We are currently on the cusp of exponential growth in the understanding of the molecular landscape of bladder cancer. Emerging data regarding the mutational burden and targetable genomic and protein alterations in bladder cancer have allowed us to tap into treatments directed toward specific molecular characteristics of bladder cancer. In parallel, these developments will enable us to better select patients for existing treatments of bladder cancer in a step toward personalized therapy. The present article reviews select discoveries that have advanced our understanding of bladder cancer and gives a glimpse of the exciting opportunities on the not-so-distant horizon. For bladder cancer, however, prognostication and treatment selection still depend primarily on clinical and pathologic characteristics.Over the last decade, new understandings in molecular carcinogenesis as well as advances in genomic sequencing technologies have ushered in a new era of targeted cancer therapy. Rational therapeutic targets have been identified and new drugs successfully deployed in the treatment of various solid tumors. For example, patients with breast and lung cancers are routinely subjected to genotypic/phenotypic assessment, and specific targeted treatments are available for several permutations3. Integrated analysis of mRNA, microRNA, and protein expression in 129 muscle-invasive tumors yielded four distinct clusters resembling the intrinsic subtypes identified in breast cancer4. Clusters I and II were similar to luminal A breast cancer and had high mRNA and protein expression of differentiation markers, including GATA3 and FOXA1. Cluster III and IV tumors were similar to basal breast cancer and had high expression of stem/progenitor cytokeratins3. These findings indicate similar pathways of tumorigenesis despite different tissue origins. In addition, these clusters broadly corroborated with the findings of three other contemporary studies  by The Cancer Genome Atlas (TCGA) Research Network produced many new insights into the genetic makeup of MIBCstudies , further3. Importantly, actionable therapeutic targets were found in 69% of the tumors, converging on three main pathways: cell cycle regulation, kinase and phosphatidylinositol-3-OH kinase (PI[3]K) signaling, and chromatin remodeling. Specifically, mutations and somatic copy number alteration were frequently found in histone-modifying genes (89%), components of the SWI/SNF nucleosome remodeling complex (64%), PI(3)K/AKT/mTOR pathway (42%), and the RTK/RAS pathway (44%)3.Another significant finding of TCGA was the large number of somatic DNA alterations found in MIBC. Mean and median somatic mutation rates were respectively 7.7 and 5.5 per megabase, more than those found in any adult malignancy other than lung cancer and melanomaEach of these three major findings in TCGA has major implications for the prognostication and treatment design for MIBC. Here, we will review advances in the understanding of MIBC since the landmark publication of TCGA and the new therapeutic strategies they have fostered. Furthermore, the use of high-throughput next-generation sequencing (NGS) has only recently been extended to non-MIBC (NMIBC). Undoubtedly, the experience garnered from studying MIBC using these methods can be readily transferred to help answer many unresolved questions for NMIBC.13. Subsequently, neoadjuvant chemotherapy (NAC) prior to surgical or radiation treatment of MIBC has demonstrated survival benefit in separate phase 3 trials and meta-analyses16. Despite its proven efficacy, NAC rendered only 38% of patients pT0, conferring a modest 5% improvement in 5-year survival. Additionally, toxicity associated with NAC is not insignificant15. In light of this marginal risk-benefit ratio, attempts have been made using clinicopathologic features to refine patient selection for NAC17. However, no clear prediction model for response to NAC exists to date, leading to ongoing debate regarding who should undergo NAC19.Since the 1980s, cisplatin-based chemotherapy has been recognized as the standard of care for metastatic urothelial carcinoma (UC), specifically with M-VAC  established as the superior combination and GC (gemcitabine and cisplatin) as an alternative20, Choiet al. from MD Anderson Cancer Center used their tripartite molecular subtyping of MIBC  to predict chemosensitivity5. They found a marked increase in chemoresistance associated with the p53-like tumors compared with the other subtypes. Similar to luminal breast cancers, this chemoresistance was associated with lower levels of proliferation and cell cycle biomarkers in the p53-like