapeutic intent and sees participation as a therapeutic option2. However, it remains subject to debate whether phase I trials genuinely offer therapeutic benefit in relation to their risks12.In the 1970s and 1980s, overall response rates (ORR) in phase I trials in oncology were estimated to be <5%13. There have been many drug approvals for MM in the last 15 years, which have significantly prolonged survival for patients14. Despite significant improvements in treatment possibilities and survival, MM remains an incurable malignancy and is characterized by high rates of relapse and therapy resistance16. In the course of disease progression, participation in an early-phase clinical trial can be considered. However, a recent systematic review to inform clinicians and patients on the risks and benefits of these trials is lacking. Therefore, we examined the rates of response and toxicities in early-phase clinical trials in relapsed/refractory MM (RRMM) and assessed differences across years of publication and drug classes.Multiple myeloma (MM) is a clonal plasma cell malignancy primarily located in the bone marrow and is the second most common hematologic malignancy17. Two researchers (NvN and RF) independently searched the publication libraries of PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials from January 1, 2010 to July 1, 2020. Search strings were formulated and verified in accordance with a Utrecht University librarian. The complete search strings are provided in the Supplementary Materials. Searches were limited to publications in the English language. We identified all publications reporting on single-arm phase I and phase II clinical trials with adult RRMM patients that received an experimental compound given as monotherapy or in combination with dexamethasone. Additional relevant articles that were found through other sources were reviewed similarly and could be included when eligibility criteria were met. Studies, where the experimental compound was combined with drugs, other than dexamethasone, were excluded. Studies were also excluded when testing the effect of a drug in a subgroup of RRMM patients, e.g., safety studies in patients with renal failure, or when studies were performed for the mere purpose of approval in one specific country. We further excluded studies related to allogeneic stem cell therapy, bone-directed therapy or supportive care, or studies testing a new route of administration. Studies had to report the activity of the experimental compound on an intention-to-treat population of at least ten RRMM patients.This systematic review is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelinesResults were extracted from the included studies and tabulated by two researchers (NvN and RF) independently. Potential conflicts were resolved by discussion with a third researcher (MCM). In case of missing data, corresponding authors of the studies were contacted. When we identified multiple publications on the same study population, results from the most recent and/or most complete original publication were used for data extraction. When not all data could be extracted from the original article, a trial registration database  was used to find additional relevant publications in order to obtain missing data. For studies that reported the results of a combined phase I and phase II trial, we manually extracted data of patients belonging to the respective trial phase.18. We included CBR since also a minor response can be a signal of single-drug activity and may have additional value to RRMM patients19. From each included study, we extracted the following characteristics: trial stage, Clinical Trial Registration Number, name, type, and a class of experimental drug, intention-to-treat population, median lines of prior therapy, response rates: ORR (≥PR) and CBR (≥MR), toxicity profile: number of DLTs or number of patients discontinuing the trial drug due to adverse events. Wherever possible, we extracted the reported response rates according to the International Myeloma Working Group definitions18.The primary outcome was the ORR, defined as a best-reported partial response (PR) or better. Secondary outcomes were toxicities, measured as dose-limiting toxicities (DLTs) and drug discontinuations, and the clinical benefit rate (CBR): a best-reported response of minimal response (MR) or better20. The package “meta” (4.12-0) was used for meta-analyses21. We applied logit transformations to turn the proportions into normal distributions suitable to pool effects. The weight of each included study in the meta-analysis was determined with the generic inverse variance method. This means that larger studies, which generally have smaller variances than small studies, will be given a relatively greater weight within the meta-analysis. Effect sizes from each study were then pooled with a random-effects model. Preplanned subgroup analyses were devised for years of publication and drug class. To evaluate the degree of statistical heterogeneity, we used the Cochran Q statistic and inconsistency index (I2). Heterogeneity was classified as low (I2 = 25%), moderate (I2 = 50%), and high (I2 = 75%)22. All effect sizes are reported with corresponding 95% confidence intervals (CI) and prediction intervals (PI). Reported P values are two-sided, with a P < 0.05 considered significant. We used the test for subgroup differences to investigate how the estimates vary across subgroups of years of publication and drug classes.We used statistical software R, version 4.0.0, for all data analyses112. The selection process is visualized in Fig. Our literature search identified 1127 original publications for review after the removal of duplicates. A further eight articles were found through other sources and added to the selection, making the total 1135 publications. After screening on title and abstract, 110 potentially relevant articles were selected for full-article review on eligibility. Of these, 88 studies were included for data extraction and quantitative analysis , 2013–2015 (n = 22), 2016–2018 (n = 35), and 2019–2020 (n = 26) (Table n = 4), proteasome inhibitors (n = 20), monoclonal antibodies (n = 18), cell therapy (n = 5), antibody–drug conjugates (n = 7), kinase inhibitors (n = 10), immune checkpoint inhibitors (n = 2), heat-shock protein 90 inhibitors (n = 5), and others (n = 27). Thirty-five (58%) of phase I trials and 29 (78%) of phase II trials reported on the median lines of prior therapies received by patients before participation in the trial. Median lines of prior therapies ranged from two to more than seven, while patients in phase I trials seem to have been more heavily pretreated than patients in phase II trials  and phase II studies . The 95% CI of the estimated overall response was 8.1–16.8% for all included phase I trials and 18.9–28.3% for all included phase II trials. The prediction interval of the estimated overall responses was 0.8–67.6% for phase I trials and 6.9–55.2% for phase II trials , but not in phase II trials (P = 0.07)  and phase II (P < 0.0001) trials  Fig. . In phasals Fig. . In phasals Fig. 113,114.FI2 = 31.5%, P = 0.02). The estimated proportion of DLTs was 9.1% (95% CI 7.3–11.4%). The prediction interval was 3.6–21.3%. . The estimated overall number of drug discontinuations was 12.49% (95% CI 9.7–15.9%), with the prediction interval ranging from 3.7 to 34.4%  and drug class (P = 0.10). For drug discontinuations in phase II trials, there were significant subgroup differences for drug class (P = 0.03) but not for years of publication (P = 0.55).For the estimate of DLTs in phase I trials, we did not find any subgroup differences for both years of publication  and phase II trials . The 95% CI of the estimated overall CBR was 13.7–24.1% for phase I trials, including 1456 patients, and 28.7–40.4% for phase II trials, involving 2397 patients. The prediction interval of the estimated overall CBR was 3.0–62.4% for phase I trials and 12.4–65.8% for phase II trials  but not phase II (P = 0.2) trials. In addition, there was a significant difference between drug classes for both phase I (P < 0.001) and phase II (P < 0.011) studies.Similar to the ORR, we analyzed subgroup differences across different years of publication and different drug