To determine the comparative efficacy and safety of all available bone-modifying agents (BMAs) for the treatment of bone metastases in patients with advanced renal cell carcinoma (RCC).Three studies (259 patients) were identified for the systematic review. Two studies that compared zoledronic acid with placebo or no zoledronic acid showed that zoledronic acid reduced the risk of skeletal-related events (SREs) by 68% . The quality of evidence was moderate. The incidence of serious adverse events (AEs) was identical (80%) for both treatment arms in one study and not reported in the other study. In the third study that compared denosumab and zoledronic acid among patients with solid tumors or myeloma, a post-hoc subgroup analysis with individual patient data (155 patients) showed an HR of 0.71 (95% CI: 0.43–1.17) for SREs and a risk ratio of 0.86 (95% CI: 0.68–1.08) for serious AEs for denosumab compared to zoledronic acid.ClinicalTrials.gov database up to January 2017 without language restriction. Only randomized controlled trials were included. When relevant data were missing, we contacted the investigators of the original study. The Grading of Recommendation Assessment, Development, and Evaluation approach was used to assess the evidence certainty.We searched the MEDLINE database, Cochrane Library, WHO International Clinical Trials Registry Platform, and Our moderate-quality evidence indicates that zoledronic acid significantly reduces SREs risk among patients with bone metastases of RCC. Bone is the second-most prevalent site of metastases in patients with advanced renal cell carcinoma (RCC) . ApproxiRandomized controlled trials (RCTs) have shown that in multiple myeloma, breast cancer, and prostate cancer, bone-modifying agents (BMAs) reduce bone pain, improve QOL, and reduce the number of and time to SREs . For blaThe current European Association of Urology (EAU) guidelines do not provide any recommendation for the treatment of bone metastases with BMAs in patients with RCC , but recIn total, 330 articles were identified by the literature search. Of these, four studies were eligible for full-text screening. Three studies met the inclusion criteria and were included for evidence synthesis. Figure The baseline characteristics of all included studies and an excluded study (with only 1 patient with RCC) are outlined in Table Figure The main study outcomes of all included studies are outlined in I2 = 0%). The quality of evidence for SREs was rated “moderate” according the GRADE approach  was 0.32 (0.19–0.55), indicating a 68% reduction in the risk of SREs associated with zoledronic acid treatment , respectively, whereas that for zoledronic acid plus everolimus and everolimus alone was 9.6 and 5.2 months (P = 0.009), respectively. In the subgroup analysis of Henry et al. [P = 0.16).Zoledronic acid significantly delayed the time to first SRE compared to controls. The median time to first SRE for zoledronic acid and placebo arms was “not reached” and 2.4 months .Only the study by Lipton et al.  reportedOsteonecrosis was not observed in the studies by Lipton et al.  and BrooP = 0.179 and 0.088, respectively). In the subgroup analysis by Henry et al. [All three of the abovementioned studies reported OS, but the absolute numbers of events were not available from the studies by Lipton et al.  and BrooNo studies reported PFS. We calculated time-to-progression (TTP) using IPD of the RCC subgroup from the study by Henry et al. , which sP = 0.054 and 0.055, respectively), whereas no detectable effect was seen in the Functional Assessment of Cancer Therapy–Bone Pain scores (P = 0.53). In the subgroup analysis of the study by Henry et al. [P = 0.045 and 0.016, respectively), although there were no significant differences in BPI interference and Euro QOL 5 Dimension scores .Broom et al.  found bey et al. , patientNone of the studies reported the cost effectiveness.A total of three RCTs , in which zoledronic acid or denosumab was administered as BMA treatment, were included in this review. The pooled results of two RCTs that compared zoledronic acid with a placebo or no zoledronic acid suggest that zoledronic acid reduces the risk of SREs by 68% in patients with RCC with bone metastases, and there was no heterogeneity across studies. With regard to denosumab, we identified only one RCT comparing denosumab and zoledronic acid; the subgroup analysis of 155 patients with RCC in this study showed a favorable efficacy of denosumab in terms of SREs, but the difference between the two groups did not meet the conventional level of statistical significance.To date, the role of BMAs in the treatment of bone metastases in patients with RCC remains controversial. Nevertheless, no systematic review has thus far evaluated the efficacy and safety of BMAs in this setting. As mentioned above, although an early subgroup analysis of a phase III trial suggested a superiority of zoledronic acid over placebo in terms of SREs , a recenIn the current EAU guidelines, no recommendation is made for the use of BMAs in patients with RCC with bone metastases . HoweverThe role of denosumab in patients with RCC with bone metastases needs to be explored further. As mentioned above, to our knowledge, only one RCT evaluated the efficacy of denosumab in patients with advanced cancer and myeloma including RCC , 17. TheThe strengths of this review include its rigorous methodology that followed a written, a priori protocol developed according to the PRISMA statement , includiDespite our important findings, this study has a few limitations that need to be addressed. First, there was clinical and methodological  heterogeneity across studies in terms of the study year and treatment outside of the study protocol. Second, although the search was thorough, it is possible that there are unpublished studies that have not been identified, but the small number of studies identified precludes the detection of any publication bias. Although we retrieved as much data as possible by requesting pharmaceutical companies and study authors to supply all available information, we cannot be completely sure that some data are not missing, especially in studies with negative findings. Finally, the study by Henry et al.  was strawww.crd.york.ac.uk/PROSPERO; registration number CRD42016032742), and the search strategy is outlined in the Supplementary document. In brief, databases including MEDLINE and the Cochrane Central Register of Controlled Trials were systematically searched up to January 2017 without language restriction. To identify completed and ongoing studies, we systematically searched both the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov. The search was complemented by additional sources including the reference lists of included studies. Two reviewers (KO and MH) screened all abstracts and full-text articles independently. Disagreement was resolved by discussion, and where no agreement was reached, a third independent reviewer (TAF) acted as an arbiter.The protocol for this review has been registered , or the same drug of different dose.The primary outcomes were the proportion of patients with one or more SREs and the proportion of those with serious adverse events (AEs) classified as grade 3, 4, or 5 according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 . We acceA data-extraction form was developed specifically to collect information on the methods, participants, interventions and other treatments, primary and secondary outcomes, statistical analysis, baseline characteristics, and results. Two reviewers (KO and MH) independently extracted the data. Missing, unclear, or important additional data were requested from primary study authors.The standard Cochrane Collaboration risk of bias tool  was usedI2 statistic. Analysis was performed using Cochrane Review Manager (RevMan) 5.3 . When meta-analysis was not feasible, a narrative synthesis was provided instead, incorporating data on HR with 95% CIs and median OS or PFS for time-to-event data and proportions (%) for categorical data. The mean and standard deviation were used to summarize continuous outcome data and were compared using the mean difference and 95% CI.Descriptive statistics were used to summarize baseline characteristics. A quantitative synthesis  was performed if methodologically appropriate. The random-effects model was used due to the anticipated clinical heterogeneity of participants and interventions. For time-to-event data, we used “O – E” (observed minus expected) and “V” (variance) statistics or hazard ratios (HR) with 95% confidence intervals (CIs) for each study. If these values were not reported for a given study, we calculated them from available statistics, if possible, using the methods described by Tierney et al. . StatistSREs are among the most-common and relevant complications in patients with advanced RCC with bone metastases, and developing an optimal strategy for preventing SREs is crucial. In this systematic review and meta-analysis, we established moderate-quality evidence to prove that treatment with zoledronic acid significantly reduces the risk of SREs for patients with RCC with bone metastases. Further studies should determine the efficacy and safety of denosumab.