subtype21. Interestingly, activation of wild-type p53-like gene expression signature was observed in post-chemotherapy tumor specimens, leading to a larger percentage of p53-like tumors in the post-chemotherapy cohort. In conjunction, these findings suggest that NAC may selectively decimate non-p53-like tumor cells, thus enriching the p53-like gene expression signature that dominates after treatment22. In a subsequent study, the authors showed that basal tumors were associated with better survival outcomes after NAC23. As only M-VAC was used to treat the cohort of tumors analyzed, it is unknown whether this chemoresistant feature of p53-like tumors can be generalized to other therapy combinations.Drawing on the success correlating intrinsic subtypes with NAC response in breast cancerERBB2 (tyrosine kinase receptor) were exclusively found in the pre-treatment tumors resected from patients with complete pathologic response (pT0)24. In addition, mutations in the DNA repair genes are linked with increased chemosensitivity. Mutations inERCC2, a nucleotide excision repair gene, were found to be enriched in patients responding to NAC25. In line with this finding, Plimacket al. discovered that alterations in one or more of the DNA repair genesATM,RB1, andFANCC were enriched in patients downstaged to ≤pT1N0M0 after chemotherapy, leading to improved overall survival26. The authors postulated that the deleterious defects in the DNA repair genes represent a fatal flaw for the associated tumors, making it impossible to recover from the DNA damage incurred by the alkylating agent cisplatin.On the other hand, NGS studies have also linked platinum chemosensitivity to specific genomic alterations. Activating mutations ofThough intriguing, these findings need to be validated in larger studies encompassing diverse patient demographics and chemotherapy regimens. Fortunately, this effort is currently under way, as are efforts to assess the benefit of combining genomic signatures with clinicopathologic characteristics for the prognostication of response to NAC. The knowledge gained will aid in the development of novel chemotherapy/targeted therapy agents in the future.28. The prognosis is especially dismal for patients with relapse after chemotherapy, and median survival ranges from 5 to 7 months29. Moreover, no new drug therapy has been found to be effective in the four decades since the adoption of cisplatin-based chemotherapy. As such, the recent introduction of anti-PD-L1 (programmed death ligand 1) treatment for metastatic UC was met with great enthusiasm31. PD-L1 negatively regulates T-cell function by binding to its receptors programmed death 1 (PD-1 or B7-1) on activated T lymphocytes and other immune cells. The overexpression of PD-L1 in the tumor microenvironment is thought to be the mechanism by which tumor evasion of the host immune system occurs. Blockade of the PD-L1 pathway with a high-affinity engineered human anti-PD-L1 monoclonal immunoglobulin-G1 antibody (atezolizumab) was shown to improve objective response rate in a heavily pre-treated population with poor prognostic features33. Extended median overall survival ranging from 7.9 to 11.4 months was observed. One-year overall survival ranged between 36% and 48% compared with the historic rate of 20% from a pooled analysis34.Overall survival with cisplatin-based chemotherapy, despite its firmly established efficacy in the treatment of metastatic UC, remains rather poor33. The finding that PD-L1 was more efficacious in tumors with higher mutation load was consistent with patterns recognized in other malignancies36. Non-synonymous somatic mutations are thought to increase tumor neoantigen burden, leading to increased T-cell recognition and more potent tumoricidal activities unleashed by PD-L1 treatment.Objective response rate, progression-free survival, and overall survival were found to be directly related to PD-L1 expression status on the infiltrating immune cells (ICs). In addition, treatment response correlated with mutation load and was found to be the highest in the luminal tumors subtyped within cluster II of the TCGA schemeInterestingly, TCGA subtyping was found to have prognostic implications independent of the PD-L1 expression levels in ICs. Despite having lower IC PD-L1 expression, cluster II tumors responded to treatment at a higher rate than the basal cluster III and IV tumors. Their higher response rate to PD-L1 treatment may be attributed to the intrinsic biology of the cluster II tumors. Alternatively, additional immunosuppressive pathways may be used by basal tumors to prevent effective immune activation. Of course, these