classes. The test for subgroup differences was significant for years of publication for phase I  were higher than for the ORR , while the range of the prediction interval of the CBR was comparable to the prediction interval of the ORR . Although ORR and OS are associated, a higher ORR might not necessarily implicate an improvement in OS114. These and other promising novel forms of immune therapy may substantially increase response rates without increasing toxicity. Another step that may improve therapeutic success is an intrapatient dose escalation, which helps patients to receive safe and higher doses of a potentially active novel drug. In addition, biomarker selection can improve the selection process of patients likely to benefit from a novel drug116.There are several factors that may contribute to a further increase in the efficacy of early-phase clinical trials in the near future. Part of the heterogeneity between studies was due to the high ORR of studies testing anti-BCMA CAR T cellsThe increased understanding of cancer pathobiology—and MM especially—has resulted in many novel drugs that specifically target malignant cells. Immunotherapies have been developed for MM patients and have opened a completely new set of treatment possibilities. Consequently, response rates in early-phase clinical trials have improved over the past decades. In this meta-analysis, we characterized the overall effect of participating in early-phase clinical trials for RRMM patients over the past decade. We found that the ORR of early-phase clinical trials is highly variable, but seems to have improved over the past decade without a concurrent rise in toxicities. These improvements are mainly due to novel classes of therapy, such as PIs, IMiDs, and CAR T cells. Our findings can be used to facilitate debate on the risks and benefits of participation in early-phase clinical trials in oncology in general and may be used by clinicians to guide assessment and communication on enrollment of RRMM patients in early-phase clinical trials.supplementary content


Sun exposure is a major environmental risk factor for skin cancers and is also an important source of vitamin D. However, while experimental evidence suggests that vitamin D may have a protective effect on skin cancer risk, epidemiologic studies investigating the influence of 25-hydroxyvitamin D (25(OH)D) level and/or vitamin D intake on skin cancer risk are conflicting. A systematic review and dose–response meta-analyses of prospective studies was conducted to clarify these associations. Relevant studies were identified by searching the PubMed database up to 30th August 2019. Random effects dose–response meta-analyses were used to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs). Overall, thirteen prospective studies were included. Circulating level of 25(OH)D was associated with higher risks of melanoma (SRR (95% CI) per 30 nmol = 1.42 (1.17–1.72)) and keratinocyte cancer (KC) (SRR (95% CI) per 30 nmol/L = 1.30 (1.13–1.49)). The SRR (95% CI) per 30 nmol/L increase in 25(OH) D level was 1.41 (1.19–1.67), and 1.57 (0.64–3.86), for basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), respectively. However, while we found that vitamin D intake  was not associated with risks of melanoma and SCC, vitamin D intake was associated with slightly increased BCC risk, albeit with no heterogeneity across skin cancer type. This meta-analysis suggests positive associations between circulating 25(OH)D level and risk of melanoma and KC, however, this finding is most likely confounded by sun exposure. We found no associations between vitamin D intake skin cancers, except positive associations with BCC risk. Melanoma is the most lethal form of skin cancer5, with highest incidence rates observed in Australia and New Zealand, followed by Northern America and Europe, and the lowest rates in Asian and African populations1. Although keratinocyte cancers (KCs), namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), have low mortality rate, they have relevant impact on quality of life and healthcare costs7. The incidence of skin cancer has been expected to increase over the coming decades due to the increasing intensity of ultraviolet (UV) radiation received at the Earth's surface, which is caused by ozone depletion and global warming8. Established risk factors for skin cancer include sun exposure9, which is currently the only factor on which prevention can be based, pigmentary traits10, and family history of skin cancer11. However, some dietary factors, such as an antioxidant and anti-inflammatory-rich diet, have been suggested to prevent skin cancer13, whereas associations between vitamin D and skin cancer have produced a controversial debate in scientific and public communities.Skin cancers are the most common type of malignancies in Caucasian populations14. Vitamin D2 and D3 are then metabolized in the liver into 25-hydroxyvitamin D (25(OH)D), which represents the major circulating form and reflects vitamin D status15. Besides its known role in maintaining bone health16, vitamin D is involved in numerous biologic functions including anti-proliferative, anti-angiogenic and modulation of the immune system17. Emerging evidence suggests that vitamin D plays also a protective role against several types of cancer21. However, findings from epidemiologic studies investigating the association between vitamin D and risk of skin cancer remain inconsistent22. Several studies have indeed addressed the association between vitamin D and skin cancer risk23 which has been studied by exploring intakes of dietary vitamin D (from food or supplements), or circulating levels of 25(OH)D (a biomarker of vitamin D status reflecting both intake and synthesis related to sun exposure). Regarding 25(OH)D levels, most of the studies suggested an increased risk of melanoma and KC25 and some studies reported inverse27 or null associations29. While a recent meta-analysis based on four studies observed no association between high serum levels of 25(OH)D and melanoma risk, high 25(OH)D levels have been reported to be associated with increased risk of KC, particularly of BCC30. Nevertheless, this meta-analysis was limited by a small number of cases (392 melanoma cases and 768 KC cases) as well as by the lack of dose–response and subgroup analyses stratified by study characteristics, which were not possible due to small numbers of studies. Since the publication of this meta-analysis, several prospective studies have been published on vitamin D status and skin cancer34, and no previous meta-analysis has investigated the potential nonlinear dose–response relationship between 25(OH)D status and skin cancer risk. This could be useful for evaluating the balance between the potential benefits and risks for skin cancer prevention. In addition, previous epidemiologic studies have also yielded inconsistent results regarding the influence of dietary vitamin D on the risk of skin cancer23; some studies suggested that a high intake of dietary vitamin D may protect against skin cancer development35, while other studies found null results36. Caini and colleagues observed no statistically significant association for the highest versus lowest intake of vitamin D in relation to skin cancer30. In contrast, since then, new cohort studies on vitamin D intake and skin cancer have been published34 and no dose–response meta-analysis has been published to our knowledge.Vitamin D is a fat-soluble vitamin that occurs in two natural forms, ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). These forms may be found in some food groups , fortified foods , or dietary supplements. Most vitamin D is synthesized by exposure to ultraviolet radiation (UVR) in the skin, where 7-dehydrocholesterol is converted into vitamin D3Therefore, we conducted a systematic review and dose–response meta-analysis of prospective studies to investigate the association between vitamin D exposure  and risk of skin cancer, including melanoma and KC (BCC and SCC).37 and the PRISMA guidelines38 was conducted.A systematic review following the guidelines for Meta-Analyses and Systematic reviews for Observational Studieshttps://www.wcrf.org/sites/default/files/skin-cancer-protocol.pdf. However, since all the relevant studies