Pancreatic cancer is acquiring increasing prominence as a cause of cancer death in the population. The purpose of this study was to analyze long-term pancreatic cancer mortality trends in Spain and evaluate the independent effects of age, death period and birth cohort on these trends.Population and mortality data for the period 1952–2012 were obtained from the Spanish National Statistics Institute. Pancreatic cancer deaths were identified using the International Classification of Diseases ICD-6 to ICD-9 (157 code) and ICD-10 (C25 code). Age-specific and age-adjusted mortality rates were computed by sex, region and five-year period. Changes in pancreatic cancer mortality trends were evaluated using joinpoint regression analyses by sex and region. Age-period-cohort log-linear models were fitted separately for each sex, and segmented regression models were used to detect changes in period- and cohort-effect curvatures.In men, rates increased by 4.1% per annum from 1975 until the mid-1980s and by 1.1% thereafter. In women, there was an increase of 3.6% per annum until the late 1980s, and 1.4% per annum from 1987 to 2012. With reference to the cohort effects, there was an increase in mortality until the generations born in the 1950s in men and a subsequent decline detected by the change point in 1960. A similar trend was observed in women, but the change point occurred 10 years later than in men.Pancreatic cancer mortality increased over the study period in both sexes and all regions. An important rise in rates -around 4% annually- was registered until the 1980s, and upward trends were more moderate subsequently. The differences among sexes in trends in younger generations may be linked to different past prevalence of exposure to some risk factors, particularly tobacco, which underwent an earlier decrease in men than in women.The online version of this article (10.1186/s12885-018-4494-3) contains supplementary material, which is available to authorized users. Though, in terms of incidence, pancreatic cancer is not among the most frequent cancers, its high lethality places this malignant tumor among those that cause a higher number of deaths worldwide . The oveIn Spain, 6367 new pancreatic cancer cases were estimated to occur in 2012, with age adjusted incidence rates (European standard population) of 11.5 cases per 100,000 males and 7.6 cases per 100,000 females [As regards to mortality, in 2012 pancreatic cancer ranked seventh as cause of cancer death among Spanish men, with age adjusted mortality rates of 10.7 per 100,000 inhabitants , being tHelicobacter pylori infection (with moderate evidence) have been considered the major risk factors for pancreatic cancer, in terms of their population attributable fraction, in a recent review [The etiology of pancreatic cancer is unclear  and, as t review . Accordit review . Other et review –9. On tht review –8.This study aimed to monitor pancreatic cancer mortality trends since the middle of the twentieth century until recent years in Spain, using joinpoint regression models and age-period-cohort analyses to evaluate the independent effects of age, death period and birth cohort on these trends.Instituto Nacional de Estadística) at national level. During this period, different revisions of the International Classification of Diseases (ICD) have been used. Codes selected to identify deaths due to pancreatic cancer were adapted accordingly: code 157 in the ICD-6 to ICD-9 and code C25 in the ICD-10. Population data corresponding to censuses and municipal rolls for the midyear of each quinquennium were also obtained from the Spanish National Statistics Institute.Mortality data for the calendar period 1952–2012 were obtained from the Spanish National Statistics Institute , calendar year and region (Autonomous Community). Age-adjusted mortality rates (AAMR) per 100,000 person-years were then calculated, by the direct method, for each sex, five-year calendar period and region, using the 1976 European Standard Population (ESP). Age-adjusted mortality rates were also calculated using the 2013 ESP to allow comparison with other works  at the national level. Then, separate log-linear Poisson models were fitted to study the effect of age, period of death and birth cohort for each sex on mortality trends. To address the “non-identifiability” problem , we used Osmond and Gardner’s solution , as wellThe presence of change points and 95% confidence intervals in the curvatures of the cohort and period effects was evaluated by fitting segmented models to the relationship between curvature effects and time. Details of the recursive algorithm used to estimate the segmented regression have been published elsewhere , and theAs a geographic reference, Fig. The results from joinpoint regression analyses over the period 1975–2012 by Autonomous Community and sex, and in Spain as a whole are presented in Table Figure Table Our results show that pancreatic cancer mortality rates increased over the study period in Spain in both sexes and all regions. In general, this rise was similar in both sexes and in areas with higher and lower rates compared to Spain as a whole. In men, age-adjusted mortality rates annually grew on average by 4.1% in the period 1975–86, and by 1.1% between 1986 and 2012. In women there was a similar trend, with a bigger increase until the late 1980s  than in the years after (1.4% in the period 1987–2012).The age-period-cohort analysis shows that, taking the mean rate for all cohorts as reference, the risk of dying from pancreatic cancer increased in generations born between 1870 and 1960 in men and women. This similarity in the trends could be related to changes in the exposure to risk factors linked to birth cohort and shared by both sexes. The rates observed in young men may indicate a levelling off in mortality in the most recent generations. Among women, this phenomenon is less clear, though the stabilization of the rates in the youngest age group could indicate that trend might soon parallel that of men.For the period effect, there is a change in the general trend around 1962–1965 in males and females and a second change point in men around 1988. Though survival in pancreatic cancer is still very low, a slight improvement has been described in some countries in the last years –19, whicIn Europe, there are geographical differences in pancreatic cancer mortality trends. Mortality rates have increased in the last three decades in countries like France, Germany, Greece, Italy, Romania or Bulgaria, whereas in Sweden, the United Kingdom and Norway they have decreased (in the last two countries only in men). In Denmark, Ireland, Finland and Holland, mortality in men diminished until 1990s and then began to increase . In the Understanding the reasons of the increase in pancreatic cancer mortality is challenging, given the complex and not well understood etiology of this neoplasm. In contrast with other cancer locations, like lung or cervical cancer, which are mainly associated with a unique risk factor, pancreatic cancer has been associated with multiple factors with modest effect sizes and, some of them, with high prevalence of exposure in the general population . ProbablAmong the risk factors for this cancer, the only universally accepted one is tobacco consumption . Trends Helicobacter pylori infection [H. pylori infection. Though this effect is not as clear as it is in gastric cancer [H. pylori infection and pancreatic cancer, there seems to be some coincidence in time between both tumors, especially in women.Another suspected risk factor for pancreatic cancer is nfection . Again, c cancer , which cThough with limited evidence, other factors have been suggested to play a role in the etiology of pancreatic cancer. Among proposed risk factors, extensive research has focused on the role of diet and anthropometric factors , 27. As A different aspect that could have played a role in the observed upward trend in pancreatic cancer mortality is the introduction of Computerized Tomography in Spain during the late 1970s of the twentieth century, and the spreading of its use during the 1980s. In this sense, advances in diagnosis and better death certification would have yielded a rise in the period effect. However, trends become less pronounced from the 1980s onwards.This study has some advantages and limitations that should be taken into account. Among its strengths, it involves the follow-up of the total Spanish population through 60 years. This is a dynamic cohort, with entries and exits across the study period, which encompasses generations born approximately from 1865 to 1975–1985 and thus constitutes a long time series. Also, survival of pancreatic cancer continues to be very low , and theThis study summarizes the trends in pancreatic cancer mortality in Spain, allowing for a detailed analysis of the influence of age, period and cohort effects in each sex. Like in other developed countries, pancreatic cancer mortality has been increasing over the last decades. However, differences have been identified between sexes. In men, mortality rates show a stabilization or even a decrease since the early 1990s, mainly among post-1960 birth cohorts, while in women, a stabilization in the trend is observable only among the youngest generations (born after the late 1970s). These differences may partially mirror the evolution of some established risk factors for pancreatic cancer, such as tobacco exposure, in men and women. Further research on the causes of pancreatic cancer is needed. In the meanwhile, recommendations to reduce exposure to preventable risk factors that have been associated with pancreatic cancer, such as tobacco smoking, obesity, diet and lack of physical activity may serve to reduce the impact of this and other chronic and malignant diseases.Additional file 1Figure S1. Pancreatic cancer mortality in Spain (2008–2012): AAMR per 100,000 person-years (2013 ESP) by Autonomous Community. (PDF 529 kb)Additional file 2Table S1. Pancreatic cancer mortality in Spain. AAMR per 100,000 person-years (2013 ESP) by sex, Autonomous Community and calendar period. (DOCX 30 kb)