tumors were previously treated with cisplatinum, which itself has effects of subtype migration as elucidated earlier. Nonetheless, the differential response to PD-L1 therapy in the different tumor subtypes highlights the need for further understanding of their associated immunobiology.37. Disappointingly, no trial to date has proven efficacy for any rationally designed targeted agent in advanced UC38. The conundrum of futility against the preponderance of potential therapeutic targets can partially be explained by the highly variable genomic landscape of UC uncovered by recent studies. A key finding in a multi-platform analysis of 12 cancer types was the genetic diversity of bladder cancer, splitting into three pan-cancer subtypes39. Such heterogeneity found in advanced UC renders ineffective the one-size-fits-all approach undertaken by most previous trials.Genetic alterations in the mTOR, FGFR, EGFR, and HER2 pathways have long been recognized in subsets of bladder cancer. TCGA and other studies have identified actionable drug targets in over 60% of the tumors interrogated41. Although the trial as a whole failed to achieve the predetermined progression-free survival end point, whole genome sequencing in an exceptional responder revealed mutations that enhanced therapeutic efficacy. Subsequently, by using the newly discovered mutation as a biomarker, the authors were able to demonstrate treatment efficacy in a smaller pre-selected subset40. This prompted the Exceptional Responders Initiative launched by the National Cancer Institute to identify molecular indicators in malignant tissue from exceptional responders using NGS . With this strategy, afatinib (tyrosine kinase inhibitor of the ErbB receptor family) was found to have efficacy in the subpopulation of patients with platinum-refractory UC with somatic ERBB family alterations42.Instead, careful patient selection is needed for targeted drug trials to increase the signal-to-noise ratio derived from effective treatment. Alternatively, in-depth retrospective analysis of exceptional responders may provide insight for refining trial design to yield meaningful outcomes. One such example was illustrated by the phase II study of everolimus in a metastatic UC trial43 in an effort to identify more patients with specific mutations as candidates for various ongoing clinical trials. In addition, those with higher mutational burden or specific tumor subtypes may be selected for immune checkpoint blockade.Furthermore, the recently published National Comprehensive Cancer Network (NCCN) Bladder Cancer Guidelines recommend broadening the scope of molecular profiling for advanced UCin situ44 has been challenged by a proposed subtyping scheme spanning both MIBC and NMIBC7. Others have found NMIBC to exhibit markedly different gene expression profiles than MIBC, leading to its own assigned cluster group on unsupervised hierarchical cluster analysis45.The NGS technology that has brought such major advances in the understanding of MIBC has only recently been used in the study of NMIBC. The traditional dichotomization of bladder cancer into low-grade papillary tumors and invasive carcinoma that arise from flat dysplasia and carcinoma46. However, the authors found imperfect reconciliation between these subtypes to the basal and luminal subtypes found in MIBC. They hypothesized that the three subgroups represented three different developmental pathways of NMIBC.A recent multi-institutional study of 460 early stage UC identified three major subgroups of NMIBC with basal- and luminal-like characteristics, each associated with different clinicopathologic features and progression-free survivalSHH) expression as an important molecular switch on the path to MIBC47. These are fascinating times both for us in the scientific community and for our patients, and there is hope on the horizon to truly advance the needle in the quest for cure.Further studies using NGS technology in NMIBC are warranted to characterize this group of diverse tumors. Along the way, new insights into the biology of development and progression are likely to be uncovered. Conceivably, biomarkers or subtypes may be identified for susceptibility to intravesical treatment with chemotherapy or bacillus Calmette-Guérin. On the other hand, molecular characteristics of progressive tumor may be collected early on to select patients for early radical treatment to avoid metastatic spread. In fact, evidence is already emerging from transgenic mouse models demonstrating the loss of sonic hedgehog K, phosphatidylinositol-3-OH kinase; TCGA, The Cancer Genome Atlas; UC, urothelial carcinoma.