were initially identified by the PubMed search, we have changed the protocol and searches were updated to 30th August 2019 using the same search strategy only in the PubMed database. We additionally conducted the search in Google Scholar using the same specific key terms, and no new relevant articles were identified compared to PubMed search. In addition, we searched the reference lists of the relevant publications, reviews and meta-analysis for further studies.A systematic search using several databases, such as PubMed, Embase, CAB Abstracts, ISI Web of Science, up to September 20th 2018, was performed by several reviews for eligible studies as part of the Continuous Update Project of the World Cancer Research Fund (WCRF-CUP) at Imperial College London. The protocol used for the search strategy can be accessed at 39. Case–control studies, ecological studies, case reports, reviews and editorials were excluded from the meta-analysis. Studies which focused on the relationship between vitamin D exposure and survival from melanoma, recurrence or prognostic factor for melanoma  were also excluded. The present study focused only on vitamin D exposure and risk of primary skin cancer.We included in this meta-analysis prospective cohort or nested case–control studies investigating the association between either 25(OH)D level or vitamin D intake  and risk of melanoma or KC. Estimates of the relative risk (RR)  with the 95% confidence intervals (CIs) had to be available in the publication, and for the dose–response analysis, a quantitative measure of intake or level of 25(OH)D, the total number of cases and person-years or non-cases had to be available in the publication. If several articles were published using the same study population on the topic, the one with the largest number of cases was selectedFor each relevant study included in this meta-analysis, the following information was extracted by two reviewers: first author’s last name, publication year, country where the study was conducted, study name, study design, follow-up period, sex, age, number of cases, case ascertainment, exposure assessment, outcome, comparison, RRs and 95% CIs and adjustment factors Table  and S2.40.To assess the risk of bias and quality of the included studies, we used the Cochrane risk of bias tool ROBINS-I, which grades studies on a scale from critical risk of bias to low risk of bias due to confounding, selection, outcome and exposure assessment, classification as well as missing data41. We used the method described by Greenland and Longnecker42 for the dose–response analysis to compute the trend from the correlated RRs and 95% CIs across categories of exposure when not provided in the publications. This method required the distribution of person-years, cases, median exposure, RRs, and 95% CIs for at least three categories. For studies that did not provide the distribution of person-years or the number of cases per categories, we estimated the distribution by dividing total person-years or case by the number of categories. The median of the exposure in each category was used if provided in the articles, and if not reported, the midpoint of the upper and lower boundaries was estimated as range in each category. When the highest and lowest categories were open-ended or had extreme upper or lower values, we used the width of the adjacent interval to estimate the upper and lower boundaries for the category. For studies that reported plasma or serum 25(OH)D level in ng/ml32, we converted the data to nmol/L by multiplying the concentration in ng/ml by 2.5, and for studies of vitamin D intake43, data in µg/day were divided by 0.025 to convert the data to IU/day.Dose–response and highest versus lowest meta-analyses were conducted to summarize the associations between vitamin D status or intake and risk of skin cancer by using random-effects models that consider both within study and between-study variation25, we combined the results by the Hamling procedure to obtain an overall estimate for KC44. The dose–response meta-analyses were conducted in increments of 30 nmol/L for 25(OH)D level45 and 100 IU/day for vitamin D intake46 based on the previous published studies46.For studies that reported results separately for BCC and SCC48. We also conducted subgroup and meta-regression analyses to investigate potential sources of heterogeneity by study characteristics such as sex, duration of follow-up, geographic location, risk of bias and adjustment for confounding factors. Statistical heterogeneity between studies was assessed by the Cochran Q test and the I2 statistic49. Small-study effects, such as publication bias, were assessed by visual inspection of funnel plot and with Egger’s test50, and the results were considered to indicate potential small-study bias when P values were < 0.10. Sensitivity analyses excluding one study at a time were conducted to clarify whether the results were simply due to one large study or a study with an extreme result. Stata version 14 software  was used for the statistical analyses.To explore the shape of the association between vitamin D levels and/or dietary vitamin D and incidence of skin cancer, we conducted non-linear dose–response meta-analysis using restricted cubic splines with 3 knots at 10th, 50th, and 90th percentiles of the distribution53 were eligible for inclusion. Of these, ten studies were included in the meta-analysis of 25(OH)D level and skin cancer53 and four studies were included in the meta-analysis of vitamin D intakes from diet and supplement and skin cancer risk52 D level and risk of melanoma were included in the dose–response meta-analysis with a total of 1,644 cases among 241,893 participants. We observed a positive association between 25(OH) D level and melanoma risk  . Because of differences in the 25 (OH)D levels in the reference category among the studies, we could not fit an interpretable nonlinear model. However, when we excluded one study with the highest 25(OH)D level in the reference category32, we found no evidence of a nonlinear dose–response association (Pnonlinearity = 0.08) (n = 3 studies) D level was positively associated with melanoma risk   D level and risk of KC, including 7,485 cases and 249,108 participants. We found that 25(OH) D levels were associated with higher risk of KC  (Table P = 0.94). There was indication for a nonlinear dose–response association between 25 (OH) D level and KC (Pnonlinearity = 0.01) (n = 3 studies) 53  .A total of eight studies2 = 44%, Pheterogeneity = 0.15) for an increase of 30 nmol/L  (Table 28. The SRR per 30 nmol/L increase in 25(OH)D level was 1.57  for SCC, suggesting a positive but not precisely estimated, expressed by the wide 95% CIs (251 cases and three studies)25, and no heterogeneity across skin cancer types was detected (Pheterogeneity = 0.53) (Table nonlinearity = 0.004) (n = 3 studies)  (n = 2 studies) D level and BCC risk  for dietary vitamin D, 1.00  for supplemental vitamin D and 1.01  for total vitamin D (Table nonlinearity = 0.03)   (n = 3 studies)  and SCC, respectively . While we observed positive associations between vitamin D intake (SRR per 100 IU/day increment = 1.04 (95% CI = 1.02–1.06) for dietary, 1.02 (95% CI = 1.00–1.03) for supplemental and 1.02 (95% CI = 1.00–1.03) for total vitamin D) and risk of BCC . Non-linear dose–response analysis could not be done for vitamin D intake and BCC and SCC due to insufficient studies.Three53 to 1.51 (95% CI = 1.11–2.07) when excluding the Copenhagen database (CopD) study33 .Associations between vitamin D status and melanoma risk persisted in most subgroup analyses including analyses by sex, duration of follow-up, number of cases, geographical location, risk of bias and adjustment for confounding factors, including sun exposure. While there was no evidence of between-subgroup heterogeneity, heterogeneity within subgroup analyses was still present Table . In sensheterogeneity = 0.01); however only one study was available for men. There was heterogeneity between subgroup analyses of KC including those by geographical location with stronger associations among the European studies (Pheterogeneity = 0.01), by number of cases with stronger associations for studies with more than 500 cases (Pheterogeneity = 0.04), and by risk