We systematically reviewed the literature for trials addressing the efficacy of prophylactic cranial irradiation (PCI) in patients with non-small-cell lung cancer (NSCLC) treated with a curative intent.Randomized controlled trials (RCT) comparing PCI to no PCI in patients with NSCLC treated with a curative intent were eligible for inclusion. We searched EMBASE, MEDLINE, PubMed, and CENTRAL between 1946 and July 2016. We also received continual search alerts from PubMed through September 2017. Search terms included “non-small-cell lung carcinoma,” “cranial irradiation,” and “randomized controlled trials.” We conducted meta-analyses using random-effects models for relative measures of treatment effect for the incidence of brain metastasis, overall survival (OS), and disease-free survival (DFS). We used Parmar’s methodology to derive hazard ratios (HR) when not explicitly stated in RCTs. We narratively synthesized data for the impact of PCI on quality of life (QoL) and neurocognitive function (NCF). We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation methodology.Out of 3,548 citations captured by the search strategy, we retained 8 papers and 1 abstract, reporting on 6 eligible trials. Patients who received PCI had a significant reduction in the risk of developing brain metastases as compared with patients who did not . However, there was no OS benefit . Sensitivity analysis excluding older studies did not show substantively different findings. DFS was reported in the two most recent trials that included only stage III patients. There was significant improvement in DFS with PCI . Two studies that reported on QoL reported no statistically significant differences. There was no significant difference in NCF decline in the only study that reported on this outcome, except in immediate and delayed recall, as assessed by the Hopkins Verbal Learning Test.There is moderate quality evidence that the use of PCI in patients with NSCLC decreases the risk of brain metastases, but does not provide an OS benefit. However, data limited to stage III patients suggests that PCI improves DFS, with no effect on QoL. Lung cancer is predicted to be the second most commonly diagnosed cancer in 2017 in the United States, second to breast cancer in women and prostate cancer in men .The brain is a frequent site of metastasis in both small cell lung cancer (SCLC) and NSCLC. The advances of the past two decades in the use of multimodality therapy, effective systemic therapy, and optimization of radiation therapy (RT), have improved locoregional and systemic control of the cancer. However, these have also paradoxically led to an increase in the proportion of patients with brain metastases –7. The bBrain metastases can be devastating to the patient, leading to impaired quality of life (QoL), worsened neurocognitive function (NCF), potential life-threatening conditions, and decreased survival . The resThe most commonly accepted means of reducing the incidence of brain metastases is the use of prophylactic cranial irradiation (PCI).Prophylactic cranial irradiation is currently recommended for the management of small-cell lung cancer based on a large body of evidence. The use of PCI in limited-stage SCLC (LS-SCLC) was started in 1977 –26 and aHowever, to date, PCI has not been shown to be associated with superior survival and is thus not routinely employed or recommended in the management of NSCLC. A Cochrane review published in 2005 and including four RCTs, compared PCI to no PCI in patients with NSCLC treated with a curative intent . This reThis study aimed at systematically reviewing and, wherever possible, meta-analyzing the benefits and harms of PCI compared to no PCI in patients with NSCLC treated with a curative intent. It also aimed to explore whether the effects of PCI differed in the highest-risk NSCLC patients.Is PCI beneficial in patients with NSCLC in terms of reducing the incidence of brain metastases, conferring an OS or disease-free survival (DFS) benefit, or improving QoL?We report this systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .We included all prospective RCTs, with no restriction to language, publication date, or publication status .We included trials recruiting participants with non-metastatic NSCLC of any age and stage who completed definitive locoregional therapy  with or without chemotherapy, with complete response, partial response, or stable disease after therapy. We excluded studies including participants who were treated in a palliative intent.We included studies that compared PCI to no PCI, irrespective of the PCI dose or RT technique used.The outcomes of interest were incidence of brain metastasis, time-to-brain metastasis, OS, DFS, and QoL.We developed a protocol that detailed the pre-specified objectives, eligibility criteria, outcomes of interest, search strategy, and analyses plan. We published the protocol in the International prospective register of systematic reviews (PROSPERO 2015: registration number CRD42015023982) .We systematically searched the literature using the electronic databases EMBASE, MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials (CENTRAL). The search was run initially between 1946 and February 2014, then was updated until July 2016. We also received continual search alerts from PubMed through September 2017. We applied no limits for language. Search terms included “non-small-cell lung carcinoma,” “cranial irradiation,” and “randomized controlled trials.” The detailed search strategy can be found in Supplementary Data S1 in Supplementary Material.http://ClinicalTrials.gov, EU Clinical Trials Register (EU-CTR), the International Clinical Trial registry Platform, and the International Standard Randomised Controlled Trial Number registry, and contacted their principal investigators. Also, we screened the reference lists of relevant studies  and pertinent books, as well as proceedings of oncology meetings . Experts in the field were consulted for information on potential unpublished data.We also searched the Cochrane Database for Systematic Reviews, and the following clinical trials registers: After removing duplicate publications, a team of two reviewers screened the title and abstracts of all identified citations in duplicate and independently. We obtained the full text of citations judged as potentially eligible by at least one of the two reviewers. We screened all full texts for eligibility by teams of two reviewers in duplicate and independently. We used a pilot tested screening form. Disagreement between reviewers was resolved by consensus or by seeking the opinion of an expert in the field. When multiple reports for the same RCT were found, we retained the one with the most recent results. When different manuscripts or abstracts reported different outcomes for the same study, we included results from these different reports.Two reviewers  conducted data extraction in duplicate and independently. They resolved disagreements by discussion. When agreement was not reached, the senior author (Fady B. Geara) made the final decision. Whenever needed, we attempted to contact trial authors to confirm accuracy of information, request missing information, or request information needed for subgroup analysis. When author contact was unsuccessful, we attempted to extract data from figures .–study design, year of publication–inclusion/exclusion criteria–characteristics of trial participants: age, gender, performance status, stage, type of NSCLC with histological confirmation of the diagnosis , type of treatment received (surgery and/or chemotherapy and/or thoracic RT)–characteristics of the intervention: dose and fractionation of PCI versus no PCI–outcomes assessed: occurrence of brain metastasis, time-to-brain metastasis, OS, DFS, QoL , and NCF.We used a standardized and pilot tested data abstraction form. We extracted the following data from each of the included trials:We used the Cochrane Collaboration’s tool for assessing risk of bias in the included trials. This tool covers six domains of bias: (1) selection bias, as assessed by random sequence generation and allocation concealment, (2) performance bias, as assessed by blinding of participants and personnel, (3) detection bias, as assessed by blinding of outcome assessment, (4) attrition bias, i.e., incomplete outcome data, (5) reporting bias due to selective outcome reporting, (6) other biases due to problems not covered elsewhere . We lookTwo independent reviewers assigned a judgment of high, low, or unclear risk of bias for each of these six domains, and then provided a summary assessment for the risk of bias for each study. We did not exclude studies based solely on the risk of bias.We used relative risks (RR) for brain metastasis and the hazard ratios (HR) for OS and DFS. We derived HR based on Parmar et al., Spruance et al., and Guyot et al. methods –39. Suppp-value ≤ 0.1. We quantitatively assessed it using I2, which measures the degree of inconsistency across studies in a meta-analysis.We computed the pooled RR or HR and 95% confidence interval (CI) for each outcome using the random-effects model. We assessed statistical heterogeneity among trials using the Chi-squared tests with significance at I2 as follows: “low” for I2 below 25%, “moderate” for I2 below 50%, and “high” for I2 above 50%, respectively , for the different radiation doses, and for the types of NSCLC histology (squamous versus non-squamous). However, we were not able to perform these analyses due to the lack of data.We performed sensitivity analyses, excluding older studies (published before 1995), as we expected the potential benefit of PCI to be more evident in more recent studies after the introduction of cisplatin-based chemotherapy, and these latter studies to have a more rigorous methodology.One of the eligible trials  did not provide the needed data for inclusion in the meta-analysis, so we derived HR by working backwards from the KM graph (using WebPlotDigitizer). We opted to exclude this study from the primary analysis and include it in a sensitivity analysis.We assessed the quality of evidence  for the outcomes of interest using the Grading of Recommendations, Assessment, Development, and Evaluation approach . This inFigure Our search strategy identified a total of 3,548 records, of which 2,741 remained after removal of duplicate records. Out of these records, we judged eight reports of six trials , 49–52 an = 1), pilot phase II study (n = 1), preliminary reports/abstracts of RCT , review article (n = 1), and use of PCI not randomized (n = 3). We excluded Pottgen et al.  , and most had a Karnofsky Performance Status of more than 70% or an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, indicating that most patients were ambulatory and able to care for self. Moreover, all of the included studies mandated histological or pathological confirmation in the diagnosis of NSCLC. Most of those patients had stage III of the disease; exclusively stage III in 3 of the included studies , 49, 52,However, there were several important individual differences among the included trials. First, distribution of NSCLC histologies  differed markedly from one study to the other. For instance Li et al. included predominantly adenocarcinoma , while MSecond, curative treatment preceding PCI administration also differed between trials, with some that could be considered suboptimal based on today’s standards of care, such as old RT techniques, inadequate doses of thoracic RT, and suboptimal or no chemotherapy in a setting where it would have been otherwise indicated based on nowadays standards. For instance, the details of the curative therapy used in Umsawasdi et al., discussed in another publication , consistThird, most studies mandated a radionuclide/radioisotopic brain scan , 31, a CMost studies used 30 Gy (in 10 or 15 fractions) as a total dose for PCI, except the first 34 patients in Miller et al. who received 37.5 Gy in 15 fractions , and theThe outcomes studied were the incidence of brain metastases and OS in all of the six included studies , 49, 52,Heterogeneity between studies was also seen at the level of differences in follow-up protocols. In some studies, their protocols required brain imaging only if symptoms developed –32, whilRisk of bias assessment across all studies is shown in Figure Incomplete patient data were improperly addressed in two of the included studies , 31. In Intention-to-treat analysis was performed in four of the trials , 49, 50,www.rtog.com and http://clinicaltrials.gov, thus obviating the risk of reporting bias. The remaining five studies were all at high risk for reporting bias as no protocols were found for them.Furthermore, only one study (RTOG 0214)  had predAll of the six included studies individually showed a reduction in the incidence of brain metastases with PCI as compared to no PCI, with most being significant , 50, 52,I2 = 0%]. The inverted funnel plot did not suggest publication bias . Figure Five of the six included studies contributed data to the meta-analysis for OS Figure ; Table 3I2 = 46%). We also conducted another sensitivity analysis restricted to studies published after 1995 (I2 = 78%). We rated the quality of evidence as low due to high risk of bias, as well as imprecision of the data . We rated the quality of evidence as high, since the evidence was direct, precise, consistent, and free of biases  , 52, 59 es Table .p-value = 0.002)  . Similar= 0.002) . Moreovep-value < 0.001)  as compared to baseline. However, the study notes “a trend” toward greater decline in patient-reported cognitive functioning in the PCI arm compared to no PCI  (p = 0.88). The only significant difference in the NCF analysis was in the Hopkins Verbal Learning Test (HVLT), whereby patients who received PCI showed a greater deterioration in immediate recall (p = 0.03) and delayed recall (p = 0.008) at 1 year compared to no PCI  . The samo no PCI . We rateThis review shows that PCI, compared to no PCI, significantly decreases the incidence of brain metastases in NSCLC (by approximately 70%) and improves DFS in stage III patients. However, it appears to have no effect on OS or QoL, although it can result in some radiation-induced cognitive impairment.p = 0.004)  . Our met= 0.004) , did not= 0.004)  or any o= 0.004) , 50. TheA non-randomized, population-based study using the Surveillance, Epidemiology, and End Results database also addressed the effect on PCI on survival in NSCLC patients. It included a total of 17,852 patients with NSCLC, among whom only 1.8% received PCI as part of their treatment. No statistically significant difference in survival was found between the patients who received PCI and those who did not , even in subgroups of patients at higher risk of brain metastases  . We wereOur review found no deterioration in patients’ QoL with the use of PCI. In contrast, previous studies have demonstrated that whole-brain radiotherapy in patients with brain metastases was associated with neurocognitive deterioration which preceded QoL decline by 9–153 days . Althougp < 0.0001) and 12 months . PCI was also associated with a significant decline on HVLT-Recall and HVLT-Delayed Recall at 6 and 12 months, but was not closely correlated with decline in SRCF at the same time points . PCI was not associated with a decline in global health status/QoL or any other EORTC QLQC30 symptom or functional scales. Age >60 years was associated with higher rates of HVLT-DR decline at 12 months . However, patients randomized to the second arm received a more aggressive locoregional treatment  than patients in the first arm. In that study, PCI successfully reduced the rate of brain metastasis as first site of failure, and the overall brain relapse rate. However, there was no significant difference in neurocognitive performance between the PCI and control arms . This is2 months . These rThe first systematic review published on the use of PCI in NSCLC was a Cochrane review . The twoBrown et al. published another systematic review on the same topic in the form of two abstracts in 2015 , 67. HowOur study has a number of strengths. First, the systematic review methodology is rigorous and in accordance with the Cochrane Handbook of Systematic reviews, the search strategy is thorough and exhaustive, and the data included are up-to-date, covering the most recent trials conducted on the topic. Our study also fills a knowledge gap; it is the only meta-analysis done on stage III patients specifically, although formal subgrouping—stage III versus I–II and stage IIIB versus IIIA, pre-specified in the protocol, was not made possible by the available data. To elaborate, we believe that the therapeutic ratio of benefits versus risks is more advantageous in this group of patients (stage III) compared to those with earlier stages of NSCLC, because the propensity for brain metastases in the stage III patients is much greater. However, results of our meta-analysis showed otherwise; even in this specific subset of patients, PCI seems to have no OS benefit, despite a significant DFS benefit.Our review is not free of limitations. First, we were unable to perform all the planned subgroup analyses because most corresponding authors of the included trials did not answer our e-mails. In particular, we were not able to stratify by stage (stage IIIA versus stage IIIB) or histology.Moreover, in Cox et al. , 13% of Overall, in our review, PCI was definitely shown to change the failure pattern in NSCLC, from failing in the brain first to failing outside of the brain. However, more information is still needed from more RCTs to determine whether a specific subset of patients might derive a survival benefit from PCI versus no PCI compared to the rest of patients. Patients at high risk for brain metastases include (1): patients with superior sulcus tumors, also known as Pancoast tumors, who have a 40% risk of failing in the brain , 77, (2)Supplementary Data S3 in Supplementary Material lists all the ongoing trials on this topic that are trying to address these gaps.In summary, there is moderate quality evidence that the use of PCI in NSCLC decreases the risk of brain metastases, but does not provide an OS benefit. However, data limited to stage III patients suggest that PCI improves DFS, with no effect on QoL. More evidence is still needed for us to be more confident about the benefits versus harms of PCI in NSCLC. It would be important to incorporate prospective NCF testing in all future studies. Efforts to identify high-risk groups, using predictive biomarkers might also help in the selective application of PCI.KF designed and directed the project, and contributed to the implementation of the research, to acquisition of the data, analysis of the results, and writing of the manuscript. RB and AK contributed to the analysis of the results and to the writing of the manuscript. FG and EA contributed to the conception, design and implementation of the project, and revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Studies reporting the treatment of early colorectal cancer (ECC) by endoscopic submucosal dissection (ESD) in elderly patients are lacking in China. The aim was to evaluate the efficacy, safety and overall quality of life of elderly patients with ECC who undergoing ESD.  Three hundred and seventy-nine patients with 401 colorectal lesions entered into our study from March 2013 to March 2016 (Patients with an age 70 years old or older were divided into the elderly group and those who were less than 70-year-old entered the non-elderly group). P > 0.05). No significant differences were observed between the groups in terms of complications during and after ESD procedure (P > 0.05). There were no statistical differences between two groups in Quality of life index (QL-Index) and European Organization for Research and Treatment quality of life version 3.0 questionnaire (EORTC QLQ-C30) scores (P > 0.05).  No significant differences were found in sex ratio, body mass index, location, endoscopic classification, pathological pattern, lesion size, mean procedure time, hospitalization days, complete excision, and en bloc resection rate between the two groups ( ESD was relatively safe and effective for elderly patients with ECC, and it may be an recommended first-line treatment. Colorectal cancer (CRC) remains one of the common malignant tumours worldwide. In recent years, the incidence of CRC in China is increasing, and it is expected that the incidence and mortality will be rising in the near future, severely impairing people's health and quality of life (QOL) , 2.Early colorectal cancer (ECC) is defined as colorectal cancer which confined to the mucosa or submucosa, irrespective of the presence of regional lymph node metastases. Surgical operation is the mainstay in the management of CRC. However, the incidence of chronic disease may increase with increasing age; elderly patients with systemic diseases, such as diabetes and high blood pressure, together with poor gastrointestinal function, might not be able to endure such severe surgical trauma . EndoscoThus, the aim of this study was conducted to investigate the safety, efficacy, and overall quality of life about the ESD in elderly patients with ECC.This retrospective study was carried out from March 2013 to March 2016 in the Digestive Endoscopy Center of Ji'nan Central Hospital Affiliated to Shandong University, Ji'nan, China. A total of 401 colorectal lesions in consecutive 379 patients, all of whom underwent ESD for ECC, were included in the study. The study protocol was approved by the ethics committee for clinical research in our hospital.All patients were provided written and informed consent prior to ESD. Patients with severe or refractory hypertension, heart disease, diabetes, liver disease, respiratory disease, and active bleeding were excluded from the study. Prior to the ESD, all patients had undergone examinations, including endoscopic ultrasonography, chromoendoscopy, thoracoabdominal computed