To assess efficacy and safety of palbociclib plus fulvestrant in Asians with endocrine therapy–resistant metastatic breast cancer.The Palbociclib Ongoing Trials in the Management of Breast Cancer 3 (PALOMA-3) trial, a double-blind phase III study, included 521 patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer with disease progression on endocrine therapy. Patient-reported outcomes (PROs) were assessed on study treatment and at the end of treatment.P = .0065). The most common all-cause grade 3 or 4 adverse events in the palbociclib arm were neutropenia (92%) and leukopenia (29%); febrile neutropenia occurred in 4.1% of patients. Within-patient mean trough concentration comparisons across subgroups indicated similar palbociclib exposure between Asians and non-Asians. Global quality of life was maintained; no statistically significant changes from baseline were observed for patient-reported outcome scores with palbociclib plus fulvestrant.This preplanned subgroup analysis of the PALOMA-3 study included premenopausal and postmenopausal Asians taking palbociclib plus fulvestrant (n = 71) or placebo plus fulvestrant (n = 31). Palbociclib plus fulvestrant improved progression-free survival (PFS) compared with fulvestrant alone. Median PFS was not reached with palbociclib plus fulvestrant  but was 5.8 months with placebo plus fulvestrant (95% CI, 3.5 to 9.2 months; hazard ratio, 0.485; 95% CI, 0.270 to 0.869; This is the first report, to our knowledge, showing that palbociclib plus fulvestrant improves PFS in asian patients. Palbociclib plus fulvestrant was well tolerated in this study. Asian patients in this analysis were defined as all patients who self-identified their race as Asian to investigators from the following options provided on the case report form: white, black, Asian, or other. Asian patients were included from eight study sites in Japan (n = 35), five sites in Korea (n = 43), and two sites in Taiwan (n = 4); 23 other Asian patients also were included in this analysis.PALOMA-3, an international, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase III clinical trial, included women with HR-positive/HER2-negative advanced breast cancer whose cancer had relapsed or progressed  during or within 12 months of completing adjuvant endocrine therapy or while on or within 1 month from prior endocrine therapy for advanced breast cancer or MBC.14 In premenopausal patients, any luteinizing hormone–releasing hormone (LHRH) agonist was administered starting at least 4 weeks before study therapy initiation. Patients who did not receive goserelin as their LHRH agonist before study entry were switched to goserelin from the time of random assignment through the entire study treatment period. The primary objective was investigator-assessed PFS; secondary objectives included clinical benefit response (CBR), objective response rate (ORR), survival probabilities, safety and tolerability, and patient-reported outcomes (PROs). In April 2015, the independent data monitoring committee reviewed the results of the study and concluded that its primary objective had been met as the study crossed the prespecified Haybittle-Peto efficacy stopping boundary (α = .00135).13 The updated results of the overall population have been previously published, and these data  were also used in this present analysis.13Patients were randomly assigned 2:1 to receive palbociclib plus fulvestrant or placebo plus fulvestrant. Patients received placebo or palbociclib 125 mg/d orally for 3 weeks followed by 1 week off; fulvestrant 500 mg was administered intramuscularly on days 1 and 15 of cycle 1 and then every 28 days (± 7 days) thereafter starting from day 1 of cycle 1.14An institutional review board/independent ethics committee approved the protocol; the study was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent before any study procedures were started. Additional patient eligibility criteria and study design details have been described previously.PFS was defined as the time from the date of random assignment to the date of first documentation of objective progression of disease or death as a result of any cause in the absence of documented progression of disease, whichever occurred first. CBR was defined as the overall rate of complete response, partial response, or stable disease ≥ 24 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Objective response was defined as the overall complete response or partial response according to RECIST version 1.1. Using x-ray, computed tomography, or magnetic resonance imaging, tumor assessments were performed at baseline and every 8 weeks for the first year and then every 12 weeks. The type, incidence, severity, and seriousness of AEs and the relationship of AEs to study medications were recorded. Severity of AEs was graded on the basis of the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. A serious AE was defined as an AE