of bias with higher association for studies with moderate compared to those with serious risk of bias (Pheterogeneity = 0.02). In addition, there was heterogeneity by adjustment for hair color (Pheterogeneity = 0.02), skin color (Pheterogeneity = 0.01), adjustment for physical activity (Pheterogeneity = 0.05), smoking status (Pheterogeneity = 0.05) and BMI (Pheterogeneity = 0.05). However, in the remaining subgroup analyses, between-subgroup heterogeneity was not significant, and the positive associations persisted in most of them, although the results were more imprecise. In sensitivity analyses excluding the most influential studies for KC, the summary RR per 30 nmol /L increment ranged from 1.24 (95% CI = 1.07–1.42) when excluding the Copenhagen City Heart Study53 to 1.38 (95% CI = 1.22–1.55) when excluding the Osteoporotic Fractures Study32 . Subgroup analyses of vitamin D intakes and risks of melanoma and KC could not be done because of the limited number of studies.In stratified analyses according to sex, the association between 25(OH)D level and KC risk was positive among women, whereas an inverse association was observed among men with heterogeneity detected across sex D was respectively associated with 42%, 30% and 41% increase risks of developing melanoma, KC and BCC. In non-linear dose–response meta-analysis, the association was significant for KC, with higher relative risk observed at a level of approximately 60 nmol/L of 25(OH) D, and a weaker association beyond this level. However, while dietary, supplemental and total intakes of vitamin D were not associated with melanoma and SCC risks, these latter were slightly associated with higher risk of BCC, although with no heterogeneity across skin cancer type. Similar findings were observed in high versus low meta-analysis.55, including cancer risk57. Animal and human studies have indeed demonstrated that vitamin D status may influence some cancers, such as colon, stomach, kidney as well as skin through down regulation of cell growth59 and modulation of the immune system60. Vitamin D is mainly synthesized in the skin after exposure to UV radiation, and it has been estimated 80–90% of vitamin D are from sun exposure and the remainder amount is from the diet and supplements intake61. However, although UV radiation is recognized as a major skin carcinogen, the same spectrum of UV exposure which can lead to DNA damage in skin cells also induce vitamin D synthesis63. This latter has been suggested to have anticancer properties in normal and skin cancer cells66. Consequently, this has led to a strong debate among scientific and public communities about the balance between the potential benefits and risks of UV-induced vitamin D production and skin cancer prevention. A meta-analysis, based on 4 case–control or cohort studies published between 2009 and 2013, suggested no statistically significant association between serum 25-(OH)D levels and the risk of melanoma, while a positive association was found with KC risk30. Unfortunately, this previous meta-analysis did not conduct dose–response meta-analyses or subgroup analyses by confounding factors that are critical to consider due to the conflicting results among published studies to date. The dose–response curve for vitamin D status and skin cancer provides insights regarding an optimal value for vitamin D status, which can be identified for skin cancer prevention, and for proposing an optimal level.Previous research has suggested that high plasma/serum 25(OH)D concentration could have a protective effect against several chronic diseases30. In the present meta-analysis, we found that high vitamin D status was associated with greater risks of melanoma and KC. We found some evidence of a non-linear dose–response association between circulating 25(OH)D levels and KC risk, with the strongest summary relative risk observed at a level of approximately 60 nmol/L of 25(OH) D, which may be considered as insufficient vitamin D status. While levels of 25(OH)D below 50 nmol/L have suggested to be associated with severe vitamin D deficiency, levels between 50 and 74 nmol/L have been described as moderate vitamin D deficiency or insufficiency, and levels between 75–99 are considered as sufficient. Serum 25(OH)D levels between 100 and 150 nmol/L are indicated as adequate and healthy68. However, consistent with our findings, a recent prospective study suggested that higher levels of 25(OH)D was significantly associated with a higher incidence of skin cancer, with the hazard ratio seemed to peak around a vitamin D status of 80 nmol/L in the non-linear trend analysis33. Because of the limited number of studies included in our non-linear dose–response meta-analyses, mainly due to the missing information on the range of vitamin D levels, further studies should aim to clarify the shape of the dose–response relationship.To our knowledge, this is the first meta-analysis to explore the linear and non-linear dose–response association between vitamin D status and the risk skin cancer, including only prospective studies, and the first to investigate subgroup analyses of the associations. Additionally, this is an updated meta-analysis to investigate the highest versus lowest serum or intake of vitamin D in relation to skin cancer30. UV exposure induces both DNA lesion and immune suppression through production of reactive oxygen species which can alter the cellular redox equilibrium leading to premature skin aging and lipid peroxidation70. DNA damage caused by both UVB and UVA, together with UV-induced immune suppression contributes to the development of skin cancer71. Although, UVA and UVB are both implicated in skin cancer development72, studies reported that UVA plays a larger role in melanoma, whereas keratinocyte cancers are mainly related to UVB exposure73, which known to induce vitamin D production. Several studies suggested that UVB exposure induces genetic alterations, which in turn promote skin carcinogenesis76. UVB is mainly absorbed within the epidermis and upper dermis and is associated with skin burning and cause damage to keratinocytes in vitro77. However, while UVB radiation contributes to increase skin cancer risk, ecological studies reported an inverse correlation between solar UVB doses and other cancer risk81. Another hypothesis to explain the positive association between vitamin D status and skin cancer risk may be attributed to genetic factors. Several studies have addressed the issue of whether single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene are associated with the risk of developing different types of cancer83, and several VDR variants have been investigated in relation to skin cancer risk85, with three meta-analyses supporting a positive association, particularly with FokI and BsmI88. Since vitamin D exerts a function of engagement of its receptor VDR, it is likely that some SNPs of the VDR gene affect the ability of interacting with its ligand, which ultimately would lead to different levels of the biologic activity of vitamin D and increase skin cancer risk. Additional research is required to confirm the potential role of VDR gene in skin cancer incidence and to explore their interaction with sun exposure. A recent study based on the UK Biobank data, using a methodically robust Mendelian randomization, found no evidence of a causal association between genetic determinants of vitamin D concentrations and risk of melanoma89. However, while a Mendelian randomization study found no evidence for a causal association between genetically predicted vitamin D concentration and overall cancer risk90, another one reported a weak evidence for linear causal associations between genetic determinants of circulating vitamin D levels and risk of several cancers cancers91.The positive association between 25(OH)D levels and skin cancer risk is likely due to increased UV exposure causing both higher vitamin D levels and skin cancer risk. The current findings lend to support previous meta-analysis, published in 2014, that estimated a SRR of 1.64 (95% CI: 1.02–2.65) for the relationship between high serum 25(OH) D levels and KC risk, and of 1.46 (95% CI: 0.60–3.53) for the association with melanoma risk93. However, this aspect has been largely overlooked in