tomography, and biopsy. All ESD procedures were performed by two experienced endoscopists.Patients with an age 70 years old or older were divided into the elderly group (113 lesions in 109 patients), and those who were less than 70 years old entered the nonelderly group (288 lesions in 270 patients). Anticoagulant and antiplatelet drugs were discontinued at least 7 days before ESD procedure. We treated each lesion separately; if patients with multiple lesions, they were received scheduled treatments on different days. Bowel preparation was based on intaking of four to five liters of polyethylene glycol prior to the ESD procedure. All patients underwent conscious sedation using of intravenous administration midazolam and pethidine hydrochloride prior to the operation.First of all, narrow band imaging (NBI) endoscopy was used to observe the range of the lesion, and we marked the lesion with argon plasma coagulation (APC). Then, we raised the submucosa through submucosal injection. After that, a circumferential incision was performed by using a HOOK knife. Circumferential incisions were performed in order to lift the lesion, and all lesion dissections were operated by using IT knife. After removing the lesions, specimens were retrieved with forceps or basket. The margins were carefully investigated to ensure complete lesion resection before completing the operation . EndoscoPatients without adverse events were permitted to drinking water the first day and eating soft food on the second day after the operation. Generally, patients enjoyed their normal diets on postoperative days 4-5. Patient's general condition and auxiliary examination results, such as defecation, abdominal signs, temperature, blood biochemical and routine examination, chest X-ray, abdominal plain film, and D-dimer, were recorded in order to determine if the occurrence of postoperative complications.Follow-up colonoscopy and observation were performed at 3 and 6 months postoperatively. Moreover, we will have a long-time follow-up to all the patients.QL-Index, which has 5 items, was developed by Spitzer et al. . It was EORTC QLQ-C30 is a multidimensional questionnaire designed for measuring the QOL of patients who have cancer. The questionnaire is made up of 30 items and includes 5 functional scales , 3 symptom scales , a number of single items , financial impact, and global QOL. Most items use a 4-point scale  to 4 (very much)). Raw scores are transformed to a 0–100 scale, and a high score means a healthy or high global health status –10.In the follow-up period, patients were asked to fulfill the above two questionnaires six months after the operation.t-test, Fischer's exact probability test, and Pearson's χ2 were used to examine differences between the elderly and nonelderly groups. Continuous variables were presented as means ± SD. A P value <0.05 was considered statistically significant.Statistical analysis was performed using the SPSS Version 19.0 . Student's P = 0.643). Similarly, there were no significant differences in mean procedure time, hospitalization days, complete resection, and en bloc resection.The baseline and clinicopathological characteristics of the elderly and nonelderly patients are summarized in As shown in P = 0.596). All patients with postoperative bleeding required a repeat colonoscopy, and they were all treated by using endoscopic approach to stop bleeding. Only 1 patient in the elderly group needed a blood transfusion. The occurrence rate of postoperative perforation was 0.9% in the elderly group and 0.4% in the nonelderly, respectively (P = 0.265), and all of them were well treated. With respect to the pyrexia (defined as temperature above 38.0°C regardless of its duration), no difference was found between the two groups (P = 0.902). Two patients in the elderly group and 2 patients in the nonelderly group were diagnosed with pneumonia, and no statistical difference was found .Complications observed after ESD procedure are shown in QL-Index and EORTC QLQ-C30 questionnaires were performed at sixth month post-ESD. All patients completed the questionnaires. Elderly patients with systemic and chronic diseases, together with poor gastrointestinal function, might not be able to endure severe surgical trauma. Several studies showed that ESD procedure did not change the normal anatomic structure and physiological function of gastrointestinal tract, and it displayed lower complication and mortality rates than surgery –14. In rIn our study, we demonstrated that there was no significant difference in the mean procedure time between elderly and nonelderly patients, which is in line with a study from Japan . SimilarESD is often associated with high frequencies of intraoperative and postoperative complications . In thisPerforation is the most serious complication in colorectal ESD . It occuIn the present study, the incidence of “bradycardia” (<40 beats per minute) and “decrease in oxygen concentration” that occurred in the elderly group was 12.8% and 34.9%, which is similar with a report from Japan [As far as we know, no previous report has described the pyrexia  after colorectal ESD procedure. Several previous researches aiming at gastric ESD suggested that pyrexia may relate to many other complications, especially pneumonia, so we should pay more attention to this complication , 26. BecAssessment of QOL of the elderly patients with ECC who underwent the ESD procedure to care and monitor for both psychological and medical consequences of their ESD treatment and rehabilitation is imperative. Based on our findings, there were no statistically significant differences in QL-Index and EORTC QLQ-C30 scores between elderly and nonelderly patients performed at sixth month post-ESD. Our survey suggests that the global QOL of the elderly patients was comparability.Some limitations should be considered. One limitation is that we did not perform a randomized trial comparing the elderly and nonelderly patients. It was theoretically feasible, but this would not conform to the principles of medical ethics. Second, it was a retrospective study from a single center; however, the enough sample size may ensure the credibility of our results. Third, our follow-up time was not long enough; the global QOL of the elderly patients with long-term assessment after ESD procedure should be evaluated. Further study should pay more attention to multicentric and prospective research with a larger number of subjects and longer follow-up time.These findings indicate that compared with nonelderly patients, ESD was relatively safe and effective for elderly patients. At the same time, the postoperative overall quality of life in elderly patients was equal to the nonelderly patients. ESD may be a recommended first-line treatment for ECC in elderly patients.


Tramadol, a 4-phenyl-piperidine analog of codeine, has a unique action in that it has a central opioidergic, noradrenergic, serotonergic analgesic, and peripheral local anesthetic (LA) effect. Many studies have reported contradictory findings regarding the peripheral analgesic effect of tramadol as an adjuvant to LA in brachial plexus block (BPB). This meta-analysis aimed to evaluate the effects of tramadol as an adjunct to LA in BPB during shoulder or upper extremity surgery.We searched the PubMed, EMBASE, Cochrane, KoreaMed databases, and Google Scholar for eligible randomized controlled trials (RCTs) that compared BPB with LA alone and BPB with LA and tramadol. Primary outcomes were the effects of tramadol as an adjuvant on duration of sensory block, motor block, and analgesia. Secondary outcomes were the effects of tramadol as an adjuvant on time to onset of sensory block and motor block and on adverse effects. We performed the meta-analysis using Review Manager 5.3 software.P = 0.0004), motor block , and analgesia  compared with BPB without tramadol. Tramadol also shortened the time to onset of sensory block  and motor block . In subgroup analysis, the duration of sensory block, motor block, and analgesia was prolonged for BPB with tramadol 100 mg (P < 0.05) but not for BPB with tramadol 50 mg. The quality of evidence was high for duration of analgesia according to the GRADE system. Adverse effects were comparable between the studies.We identified 16 RCTs with 751 patients. BPB with tramadol prolonged the duration of sensory block (mean difference [MD], -61.5 min; 95% CI, -95.5 to -27.6; In upper extremity surgery performed under BPB, use of tramadol 100 mg as an adjuvant to LA appears to prolong the duration of sensory block, motor block, and analgesia, and shorten the time to onset of sensory and motor blocks without altering adverse effects. A brachial plexus block (BPB) provides anesthesia and analgesia during surgery involving the upper limb and for acutely painful conditions, and is the most frequent plexus block performed by anesthesiologists. It is worthwhile to explore the options for extending pain relief while minimizing the adverse effects of local anesthesia. Local anesthetics (LAs) have been used with various perineural adjuvants, including dexamethasone , 2, clonSystemic opioids have been used to relieve pain during surgery for many years, but the effects of perineural opioid adjuvants on BPB are controversial. Some studies have reported that addition of opioids such as fentanyl, alfentanil, morphine, buprenorphine, and meperidine to BPB improves sensory block, motor block, and analgesia, but other studies have found no such effect –9.2-adrenergic and serotoninergic activity [+ channels [Tramadol administered parenterally or orally has proven effective in managing acute postoperative pain in adults . Tramadoactivity , 12. Theactivity . Tramadochannels . Clinicachannels . Many stchannels –31. HoweThe purpose of this meta-analysis and systematic review was to evaluate the effects of tramadol as an adjunct to LA in BPB on the onset and duration of sensory block, motor block, and analgesia, as well as the adverse effects associated with BPB when used for shoulder and upper extremity surgery.This meta-analysis of randomized controlled trials (RCTs) evaluated the effect of tramadol as an adjuvant to LA in BPB and was performed according to the recommendations of the PRISMA statement. The systematic review was registered on PROSPERO under the number CRD42015023489.Following the protocol recommended by the Cochrane Collaboration, we performed a systematic literature search for RCTs to evaluate the effects of tramadol as an adjunct to LA in BPB for shoulder or upper extremity surgery. The PubMed, EMBASE, Cochrane CENTRAL, and KoreaMed databases as well as Google Scholar were systematically searched for RCTs performed in adults (aged older than 18 y) up to