that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or results in congenital anomaly or birth defect. An AE could additionally be considered serious by the investigator if it jeopardized the patient or required intervention to prevent one of the other AE outcomes.16 For functional and global QOL scales, higher scores represent a better level of functioning. For symptom-oriented scales, a higher score represents more severe symptoms. PRO questionnaires were completed before dose on day 1 of cycles 1 to 4, then on day 1 of every other subsequent cycle starting with cycle 6, and finally, at the end of treatment. For PK assessments, a post hoc analysis was used for the comparison of racial subgroups.In addition, pharmacokinetic (PK) data and PROs were assessed by race. Trough PK samples for determination of palbociclib plasma concentrations were collected from all randomly assigned patients on day 15 of cycles 1 and 2. PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30, a 30-item questionnaire that includes functional scales, symptom scales, and a global health status/quality-of-life (QOL) scale.Study assessments of efficacy, safety, and PROs were prespecified; efficacy subgroup analyses by various baseline variables, including race, were preplanned in the protocol and statistical analysis plan. Statistical analyses by race were conducted for exploratory purposes. Demographic and baseline disease characteristics were summarized by treatment arm in a frequency table for Asians and non-Asians. Quantitative baseline variables, including age, weight, and height, were summarized using descriptive statistics . Quantitative baseline variables were compared between the two treatment arms using a Wilcoxon two-sample test without adjusting for multiplicity. Efficacy analyses were performed using the intent-to-treat principle. Kaplan-Meier estimates of median PFS and the respective 95% CIs were provided for both treatment groups. PFS data between the treatment groups were compared using a log-rank test. HR was estimated from the Cox proportional hazards regression model. The odds ratio estimator and the exact test were used to compare the rates of binary efficacy end points. AEs were summarized using descriptive statistics in Asians who took one or more doses of study treatment. The within-patient averages of the palbociclib steady-state trough PK samples were summarized and compared across subgroups. PRO analyses were based on the PRO-evaluable population . Completion rates were summarized by cycle. Repeated-measures mixed-effects analyses were performed to compare on-treatment overall scores and changes from baseline between treatment groups while controlling for baseline.v 57.7 years, respectively; P = .0013) and weighed less . In non-Asians, the median PFS was 9.5 months  in the palbociclib arm compared with 3.8 months  in the placebo arm . In Asians, the CBR was 70%  with palbociclib plus fulvestrant and 52%  with placebo plus fulvestrant . The ORR in Asians was 19% in the palbociclib arm and 13% in the placebo arm. The sample size was underpowered to perform any statistical analysis. However, the degrees of improvement for CBR and ORR in Asians were similar to those seen in non-Asians.The degree of PFS improvement in the palbociclib arm versus the placebo arm was similar in Asians and non-Asians . The medv 44%, respectively) was lower, and the rates of neutropenia , stomatitis , rash , and nasopharyngitis  were higher  in the palbociclib arm and 23% (seven of 31 patients) in the placebo arm Appendix . In non-Comparison of the within-patient mean steady-state palbociclib trough concentrations in Asians and non-Asians demonstrated relative consistency in the central tendency and range of the observed values across subpopulations, indicating similar palbociclib exposure in these subpopulations . Geometrv 9.2, respectively; P < .05; Appendix Questionnaire completion rates were high at baseline and during treatment . In Asians, no significant deterioration from baseline in global QOL was observed within the palbociclib arm. Among the Asian subgroup in the study, no significant differences between treatment arms were observed for global QOL, functioning, pain, fatigue, or nausea and vomiting Appendix . Signifi17 Palbociclib, the first-in-class CDK4/6 inhibitor approved for the treatment of HR-positive MBC, has shown impressive PFS improvement when combined with either an aromatase inhibitor18 or selective estrogen receptor downregulator14 in both patients who are endocrine sensitive and endocrine resistant. In the PALOMA-1 phase II study and PALOMA-2 phase III study of patients who had not previously received endocrine therapy, longer PFS was reported with palbociclib plus letrozole versus letrozole alone.19 Similarly, in the PALOMA-3 study, in patients who had previously received endocrine therapy, palbociclib plus fulvestrant resulted in longer PFS than fulvestrant alone.14 Palbociclib has been