previous studies. Although there was a high level of heterogeneity across studies investigating vitamin D status in relation to SCC, no heterogeneity was detected for BCC, suggesting that difference in KC type may lead to important study heterogeneity.Given the contrasting and confounding effects of sun exposure and others factors such as pigmentary trait and dietary vitamin D on vitamin D status, it is, to date, difficult to examine an independent influence of vitamin D status on skin cancer risk. In our subgroup analysis, the positive association between circulating 25(OH)D levels and risk of melanoma was observed across all subgroup analyses. For KC, the positive association was stronger among studies conducted in Europe, in those with more than 500 cases and with moderate risk bias and in those adjusted for hair color, whereas association were not significant among studies adjusted for skin color, physical activity and BMI. In addition, our findings suggested a moderate and a substantial heterogeneity among studies for melanoma and KC, respectively. Part of heterogeneity for melanoma appeared to be attributed to study duration of follow-up; number of cases; risk of bias and some adjustment for confounders. This heterogeneity could also be related to melanoma localization or histologic type. Previous studies suggested the model of heterogeneity for melanoma by showing distinct etiologies for different body sites and tumor types95, and 1,25(OH)D has been shown to regulate multiple signaling pathways involved in differentiation, inflammation, invasion, angiogenesis and metastasis17. Recently, a pooled analysis of 25 studies showed that lower vitamin D levels were associated with higher Breslow thickness and mortality rates in patients with melanoma96. Several studies suggested that higher vitamin D levels may confer better prognosis from melanoma including Breslow thickness97. UV exposure has also been reported to be associated with a better prognosis and survival rate in several cancers sites98, and some authors proposed that these may include melanoma100, which could be explained by UV exposure–induced high serum levels of vitamin D and lead to a better prognosis. Holiday sun exposure before melanoma diagnosis has been reported to be associated with lower thickness and the exposure after melanoma diagnosis was also associated with reduce melanoma recurrence101. Furthermore, increasing evidence has been suggested that circulating levels of vitamin D may play a protective role against several types of cancer such a bladder102 and colorectal103. Also, a recent pooled analysis of two randomized controlled trials (RCTs) and a prospective cohort found that higher 25(OH)D levels were inversely associated with breast cancer risk with levels ≥ 60 ng/ml ((≥ 150 nmol/L) being most protective 104.Nevertheless, anti-proliferative and pro-apoptotic properties of vitamin D have indeed been demonstrated in animal and in vitro studies106. A meta-analysis of RCT suggested that evidence is stronger for cancer mortality rather than cancer incidence107.Regarding intake of vitamin D, our finding suggested that intake of vitamin D from diet or supplement was not associated with melanoma and SCC risk, whereas there was a weak positive association with BCC risk, although with no heterogeneity across skin cancer type. Two studies from the NHS and HPFS were indeed included in these analyses. As mentioned by the authors, the positive association was mainly attributed to the vitamin D-rich foods such as fish and cereal which were associated with BCC after adjustment for several known risk factor of skin cancer. It could be argue that arsenic present in fish and breakfast cereals, including rice, may be responsible for the positive association. These findings were based on few studies, and thus, the results need to be interpreted with caution. Despite this research, mounting evidence reported a beneficial effect of vitamin D supplementation in reducing cancer incidence and mortality24. In support of this supposition, previous study have reported a correlation of 0.70 for repeated measures of plasma 25(OH)D within individuals over time, suggesting that a single measurement is a reasonable proxy for long-term levels of 25(OH)D108. Further limitations of this meta-analysis include risk of bias of the primary studies, including potential measurement error in the assessment of exposure, residual confounding, especially regarding sun exposure. In addition, some of our meta-analyses were based on a low number of primary studies, and thus, subgroup and analyses by e.g. sun exposure level, season and pigmentary traits were not possible or relied on small numbers of studies.Our meta-analysis has several strengths including the prospective studies, the relatively large sample size, and the linear and nonlinear dose–response analyses. As many previous published meta-analysis, the current analysis has several limitations. First, it is important to notice that all included studies have considered only a single baseline measure of 25 (OH)D, which may not necessarily represent long-term status. Also, most of studies lacked sensitivity analyses excluding skin cancer cases diagnosed within 2, 4, or 6 years of blood draw in order to assess whether reverse causation could have influenced the findings. Thus, we could not investigate a subgroup analysis by time of vitamin D measurement. However, one measurement of plasma 25(OH)D has been suggested to reflect long-term sun exposure and seemed to predict skin cancer riskIn conclusion, our finding suggests that high vitamin D status was associated with increased risks of melanoma and KC. Given that 25 (OH)D level is mainly from sun exposure, higher risk of skin cancer may be confounded by sun exposure, data for which is lacking in most studies. However, while we found that intakes of dietary or supplemental vitamin D were not associated with risk of melanoma and SCC, high intakes of vitamin D from diet and supplements were slightly associated with BCC risk, albeit with no heterogeneity across skin cancer. Overall, the current evidence suggests that unprotected sun exposure should be avoided in order to achieve high vitamin D status, and that an adequate amount of vitamin D should be obtained from a healthy diet.Supplementary Information.


Triticum turgidum ssp. Durum L.) and bread (Triticum aestivum L.) wheat flours were analyzed in order to point out their potential nutritional and health claims allege according to the current European regulation (Regulation (EU) No 432/2012). Moreover, other bioactive compounds (phenolics and tocopherols) were quantified as a first approach to their phytochemical composition in the analyzed wheat varieties. DF was analyzed following AOAC enzymatic-gravimetric methods; arabinoxylans and total phenols were quantified by colorimetric methods; tocopherols were determined by HPLC; antioxidant activity was evaluated using three different in vitro assays. Insoluble DF was the prevailing fraction in all analyzed samples. Water extractable arabinoxylans were higher in durum wheat flours. Whole flours contained higher total phenolics compounds. Alpha-tocopherol was the major isoform. Whole flours showed higher antioxidant properties. According to the obtained results, it is possible to allege all approved health claims referred to wheat, since all analyzed samples, especially whole flour and bran fraction, showed potential health benefits, as functional ingredients or functional foods, related with their phytochemical composition.Wheat is an important cereal with a key role in human nutrition. In this study, dietary fiber (DF) and arabinoxylans of different durum ( Triticum turgidum ssp. Durum L.) are technologically more suitable for good-quality pasta production, contributing to the final bright yellow color, its capacity to retain after cooking firmness, and it is resistant to surface disintegration and stickiness . In For each centrifuged sample suspension, two aliquots (0.5 mL) of the supernatant were removed, resulting in four sample replicates for WE-AX content (two from the first sample suspension and two from the second sample suspension). Sample aliquots were collected, and 1.5 mL of distilled water was added . Arabinoxylans (TO-AX and WE-AX) were determined using a colorimetric method. A calibration curve was simultaneously prepared using a stock solution of 10 mg of D-(+)-xylose in 100 mL of distilled water. Then, triplicate standard samples were prepared using different concentrations of xylose (0.005–1 mg/mL). The values are expressed as g per 100 g dw flour.In particular, arabinoxylans (TO-AX and WE-AX) content in bran fraction were calculated using the Equation (1).Tocopherols were determined following a procedure described by Morales et al. (2015)  and CiudTotal phenols content in the methanolic extract of the different samples was estimated by a colorimetric assay, based on procedures described by Wolfe et al. (2003)  with som3+ to Fe2+, measuring the absorbance at 690 nm the microplate reader mentioned above. Inhibition of β-carotene bleaching was evaluated through the β-carotene/linoleate assay; the neutralisation of linoleate free radicals avoids β-carotene bleaching. Within β-carotene bleaching assay, measurement is done at 470 nm; at this wavelength other carotenoids in the sample might be a bias for the results. The results of the antioxidant activity are expressed as EC50 values (mg/mL methanolic extract)  in Regarding different fractions of dietary fiber (insoluble and soluble dietary fiber) and comparing the obtained results with those found by other authors, Marotti et al. (2012)  reportedArabinoxylans (AX) are one of the major components of non-starch polysaccharides (NSP) in wheat grains, representing around 70% of the NSP. These compounds are mainly found in wheat starchy endosperm and white flour fractions ,23. AX aThese compounds have several and important health benefits, such as prebiotic effect and antioxidant ability, which could explain that AX are prevention agents of colon cancer diseases. At the metabolic level, AX contributes to glycemic and cholesterol levels control, being also considered as an immunoregulator agents .In particular, AX produced from wheat endosperm have approved the following health claim according to Regulation (EU) No 432/2012 : “ConsumComparing with other authors results, Vignola et al. (2016)  analyzedMarotti et al. 2012)  studied 12  studip < 0.05) in samples of whole grain flour harvested in the second year.Vignola et al. (2016)  reportedp-coumaric acid and, largely, ferulic acid [Phenolic acids are not evenly distributed in wheat, and wheat bran presents a high concentration of these compounds, including vanillic acid, lic acid . During lic acid .It is known that total phenolics might be the major contributor of wheat antioxidant activities, since these compounds are highly correlated with this bioactivity . The pheTriticum aestivum L.) white flour, whole grain flour and bran fraction in ecological and integrated farming system. Kosík et al. (2014) [Our results were in concordance with those reported by Kosík et al. (2014)  that eva. (2014)  reported. (2014)  analyzedVitamin E is an important lipophilic antioxidant bioactive compound present in food and the term is used to describe a family of eight lipid-soluble antioxidants (tocochromanols) with two types of structures, four designated tocopherols  and the other four designated tocotrienols  . TocopheThe major isoforms in wheat grains are α-and β-tocopherol . It is kTriticum aestivum L.) varieties  and reported that α–tocopherol content in white flour ranged from 0.3 to 0.59 μg/g, being these amounts much lower than found in our study.The results obtained in the present study were in accordance with those reported by Sedej et al. 2010)  that eva010  thatT. aestivum L.) is 2.83 and 16.54 μg/g, respectively [T. aestivum L.) genotypes and reported values of 1.17–3.58 and 4.72–16.16 μg/g, corresponding to α- and β-tocotrienol, respectively. As part of HEALTGRAIN Program, the tocol composition, including tocopherols and tocotrienols, of 26 genotypes of wheat (Triticum aestivum var. aestivum) has been studied [Cereal grains are also relevant sources of tocotrienols in the human diet. These compounds are mainly located in bran and endosperm fractions. Among tocotrienols, β-tocotrienol is the prevailing isoform in wheat ,37,38. Iectively . SimilarIn addition to vitamin E (tocopherols and tocotrienols), wheat also contains other lipophilic antioxidant compounds, namely carotenoids. They are natural pigments characterized that can be classified in two main types of compounds, namely carotenes (lycopene and β-carotene) and xantophylls (zeaxanthin and lutein) . It is iTriticum aestivum L.) is widely used for bakery products elaboration and its content of carotenoids is usually lower, comparing to durum wheat (Triticum turgidum L.), which is characterized by its yellow color (attributed to the high carotenoid content) and it is used for pasta production [Bread wheat (oduction . The conoduction . T. aestivum). These authors reported values of 0.84–0.86 μg/g, 0.73–0.77 μg/g, 0.002–0.003 μg/g and 0.06–0.13 μg/g for total carotenoids, lutein, zeaxanthin and β-carotene, respectively. Furthermore, Lv et al. (2012) [Triticum aestivum L.) varieties grown in Maryland and reported that the content of lutein and zeaxanthin ranged from 0.27–0.46 and 0.08–0.13 μg/g, respectively. However, these authors did not find β-carotene in any of the analyzed flour samples. Whent et al. (2012) [Okarter et al. 2010)  studied 0  studie. (2012)  reportedAlthough carotenoids are generally minor components in wheat grains, due to the high consumption of wheat-based foods, this cereal constitute an important source of carotenoids in most world regions .The antioxidant capacity of wheat grain fractions is mainly associated to the aleurone content, which can be related to significant amounts of hydroxycinnamic acids, mainly ferulic acid. Antioxidant activity of extracts obtained from wheat bran fraction reveals a stronger potential than other wheat fractions . AntioxiTriticum aestivum L.) by the DPPH assay, and reported that the antioxidant potential of whole grain flour was significantly higher than in the white flour. Sedej et al. (2010) [Components of whole grains, whether in their native and processed states, have a similar antioxidant capacity, as do many fruits and vegetables. However, the antioxidant capacity of refined grains  is much reduced in comparison to their correspondent whole grains (about 20% of the antioxidant capacity of whole grains) . There a. (2010)  obtainedp < 0.05) in total dietary fiber content, than flours from bread wheat varieties (Cajeme and Marius). Arabinoxylans are the main components of non-starch polysaccharides in wheat grain. In the particular case of WE-AX, the content of these compounds was generally higher in flour obtained from durum wheat varieties. This fact has an important technological repercussion because WE-AX improves the quality of pasta products obtained from durum wheat flours. Both dietary fiber and arabinoxylans are important compounds from a nutritional and human health point of view. In this sense, Regulation (EU) No 432/2012 establishing three permitted health claims made on wheat (two of them are related to wheat bran fiber and the third one is related to arabinoxylans produced from wheat endosperm). In the present study, the analyzed samples met the stipulated conditions for using all these claims, supporting the possibility to consider the studied wheat flours  as functional ingredients or functional foods with approved nutritional and health claims according to the European regulation.Wheat is an important agricultural cereal and a worldwide primary food ingredient, which contains considerable beneficial nutritional components. The analyzed varieties could be considered a significant source of dietary fiber, being insoluble dietary fiber the major fraction representing up to 96% of total dietary fiber. In the case of white flours, it was observed that samples corresponding to durum wheat varieties  were significantly higher (p < 0.05) than in white wheat flours. Moreover, whole grain flours obtained from bread wheat varieties display better antioxidants properties than whole grain flour from durum wheat. Due to their phytochemical composition, analyzed wheat varieties are beneficial foods for health, whose consumption and, particularly, the consumption of whole wheat flours, must be promoted.Moreover, as far as we know, this is the first study in which the analyzed wheat varieties were characterized in terms of other phytochemical compounds, which are interesting due to their antioxidant properties, such as total phenolic compounds and tocopherols, as well as their individual vitamers. All whole flour demonstrated higher amounts of total phenols and total tocopherols, than their corresponding white flour. α-Tocopherol was the major isoform found in the studied samples, being higher in whole grain flour (