November 2015 without language restrictions. The search strategy comprised the following key words: (“tramadol”) and  and  as outlined in Supporting Information .The studies included in this analysis were peer-reviewed RCTs that compared BPB with LA alone and BPB with LA and tramadol for shoulder or upper extremity surgery in adult patients. Review articles, case reports, letters to the editor, commentaries, proceedings, laboratory studies, and other non-relevant studies were excluded. Two authors (JBJ and YKC) independently assessed the articles for compliance with the inclusion/exclusion criteria. Any disagreement was resolved by discussion or consultation with a third independent investigator (HWS).The primary outcomes were the effects of tramadol as an adjuvant to LA on duration of sensory block, motor block, and analgesia. The secondary outcomes were the effects of tramadol as an adjuvant to LA on time to onset of motor block and sensory block and on the adverse effects of BPB for shoulder and upper extremity surgery.Using standardized forms, two authors (JBJ and JYP) independently extracted the following data: the name of the first author, year of publication, type of surgery, type and dose of LA, volume of LA, dose of tramadol, number of patients, technique used for nerve guidance , type of BPB approach , definitions of sensory and motor block , and adverse effects . In our analysis, there were two studies that contained more than two groups for tramadol as an adjuvant to LA  independently evaluated the quality of the RCTs by using the risk of bias tool in Review Manager . Quality was evaluated using the following seven potential sources of bias: random sequence generation, allocation concealment, blinding of the participants, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other sources of bias. The methodology for each RCT was graded as “high,” “low,” or “unclear” to reflect either a high, low, or uncertain risk of bias, respectively.P-values are two-sided. A two-sided P-value < 0.05 was considered to be statistically significant. Statistical heterogeneity was estimated using the I2 statistic, which was deemed to be significant when I2 values were above 50%. The Mantel-Haenszel or inverse variance fixed-effects model was used for the study without significant heterogeneity, while the Mantel-Haenszel or inverse variance random-effects model was used for the study with significant heterogeneity. Sensitivity analyses were performed by excluding studies with a high risk of bias.The statistical analysis was performed using RevMan 5.3. We computed the mean difference (MD) with its 95% confidence intervals (CIs) for continuous variables and the relative risk (RR) with corresponding 95% CIs for dichotomous outcome data. The overall data were determined using a Z-test. All reported We performed subgroup analyses for primary outcomes on the basis of type of BPB approach , dose of tramadol (50 mg or 100 mg), type of LA , and volume of LA used for BPB (≤30 mL or >30 mL).P-values were < 0.1 on Egger’s linear regression test, the presence of a possible publication bias was suspected. In such cases, a trim-and-fill analysis was performed to confirm publication bias.If the funnel plot was visually asymmetric or if the There was heterogeneity with regard to the definitions of times to onset and duration of sensory block and motor block. Therefore, we assessed the strength of evidence from the RCTs using the GRADE  guidelines. The GRADE tool evaluates the quality across RCTs for each outcome. Based on key elements, including study quality, consistency, directness, precision, and publication bias, the GRADE tool classifies the strength of the synthesized evidence into four categories: high quality (further research is very unlikely to change the confidence in the estimate of effect); moderate quality (further research is likely to have an important impact on the confidence in the estimate of effect and may change the estimate); low quality (further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimate); and very low quality (there is a high degree of uncertainty about the estimate).Our initial electronic search identified 94 potential RCTs . We identified 16 studies  that useThe studies included in this review originated from eight countries, i.e., Austria , France A risk of bias assessment was performed to determine study quality and potential bias. All 16 studies mentioned randomization , and 15 P = 0.00985), duration of motor block (P = 0.01386), duration of analgesia (P = 0.00995), and time to onset of sensory block (P = 0.069381). However, no publication bias was noted for the time to onset of motor block (P = 0.5354). To compare P-values < 0.1 derived by Egger’s method, we performed a trim-and-fill analysis, and noticed a change in the significance of the results for the time to onset of sensory block . However, we noted no changes in the statistical significance of the results for duration of sensory block, motor block, and analgesia, indicating publication bias for these three parameters.We evaluated a funnel plot for every comparison and estimated the publication bias using Egger’s linear regression method. Egger’s linear regression method indicated the publication bias for the following comparisons (>10 studies for comparison): duration of sensory block  (P = 0.0002), but not in the studies with interscalene or supraclavicular approach , but not in the studies with tramadol 50 mg  . In subgI2 = 97%; P = 0.0003; P = 0.0002), but not in the studies with tramadol 50 mg , but not in the studies with tramadol 50 mg  = 22) [2 = 0%; P = 0.97; NNT = 39) [2 = 0%; P = 0.98; NNT = 30) [2 = 0%; P = 0.93; NNT = 32) [Tramadol use did not change the incidence of adverse effects after BPB between the study groups: nausea  = 22) , 29, 31,NT = 39) , 29, 31,NT = 30) , 26, 29,NT = 32) –18, 29 . This can affect the duration of analgesia at the surgical site. As an example, interscalene approaches are used for shoulder surgery, whereas axillary approaches tend to be used more for surgery on the forearm and hand. This difference in approach contributes to different results and clinical heterogeneity. We performed the meta-analysis using RevMan statistical software and performed subgroup analysis for various items  to identify the source of the heterogeneity . We coul+ channels, but tramadol exerts its effect by blocking K+ channels, as does meperidine [Tramadol as an adjuvant for BPB in our review shortened the time to onset of sensory block and motor block. These findings are attributed to the potentiating effect of opioids and the peripheral LA-like effect of tramadol. The mechanism underlying the LA effect of tramadol is different from that of LA; the action of LA is generated by blocking Naperidine . A previperidine . For theTypical adverse effects of tramadol are headache, nausea, vomiting, dizziness, and sedation when it is used for analgesia . We could not detect any differences in adverse effects between studies in our meta-analysis, which could reflect low plasma concentrations of tramadol. Use of tramadol as an adjuvant in BPB causes fewer symptoms than does intravenous administration of tramadol (36). There have been no reports of nerve damage attributed to tramadol in animal or human studies. The US Food and Drug Administration has not approved perineural administration of tramadol as it has for dexamethasone.A recent systematic review of various adjuvants for peripheral nerve block  reportedOur review has several limitations. First, the studies included in the review contained considerably clinical heterogeneity with regard to type of BPB approach, dose and volume of drug, and type of guidance used for BPB. Based on the clinical assumption that different types of BPB may lead to different sensory or motor block characteristics and analgesia. Second, the definitions of outcomes of interest such as time to onset and duration of sensory block, motor block, and analgesia varied widely between the studies. Third, this review pertains to the duration of sensory block, motor block, and analgesia, and highlighted publication bias as ascertained by the trim-and-fill analysis. As a result, the findings of our meta-analysis were influenced by publication bias among the included studies.However, our review also has several strengths. The main strength is that we tried to include all relevant databases and RCTs in our search. The methodology used was strong, with registration of the protocol for the review on PROSPERO and use of RevMan software.Our study provides evidence that tramadol 100 mg is a potential adjuvant for use with LA in BPB. Adjuvant tramadol prolonged the duration of sensory block, motor block, and analgesia and shortened the time to onset of sensory block and motor block without altering the incidence of adverse effects.S1 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOC)Click here for additional data file.


Hepatocellular carcinoma (HCC) was rarely discussed in adolescent and young adult (AYA) patients. This study aimed to discuss the character of AYA HCC patients and establish an effective prognostic nomogram for patients after hepatectomy.For all of the patients, the median OS was 57 months with 5-year OS rate 60.4%, and DFS was 48 months with 5-year DFS rate 51.4%. The tumor size, vascular invasion status and the pathological differentiation were the independent predictors for both OS and DFS. Except for that, gender, Neutrophil-lymphocyte ratio, HbeAg, and α-Fetoprotein were the predictors for OS. The c-index for OS prognostic nomogram was 0.75 , and c-index was 0.70  for DFS prognostic nomogram, which was better than American Joint Commission on Cancer 2002 and 2010, Okuda staging system, the Japanese Integrated Staging system, and Tokyo staging system.This study was based on 423 AYA HCC patients (younger than 40 years old) undergoing hepatectomy in West China Hospital between 2008 to 2014. Based on the multivariate risk factors, the nomogram was constructed for predict the possibility for overall survival (OS) and disease-free survival (DFS) rate. Harrel’s concordance index (c-index) was used to compare the predictive accuracy and discriminative ability between the nomogram and eight contemporary staging systems.Our prognostic nomogram could accurately and preciously provide individual prediction for AYA HCC patients in OS and DFS after hepatectomy. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, which remains increasing in recent years . The adoBecause of the shortage of the liver donor for liver transplantation, hepatectomy was still the most common curative approach to treat HCC , 4. But 4 copies/ml. Although 74.2% of the patients were diagnosed as liver cirrhosis, majority of patients have an acceptable liver function with child-pugh A status (n = 400). The cut-off of the neutrophil-lymphocyte ratio (NLR) was 2.8. For 334 patients, α-Fetoprotein (AFP) was observed with an increase more than 20 ng/ml, and of which, AFP increased significantly in 277 patients (≥ 200 ng/ml).Four hundred and twenty-three AYA patients meeting the inclusion were involved in this study. The characteristics of all the patients were listed in Table The median tumor size was 6 cm, and 72.1% of the tumor occurred as the single form. Majority of patients (62.2%) did not have the evidence of the MIVI and MAVI, and the poorer and the better differentiation histologic grade based on the Edmondson-Steiner (ES) classification occupied equally in those patients (51.8% vs 48.2%).p < 0.001), negative HbeAg , lower AFP , negative vascular invasion (p < 0.001), less tumor number  and better differentiation tumor grade  were associated with a better prognosis of OS. Moreover, the tumor size was also an important influence to the survival as shown in Table p < 0.001). All significant factors in univariate analysis and other clinical meaningful data like gender, HBV DNA and platelets were entered into the multivariate analysis which was expressed as hazard ratio (HR) and 95% confidence interval (CI) as shown in Table For all of the patients, the median OS was 57 months with 5-year OS rate 60.4%, and DFS was 48 months with 5-year DFS rate 51.4% Figure . The resBased on the results of the multivariate analysis, the OS and DFS prognostic nomograms were built respectively after integrating all the significant independent factors in Figure p < 0.001). Despite for the acceptable OS results that the classification provided, overlap could be found in some stage in the survival plotting, especially the intermediate stage such as I and II in AJCC and HKLC stage system, which meant that the distinguish between those mediate stages could not predict the prognostic outcome perfectly. The c-index were calculated respectively according to the different stage system, and compared with the nomogram for OS and DFS in the Figure p = 0.1, 0.1, 0.06 in OS and p = 0.48, 0.45, 0.11 in DFS in BCLC, CLIP and HKLC, respectively). While for the rest five stage system , the c-index of the nomogram was found to be significantly better .As shown in Figure Due to the shortage samples diagnosed as HCC in many oncological institutes, few studies had focused on the survival condition and risk factors for the younger patients, particularly. Thereafter, we designed the retrospective study for the AYA HCC patients younger than 40-year old, trying to find out more factors affecting the survival and creating a new prognostic model for these special group.As far as we concerned, this is one of the largest cohort concentrating on the AYA HCC patients. Comparing to the younger and elder patients, AYAs are different in their biological, psychosocial and socio-behavioral characteristics and thereafter represented a unique oncological population . In someTo quantify different risk factors influencing the outcome of the HCC patients, several institutes and organizations tried to propose staging system and stratify patients into different degrees which could representative the outcome of their characters. In our present study, we listed eight commonest stage system and compared the accuracy and effect with our new nomogram. But it must be stated that not all of the classifications were originally developed as the prognostic model. For some, like Okuda, BCLC, HKLC, CLIP and JIS, were trying to help clinics to confirm the treatment approach, while for another, involving the operative and pathological factors, like AJCC and our prognostic nomogram, are used to ascertain the long-term survival after surgery. Regardless, we applied all the stage systems to predict the outcome of OS and DFS of HCC patients after hepatectomy, and the survival was classified based on different stage and analyzed by the Kaplan–Meier method. Moreover, the Harrell’s concordance index was used to measure the prognostic capacity of different stage and to assess how well the model performed. Our nomogram indicated a better predictive ability with c-index of 0.74 and 0.70 comparing to five stage systems both in OS and DFS, and even with no statistical difference, the c-index of the nomogram was still higher than it of the BCLC, CLIP and HKLC. Besides, majority of contemporary standard model existing some shortages with a great deal of heterogeneity within each risk factors. Nomogram was a new method not only reflect the predictive value for each variable but also the complex interaction with the other variables . MoreoveIn our present study, the tumor size, vascular invasion and pathological differentiation were recognized as the variables both in nomograms for OS and DFS, which were demonstrated associating with outcomes by previous studies –26. And p = 0.068). This would be related to the high percentage of male patients in this study (79.9%) and associated with the high prevalence rate of male HCC patients in the whole population [p < 0001). But the impact of AFP was still controversial, some studies also showed there was no prognostic value for the tumor less than 3 cm [p < 0.001), and therefore was considered as a main risk factor in the OS nomogram that we proposed. Tumor number was considered as one of the most important factors affecting the long-term survival of the HCC patients and was involved in most of the contemporary staging systems [p = 0.019). While the tumor number may not be a prognostic factor in the multivariate analyses for its relationship to the aggression of tumors which may connect with vascular invasion and pathological differentiation.Gender was considered as one of the variables influencing the long-term OS in the present study, but which was without statistical difference in univariate analysis , no history of previous anticancer therapy, radical resection of macroscopic liver tumors and the histopathologically proven HCC. Exclusion criteria included the mixed type of liver cancer, simultaneously underwent resection and radiofrequency ablation and palliative resection. Finally, 423 AYA patients were involved in this study.Laboratory blood examination including routine blood test, liver and renal function, coagulation tests, hepatitis B and C immunology and tumor markers were completely tested. Hepatitis B virus (HBV) infection was identified if serum hepatitis B surface antigen (HbsAg) positively, and moreover the HBV DNA load was examined to judge whether the antiviral drug should be taken and determine the long-term of the effect of the antiviral drug. Preoperative chest X-ray, electrocardiogram (ECG), ultrasonography and enhanced CT or MRI of abdomen to exclude the cardiopulmonary diseases and confirm the HCC diagnosis and surgery approach. Preoperative diagnosis was judged by 2 types of clinical imaging in addition to a high serum level of α-fetoprotein (AFP) and a background of hepatitis infection. All the images were evaluated by two experienced radiologists independently and the discussion would be detected if any controversies were existed to generate the final report. Besides, appropriate residual liver volume (RLV) need to be assessed by surgeons to avoid the postoperative liver failure. Generally speaking, for patients without liver cirrhosis, 30% RLV after hepatectomy was adequate and more than 50% should be guaranteed if the liver cirrhosis was combined. Thereafter our institute recommend the indications for hepatectomy were as follows: lack of ascites, gastric esophageal varices bleeding, presence of Child-Pugh A of B liver function, and appropriate RLV . Since IPostoperative HCC diagnosis was confirmed by histopathological examination for all the patients. Two experienced pathologists confirmed the final diagnosis and all surgical specimens were routinely examined for the presence of the microvascular invasion. Curative hepatic resection was defined if grossly complete removal of all detected tumors and tumor-free margins confirmed by histopathology , 39. MicLiver and renal function test, routine blood test, serum AFP assay and ultrasonography were performed once in the first month after resection and then checked every 3 months in the first postoperative year and every 6 months in the subsequent years. If the recurrence was suspected, the enhanced CT or MRI was performed. Tracing and follow-up of all the patients was until June 1st 2016. Overall survival (OS) and disease-free survival (DFS) were the endpoints of our study. OS was calculated from the date of hepatectomy to the date of patient’s death or the date of last follow-up visit. DFS was measured from the date of hepatectomy to the date when tumor recurrence was diagnosed.If the recurrence of tumor was confirmed, the treatment for HCC was similar to the initial HCC. For the tumors were found in intrahepatic areas, hepatectomy was considered if the patients can tolerate the surgery based on the liver function and residual liver volume according to the indications for hepatectomy as used at the time of curative resection . RFA wasPatients were categorized according to the eight contemporary HCC staging systems including the sixth and seventh editions of American Joint Commission on Cancer (AJCC 2002 and 2010) , the Okuhttps://www.r-project.org/) according to the result of the multivariate analyses, and the methods was referred to the studies published previously [p value < 0.05 was considered to be statistical significance for all the analyses. The statistical analyses of the collected data were performed with the SPSS 19.0 statistical software  and R, version 3.3.Categorical variables were expressed as count and calculate the median survival respectively, and continuous variables were described as median and interquartile range. According to the eight major existing HCC staging system, relative clinical variables were used to stage patients. The cut-off of some continuous data, like NLR, was determined by receiver operating characteristic curve (ROC) method, in which the best cut-off could be achieved with the best sensitive and specific rate. Survival outcomes were determined by Kaplan–Meier methodology, and compared with the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazard model to acquire the prognostic factors for survival. A nomogram was formulated by R, version 3.3 (eviously , 15. A ceviously , 43, andFor clinical use of the model, based on the points that each variable achieved, the total points would be calculated according to the nomogram, and the probability of survival rate could be determined.