approved in the United States and has been used in more than 48,000 patients since February 2015.20 Palbociclib is also approved by regulatory authorities for advanced breast cancer in the following countries in Asia: Singapore, Malaysia, Macau, Hong Kong, and Korea. In many of these countries, palbociclib will be reviewed by health technology agencies, payers, or both. The positive clinical value of palbociclib in Asian patients should be considered alongside the economic implications.CDK4/6 inhibitors are now an integral part of the management of HR-positive/HER2-negative MBC.21 21% of patients in the palbociclib arm and 18% of patients in the fulvestrant arm in PALOMA-3 were Asian.14 This study adds to the limited body of literature assessing a CDK4/6 inhibitor in Asians and represents the largest patient experience with palbociclib in Asians. The present findings show that palbociclib plus fulvestrant improved PFS in Asians with HR-positive/HER2-negative MBC who experienced progression on prior endocrine therapy and that the safety profile of palbociclib plus fulvestrant in Asians was generally consistent with that observed in non-Asians. Together, these findings suggest that palbociclib is beneficial in patients who have not previously received endocrine therapy and in Asians and non-Asians who experienced relapse or progression during prior endocrine therapy.Substantial clinical experience has been accumulated in white patients. Although few Asians were enrolled onto the PALOMA-1 study,22 As a result of genetic variations in an enzyme responsible for doxorubicin metabolism,23 Asians have been shown to be more susceptible to myelosuppression induced by doxorubicin compared with whites.22 In addition, a higher incidence of febrile neutropenia with docetaxel has been reported in Asians compared with whites.22 Genetic differences associated with race also can lead to differences in treatment response and efficacy. In Koreans with MBC, CYP2D6*10/*10 genetic polymorphisms have been associated with reduced plasma concentrations of the tamoxifen active metabolites endoxifen and 4-hydroxytamoxifen, as well as reduced clinical benefit  and significantly shorter median time to progression (P = .0032).24 These racial variations highlight the importance of evaluating the efficacy and safety of cancer medications within the Asian population.Differences in racial background can be associated with variable efficacy outcomes and safety profiles.18 In the PALOMA-3 study, nonhematologic AEs were predominantly mild or moderate in severity. Moreover, an important difference of treatment exposure was observed between Asians and non-Asians in the palbociclib arm, with higher percentages of Asians experiencing dose interruptions, dose reductions, and cycle delays than non-Asians. Interestingly, the rates of grade 3 and grade 4 neutropenia were modestly higher in Asians than non-Asians. Because palbociclib exposure was similar in Asians and non-Asians, the increased rates of neutropenia cannot be explained by differential drug exposure across racial subgroups. Asian race, lower baseline ALT, and younger age were all predictors of a lower baseline ANC value. The Asians in PALOMA-3, on average, were younger and had a lower baseline ALT than the non-Asians, thus compounding effects of the covariates. Overall, in the PALOMA-3 patient population, a typical Asian patient (52 years old at enrollment with a baseline ALT of 17 U/L) had a baseline ANC value 19% lower than a typical non-Asian patient (58 years old at enrollment with a baseline ALT of 21 U/L), which may partially explain the higher rate of neutropenia observed in Asians. Importantly, race was not demonstrated to be a covariate on any of the PD response parameters, suggesting that there was no increased sensitivity to palbociclib-induced neutropenia in Asians.Similar to findings from the present analysis, the most common AEs reported in the PALOMA-1 study with palbociclib were neutropenia and leukopenia.25; these findings support additional research into assessing the efficacy of other treatments in combination with goserelin in premenopausal patients with breast cancer. MBC in premenopausal women is rare in the Western world; however, higher incidences are seen in Asian countries and in developing countries such as Mexico, Latin America, and Egypt, where breast cancer is more common in younger women and is frequently diagnosed at later stages as a result of suboptimal access to health care.29 Palbociclib plus fulvestrant improved PFS in both premenopausal and postmenopausal Asians in PALOMA-3. Because of the small number of patients in this cohort, no formal statistical analysis could be performed. Nevertheless, palbociclib plus fulvestrant in addition to an LHRH agonist could be a reasonable treatment option for younger patients with breast cancer who are premenopausal, including Asian patients.MBC in premenopausal women is not well studied