Nivolumab has changed the treatment of advanced gastric cancer (AGC). Nivolumab shows better outcomes compared to best supportive care among AGC patients who received at least two prior regimens. However, there are no reliable data regarding AGC patients with poor performance status (PS) who received nivolumab. We investigated the efficacy and safety of nivolumab among AGC patients with poor PS.We retrospectively collected clinicopathologic data from patients with AGC who underwent nivolumab monotherapy at our institution from October 2017 to June 2019.p = 0.0255). The disease control rates were 23 and 9% in the Good and Poor groups, respectively. Thirty-three percent of patients experienced immune-related adverse events in the Good group, and 18% in the Poor group.Forty-nine AGC patients who received nivolumab were assessed. Twenty-seven patients had PS 0 or 1 (Good group) and 22 had PS 2 or 3 (Poor group). The median progression-free survival and overall survival durations were 2.0 and 6.0 months in the Good group, respectively, and 1.2 and 2.8 months in the Poor group, respectively. The overall survival was significantly shorter in the Poor group (6.0 vs 2.8 months, Nivolumab is feasible but insufficient as third- or later-line treatment for AGC patients with poor PS. Gastric cancer is one of the most common forms of cancer. Its incidence is the fifth highest among cancers worldwide and it is the third commonest cause of deaths due to cancer . GloballRecently, blockade of immune checkpoint molecules with monoclonal antibodies has demonstrated promising efficacy for AGC. Nivolumab is a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1). The phase III trial of nivolumab (ATTRACTION-2) for patients with AGC after two or more previous lines of chemotherapy in Japan, South Korea and Taiwan showed a significant survival benefit, and nivolumab has been approved for AGC in Japan . AnotherIn those clinical trials, no AGC patients had poor general conditions, such as Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2–4. In the ATTRACTION-2 trial, 29% of patients had PS 0 and 71% had PS 1. In the real world in our institution, not only AGC patients in good condition but also those in poor condition receive nivolumab after two or more previous line chemotherapeutic regimens. Among AGC patients in poor condition, it remains unclear whether nivolumab has sufficient efficacy and tolerable toxicity. The aim of the present study was to assess the safety and efficacy of nivolumab among AGC patients with poor conditions and investigate their prognostic factors.This study was single institution study. The subjects were patients with AGC treated with nivolumab between October 2017 and June 2019 at the Himeji Red Cross Hospital, Hyogo, Japan. All data were collected retrospectively from electronic medical records. All procedures were performed in accordance with institutional and national standards on human experimentation, as confirmed by the ethics committee of Himeji Red Cross Hospital, and with the Declaration of Helsinki of 1964 and its later amendments.The inclusion criteria were as follows: (1) unresectable gastric cancer, (2) histologically proven gastric carcinoma, (3) refractory or intolerant to at least 2 regimens, and (4) no prior administration of immune checkpoint inhibitors. The study protocol was approved by the Institutional Review Board of the Himeji Red Cross Hospital.The patients received nivolumab 3 mg/kg infusion every 2 weeks until disease progression or intolerance (240 mg/kg since August 2018).ECOG perfomance score was defined by the clinical oncologists and chemotherapeutic nurses. Tumour response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.1. Overall survival (OS) was assessed from the date of initiation of treatment with nivolumab until death. Patients who were alive or for whom data were missing at the data cut-off point were censored. Progression-free survival (PFS) was assessed from the date of initiation of treatment with nivolumab until disease progression was confirmed. Patients for whom there was no information regarding tumour progression were treated as censored cases. OS and PFS were estimated using the Kaplan–Meier method. Statistical analyses were performed using JMP version 12 .Among the study subjects, we assessed the Japan Clinical Oncology Group (JCOG) index, Royal Marsden Hospital (RMH) index, and modified Glasgow prognostic score (mGPS). The JCOG index comprised four risk factors: ECOG PS ≥1, number of metastatic sites ≥2, no prior gastrectomy, and serum alkaline phosphatase (ALP) level . Based on these factors, the risks among patients were classified as follows: good risk (0–1 factor), moderate risk (2–3 factors), and poor risk (4 factors) . The RMHBetween October 2017 and June 2019, 49 patients received nivolumab after failure of at least 2 regimens. Their characteristics are shown in Table Forty-seven patients with measurable lesions were evaluated for tumour response. A total of 6% of patients achieved a partial response, and 17% of patients showed stable disease, resulting in a response rate (RR) of 6% and a disease control rate (DCR) of 23% , low serum sodium concentration, high neutrophil-to-lymphocyte ratio, and no prior ramucirumab suggested poor prognosis among AGC patients who received nivolumab . The resp < 0.01; median PFS 3.0 vs.1.1 months; hazard ratio [HR] 0.30, 95% CI 0.18–0.52, p < 0.01) [EGFR mutation/ALK rearrangement and poor PS were independent poor prognostic factors among NSCLC patients in a multicentre retrospective cohort study  [p < 0.001) [p = 0.0255). The same trend was observed in our study.Mishima S et al. reported significant improvements in objective RR (ORR) and PFS among patients with PS 0 compared with those with PS 1 or 2  . For oth< 0.001) . Katsura< 0.001) . Our stup = 0.028) [p = 0.918). However, 3 out of 4 patients who developed toxicities of grade 5 had poor PS [In a previous study of NSCLC , irAEs were similar for the overall population (6%) and patients with an ECOG PS of 2 (9%) . Katsura= 0.028) . Fujimot poor PS . In our In our study, patients with poor PS received limited benefit from nivolumab; only 1 patient with poor PS achieved PR due to complications such as brain infarction. Only 2 patients achieved a PFS of 6 months in the Poor group; the poor PS among both patients was due to brain infarction and osteoarthritis of the hip. In the Poor group, 20 patients recorded poor PS due to gastric cancer; the RR was 0% and the DCR was 5%. These results suggested that a high tumour burden was associated with poor outcome among gastric cancer patients who received nivolumab.In AGC patients, no biomarker has been established to predict the efficacy of nivolumab therapy. We investigated whether JCOG index, RMH index and mGPS could be predictive factor for poor PS patients, but none could be a predictive factor. The reason may be that poor PS was already included as a factor in JCOG index and RMH index. In addition, only 4 cases had mGPS of 0 in poor PS patients. We consider the need for studies to validate new predictive factors of nivolumab efficacy in poor PS AGC patients.Our results indicate that nivolumab has a modest effect and is feasible as third- or later-line therapy for AGC patients. However, among patients with poor PS, this study suggested that the effect may be insufficient. This study suggested that nivolumab is not recommended for AGC patients with poor PS. The present study had several limitations, including its retrospective design, single institution setting, and small number of patients. Further studies to investigate useful predictive factor with larger numbers of patients are needed.