Background and Aim: The vast majority of the 2.7 million individuals in the United States who are currently infected with hepatitis C virus (HCV) were born between 1945 and 1965. The median age of these patients in this particular generation at the time of this writing was 55 years. In the general population, older age is a risk factor for multiple myeloma (MM) and other monogammopathies. As the baby boomer population ages, HCV providers are increasingly likely to encounter HCV-infected patients with a monoclonal gammopathy. Guidelines for managing these patients are needed. Methods: We conducted a detailed case series investigation of 4 HCV-positive patients with MM or a monoclonal gammopathy disorder. Patients were followed at the Mount Sinai Faculty Practice liver clinic. We also performed a detailed review of the literature exploring if there is any known association between HCV, MM, and monoclonal gammopathy. Results and Conclusions: There is no convincing evidence of a causal association between HCV and MM. HCV is linked to type II and type III cryoglobulinemia, specific kinds of monoclonal gammopathies of determinable significance. Whether a link exists between HCV and MM or monoclonal gammopathy of undetermined significance is unclear. Our case series provides the first evidence that modern HCV treatments with direct-acting antivirals can be safely and effectively co-administered with MM chemotherapy. These diseases include multiple myeloma (MM) and other disorders of plasma cells. Herein, we provide background information about MM, present several cases of HCV-positive patients with plasma cell disorders, and describe diagnostic strategies and management options.Approximately 2.7 million individuals in the United States are currently infected with the hepatitis C virus (HCV). Most were born between 1945 and 1965.calcemia, renal insufficiency, anemia, and/or bone lesions (“CRAB” symptoms). MM is thought to often be preceded by monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic condition in which there is production of a small amount of monoclonal protein from a relatively small burden of monoclonal plasma cells.2 No known molecular or phenotypic markers distinguish MGUS and MM, and the genetic mutations in the abnormal antibody producing cells are largely the same.3 Characteristics of MM versus MGUS are delineated in Supplemental Table 1 . Risk factors for MM include male sex, age over 55 years, African American race, obesity, and a family history of MM.4MM is defined by the presence of more than 10% monoclonal plasma cells in the bone marrow (BM), as well as one or more of the following symptoms: hyperThis is a case series review from December 2013 to June 2016. All cases were seen in the Mount Sinai Faculty Practice liver clinic. Cases are HCV-infected patients who also have a diagnosis of MGUS and/or MM. For historical comparison, we conducted a systematic literature search on PubMed to find all studies that examined HCV and MM/MGUS.6 Subsequent accumulation of additional genetic alterations leads to increased proliferation of the altered clone(s).7 The increased proliferation results in end-organ damage as the buildup of plasma cells reduces marrow function, and the excess immunoglobulins can cause complications such as myeloma cast nephropathy and hyperviscosity.810Abnormal responses to antigenic stimulation lead to chromosomal alterations, which in turn lead to the development of one or more premalignant clones derived from postgerminal center plasma cells, resulting in MGUS.12 and the mixed cryoglobulinemias, specifically type II and type III cryoglobulinemias . HCV causes chronic antigenic B-cell stimulation and antibody production.3 While limited epidemiological studies have linked monoclonal plasma cell disorders with HCV, no direct pathophysiological proof links HCV and MM.1315HCV’s main effect is immune-mediated hepatocyte injury; however, chronic infection also increases the risk of hepatocellular carcinoma and certain lymphoproliferative disorders. HCV is most strongly associated with the non-Hodgkin’s B cell lymphomas4 The well-known associations between HCV and other B-cell abnormalities support the possibility of an epidemiological link between HCV and MM; however, published data do not show a firm epidemiological association. A recent study conducted at Kaiser Permanente Southern California reported MM rates in patients with HCV versus those without HCV and found a relative risk (RR) of 3.41 (P < .0001). However, after adjusting for alcohol abuse, tobacco use, body mass index, and diabetes, the RR was no longer significant.13 An earlier meta-analysis of data from 5 studies did not find a significant association between HCV and MM.14 One case-control study in the meta-analysis reported an odds ratio of 4.2 in HCV-positive patients for developing MM.15 However, the data presented in this small study were not stratified for any established MM or cancer risk factors. Thus, the weight of the epidemiological evidence indicates that HCV infection is not a risk factor for MM. Nevertheless, even if there is no causal relationship between chronic HCV and MM, as the cohort of HCV-infected patients reaches the age of heightened MM risk, hepatologists and other clinicians are sure to see more patients affected by both diseases and will need guidance about how to manage them.MM is a relatively uncommon cancer, representing only 1% of all cancer diagnoses and 10% of all hematological malignancies. It is estimated that 0.7% of the US population will be diagnosed with MM, with 85% of diagnoses occurring in individuals 55 or older—an age range that a steadily increasing number of HCV patients in the United States and Europe are reaching.Below, we present 4 cases from the Mount Sinai Faculty Practice Liver Clinic. Each case involves HCV-positive patients of advancing age with either MGUS or MM. It is our hope that these cases offer guidance for hepatologists and other clinicians seeing similar patients who have concomitant diagnoses of HCV and MM/MGUS.A 68-year-old Caucasian male with a history of well-controlled human immunodeficiency virus (HIV) on abacavir, lamivudine, and raltegravir , chronic HCV, genotype 1a, HCV treatment naïve with cirrhosis (transient elastography score: 21 kPa) was diagnosed with MGUS in August 2014. The diagnosis was made as a result of tests carried out to investigate an elevated total protein-albumin (TPA) ratio. The patient had no complaints of CRAB symptoms, and a skeletal survey was negative for lytic lesions. The patient was referred to the myeloma clinic where a BM biopsy was discussed, but the patient declined. He was started on a 12-week course of sofosbuvir/ledipasvir (SOF/LDV) to treat his HCV in November 2014. He tolerated the antiviral course well and achieved a sustained virological response of 4 weeks (SVR4) in March before being lost to follow-up.http://hic.sagepub.com/supplemental). Patients should be referred to a hematologist for risk stratification of their disease, determination of follow-up intervals, and consideration for clinical trial participation. Follow-up should be life-long.16 Patients with MGUS have an estimated transformation rate to MM of 25% to 30% over 25 years.2 Several basic tests are used in the MGUS/MM work-up, including a serum protein electrophoresis, serum immunofixation, serum kappa/lambda chains, urine protein electrophoresis and urine immunofixation .Asymptomatic monoclonal gammopathy encompasses both MGUS and smoldering multiple myeloma (SMM). SMM is distinguished from MGUS by a higher disease burden; however, both entities are clinically asymptomatic  presented with IgA-kappa MM with extensive lytic lesions in the skull, ribs, spine, sacrum, and left femur diagnosed in the winter of 2014-2015. There was no kidney involvement and no anemia at the time of MM diagnosis. The patient started a 12-week course of SOF/LDV 3 months after the monoclonal protein was initially discovered. Approximately 1 month after starting direct-acting antiviral (DAA) therapy, the patient was started on anti-myeloma chemotherapy with lenalidomide, bortezomib, and dexamethasone. He began monthly intravenous bisphosphonate due to the presence of the lytic lesions. Of note, the patient was on DAA therapy and chemotherapy at the same time for what amounted to a 7- to 8-week overlap see . OverallWhile there are reports of cotreatment of MM and HCV during the interferon era, we are unaware of any literature looking at patients placed on both therapies in the DAA era. 1719 It is preferable to refer patients to centers specializing in the treatment of MM, as these centers have greater access to clinical trials incorporating novel therapies and therapeutic strategies.As of the time of this writing, there are several classes of agents approved by the Food and Drug Administration to treat MM: proteasome inhibitors, traditional chemotherapeutic agents , histone deacetylase inhibitors (panobinostat), and immunotherapy . MM remains an incurable malignancy. Patients are expected to relapse after their initial therapy, and subsequent therapy consists of additional lines of therapy utilizing agents from the classes mentioned above in combination. For a detailed description of relapsed and/or refractory MM, the reader is directed to excellent reviews of this topic.Returning to the individual patient in case 3, the patient tolerated DAA treatment and chemotherapy well, with the exception of the development of peripheral neuropathy, most likely due to bortezomib.A 65-year-old Caucasian male with chronic genotype 1a HCV, stage F1 liver fibrosis (transient elastography score: 6.6 kPa), unsuccessfully treated with pegylated interferon and ribavirin over a decade previously, presented to liver clinic with a complex MM history see .The patient was diagnosed in 1992 with SMM . In October 2013, the patient was found to have an elevation in his total protein to 10.7 and an increase in his M-spike to 4.72 . The patient was complaining of rib pain at the time. A computed tomography scan of the chest showed lytic lesions and pathologic fractures of the ribs on the left side. Shortly afterward, the patient was started on bortezomib, lenalidomide, and dexamethasone. One month after starting chemotherapy, he developed a rash at the bortezomib injection site, which led to discontinuation of the agent. Patient was continued on lenalidomide and dexamethasone, which he tolerated well for several months. In March 2014, after 5 cycles of a lenaldomide-based regimen, the patient had an 85% reduction in his paraproteinemia, reflecting a successful response to therapy. Stem cells were harvested when the patient was still viremic with HCV in January 2015, his M-spike increased again, this time to 3.36. Carfilzomib was added to the patient’s chemotherapy regimen.At this time, the patient was placed on 12 weeks of SOF/LDV concurrently with his carfilzomib, lenaldidomide, and dexamethasone. Patient achieved SVR48 as of April 2016. At last report, the patient had remission of his MM after several cycles of chemotherapy with no M-spike. Again, the case illustrates the fact that MM and HCV can be treated at the same time. Providers should of course be careful of drug-drug interactions see  when com22 Epstein-Barr virus,24 and hepatitis B.26 However, we were unable to find any reports of a patient auto-infecting oneself with HCV from previously harvested stem cells. If the patient were to undergo stem cell transplant in the future, the best course of action, in our expert opinion, would be to monitor HCV viral loads and to treat again with DAAs should viremia reoccur.This case has an interesting complexity in that the patient had his stem cells harvested while he was still viremic with HCV, raising the concern that should his MM worsen again, he would need to undergo stem cell transplantation and his HCV may reoccur, prompting retreatment with DAAs. Recurrence of viremia after BM or solid organ transplantation is well described with many viruses, including, but not limited to, cytomegalovirus,As the HCV population ages, it will be important for hepatologists to be familiar with MGUS and MM. Primary care providers and hepatologists should know the basic warning signs and risk factors for MM, so that they can obtain appropriate initial data, and refer as necessary. Hepatologists should also know that while there is a paucity of data regarding the cotreatment of HCV and MM with modern therapies, simultaneous treatment is possible, as our case series illustrates, and appears to be safe for patients. Current evidence is inconclusive as to whether or not there is a link between HCV and MGUS/MM. More data are needed. However, it is our opinion that patients with HCV and MGUS/MM should be prioritized for DAA therapy.