Ataxia telangiectasia-mutated (ATM) gene contributes to repair damaged DNA and to regulate cell cycle; therefore, ATM variants seem to increase breast cancer risk; however, the results are controversial. So we conducted a systematic review and meta-analysis to clarify the pooled association between various ATM variants and the risk of breast cancer.The relevant studies were searched through Scopus, Web of Science, PubMed and Cochrane. Stratified and subgroup analyses were performed to explore heterogeneity between studies and assess effects of study quality. The pooled estimates logarithm with standard error logarithm of odds ratio and relative risk with confidence interval were calculated.This study revealed that there is association between ATM variants and the risk of breast cancer; according to the seven adjusted case-control studies, OR of this association was estimated as 1.67 (95%CI: 0.73–3.82), according to nine unadjusted case-control studies, the crude OR was 2.27 (95% CI: 1.17–4.40) and according to two cohorts, the RR was estimated as 1.68 (95% CI: 1.17–2.40).The ATM variants are associated with an increased risk of breast cancer that ATM V2424G mutation is detected as the most predisposing factor while ATM D1853V, L546V, and S707P variants have the least predictive ability. Breast Cancer is the most common cancer in women and causes the highest mortality rate in developed and developing countries . AnnuallDuring the last decade, BRCA1 and BRCA2 mutations (BRCA1/2) have been screened for hereditary breast cancer and results showed that mutations in BRCA1/2 account for 5% of hereditary breast cancer . BesidesMutations in the ATM gene caused Ataxia Telangiectasia (A-T), an autosomal recessive syndrome that patients have symptoms such as ionizing radiation sensitivity, cerebellar neurodegeneration immunodeficiency and markedly increased risk of cancers like breast cancer –14. The Since the detection of the ATM gene in 1995, several studies have been conducted on the association of mutations of this gene and the risk of breast cancer which had contradictory results and to our knowledge, no systematic study was conducted to examine the association between different variants of ATM and breast cancer. Therefore, the current study aims to clarify the pooled relationship between ATM variants and breast cancer.All methods used in this meta-analysis were according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) . The proTo evaluate the relationship between breast cancer and Ataxia Telangiectasia Mutated Proteins, four English databases including Scopus, Web of Science (EMBASE), PubMed, and Cochrane were browsed up to 20 October 2018. In current study “breast carcinoma”, “breast tumor”, “breast neoplasm”, “breast neoplasms”, “breast cancer”,” breast cancers”, “breast tumors”, “ataxia telangiectasia mutated”, “ataxia telangiectasia mutated proteins”, “ATM”,” mutation”, “mutations”, “variant”, and “variants” keywords were searched in the mentioned databases. Because of avoiding missing any papers, the reference list of primary articles was screened manually. The primary search results were reviewed, and some articles were eliminated after reviewing their title and abstract. Inclusion and exclusion criteria were set by 2 researchers separately .Articles were selected using the following criteria: (1) assessment of the association between ATM variants and breast cancer risk; (2) studies with full text articles; (3) case–control and cohort studies; (4) sufficient data for estimating an odds ratio (OR) with 95% confidence interval (CI).Full texts of each article were sensibly assessed by two independent reviewers (ES and MM) and any probable disagreements with these reviewers were resolved by consultation with another author (YM) to settle the argument, and a concluding deduction was applied. The following data were collected from each study: first author’s name, publication date, type of study, country, study population, age, sample size, type of variant, measurement of association and controlled variables.The qualities of all studies were assessed by Modified Newcastle-Ottawa Scale for Case Control studies . This chp < 0.05.Association between the ATM and breast cancer risk was analyzed by pooling odds ratio (ORs) and risk ratio (RR) with 95% confidence interval (CIs) using STATA metan module. DerSimonian and Laird method were used to compute the pooled estimate of odds ratio (OR) and risk ratio (RR) with a confidence interval (CI 95%) using random models . BecauseThe first step of search in electronic databases yielded 397 publications. In the final step, after removing the duplicates, reviewing by title, abstract and full text and considering the inclusion and exclusion criteria, 18 studies were selected for the meta-analysis of the pooled association between ATM and the risk of breast cancer . The range of OR between these studies was 0.2 to 11.60 .The pooled estimate odds ratio after synthesis results of 7 Adjusted case control studies shows that the association between ATM and risk of breast cancer was 1.67  while the lowest odds ratio was among the European population that was equal to 1.24 . This suggests that ATM variants have a greater impact on the risk of breast cancer in the Asian population than in the European and American populations . Also there is an association between homozygous variants and the risk of breast cancer with an odds ratio (OR) of 1.63 . Meanwhile, the lowest OR belonged to homo or heterozygous which was equal to 1.22 . This statistical analysis indicates that heterozygous ATM variants are the most associated with breast cancer incidence  and D1853V has the least impact on breast cancer incidence   is the most associated with breast cancer incidence    Table .I square: 0.105) and L546V has the lowest association with an OR of 0.37  .The results of two cohort studies showed a risk ratio (RR) range of 0.6 to 6.10. The pooled risk ratio between ATM variants and risk of breast cancer was 1.68  [P < 0.0001). Another meta-analysis of 19 studies by Marabelli M et al. [In the study by Easton DF et al.  in 2015, 0.0001) . Another 0.0001)  in 2016 M et al.  in 2016 M et al. . As the P < 0.0001). Another study by Goldgar DE et al. [P = 0.0005. In addition, another study by Southey MC et al. [p = 0.0012). Also, Mitui M et al. [Of the 29 different variants examined in the current study, V2424G (c.7271 T > G) missense variant had the highest association with breast cancer incidence in different subgroups of adjusted case control, non-adjusted case control and cohort studies. Although this association varied across the three subgroups analyses, all revealed that V2424G missense variant was strongly accompanied by an increased risk of breast cancer. Bernstein JL et al. [E et al.  in 2011 C et al.  in 2016 M et al.  evaluateThe meta-analysis on the adjusted case-control studies revealed that ATM D1853V missense variant has the least association with an increased risk of breast cancer. Gao LB et al.  in 2010 Another objective of our study was to investigate the association of ATM variants with breast cancer in different regions. Although the incidence of breast cancer is higher in the Americas and Europe than in the Asian continent , 39, it The overall risk heterogeneity in our study was 67.4, which could be due to the way we measured, sample-sizes designs, inclusion criteria, family history and BRCA1/2 mutation status and could distort the interpretation of our results, so we performed a sub-group analysis based on variant type, region and heterozygosity to illustrate this heterogeneous factor and thus reduced the heterogeneity up to zero.Since the primary studies used in this meta-analysis did not provide sufficient information about the exact age of the patients, the type of breast cancer, its stage and grade, the hereditary or sporadic type and unilateral or bilateral breast cancer, further subgroup analysis was not possible. Furthermore, there are few cohort studies in this area, and we need more studies.This meta-analysis shows that the pathogenic ATM variants are associated with an increased risk of breast cancer. Accordingly, ATM variants, including V2424G have the highest risk of breast cancer incidence while ATM D1853V, L546V, and S707P variants have the least impact on breast cancer incidence.