because clinical trials often exclude this patient population. One phase II study of 73 patients with HR-positive MBC showed that the efficacy of first-line therapy with letrozole plus goserelin in premenopausal patients was comparable with the efficacy of letrozole alone in postmenopausal patientsAssessing PROs is important to comprehensively define the risk-benefit profile of treatments. In the current study, Asians in the palbociclib group maintained good QOL throughout the study, which is important in establishing the benefit-risk profile of combination therapy.In conclusion, as observed in the full study population, PFS was longer in Asians with HR-positive/HER2-negative MBC who received palbociclib plus fulvestrant versus those who received placebo plus fulvestrant. Furthermore, QOL was maintained in Asians who received palbociclib. The safety profile of palbociclib was consistent with that previously reported and was similar in Asians and non-Asians. The protocol-defined dosing modification instructions for palbociclib, including adjusting dose on the basis of individual tolerability, enabled Asians to avoid discontinuation from the study as a result of an AE, allowing them to stay on treatment as long as non-Asians and thus maintain the same efficacy benefit from combination therapy. Overall, palbociclib plus fulvestrant seems to be a reasonable treatment option in Asians with HR-positive/HER2-negative MBC that has progressed on prior endocrine therapy.


Patients are increasingly using physician review websites to find “a good doctor.” However, to our knowledge, no prior study has examined the relationship between online rating and an accepted measure of quality.The purpose of this study was to assess the association between online physician rating and an accepted measure of quality: 30-day risk-adjusted mortality rate following coronary artery bypass graft (CABG) surgery.In the US states of California, Massachusetts, New Jersey, New York, and Pennsylvania—which together account for over one-quarter of the US population—risk-adjusted mortality rates are publicly reported for all cardiac surgeons. From these reports, we recorded the 30-day mortality rate following isolated CABG surgery for each surgeon practicing in these 5 states. For each surgeon listed in the state reports, we then conducted Internet-based searches to determine his or her online rating(s). We then assessed the relationship between physician online rating and risk-adjusted mortality rate.P=.13). Risk-adjusted mortality rates were similar for surgeons across categories of average online rating (P>.05), and surgeon average online rating was similar across quartiles of surgeon risk-adjusted mortality rate (P>.05).Of the 614 surgeons listed in the state reports, we found 96.1% (590/614) to be rated online. The average online rating was 4.4 out of 5, and 78.7% (483/614) of the online ratings were 4 or higher. The median number of reviews used to formulate each rating was 4 (range 1-89), and 32.70% (503/1538) of the ratings were based on 2 or fewer reviews. Overall, there was no correlation between surgeon online rating and risk-adjusted mortality rate (In this study of cardiac surgeons practicing in the 5 US states that publicly report outcomes, we found no correlation between online rating and risk-adjusted mortality rates. Patients using online rating websites to guide their choice of physician should recognize that these ratings may not reflect actual quality of care as defined by accepted metrics. Consumers have long used reviews of goods and services to inform their choices. Recently, these trends have spread to the health care arena in the form of online physician review websites -14. AccoWhile patients are increasingly using physician review websites to find “a good doctor,” it remains unclear whether online physician ratings actually reflect quality of care. Segal et al analyzed online ratings in relation to surgeon case volume, which they considered to be a proxy for quality of care, and found no correlation between numerical rating and number of procedures performed . SimilarThe purpose of this study was to assess the degree to which online physician ratings reflect quality of care. In the US states of New York, New Jersey, Massachusetts, Pennsylvania, and California—which together account for over one-quarter of the US population —risk-adjIn June 2015, we accessed the cardiac surgeon “report cards” for all 5 states that publicly report risk-adjusted cardiac surgery mortality rates For each surgeon listed in the state reports, we conducted Internet-based searches between July and September 2015 to determine his or her online rating(s). Searches were conducted using surgeon name, location, and specialty. For each online rating identified, we recorded the name of the website, the overall rating, and the number of reviews used to formulate the rating. Online ratings were out of 5. The individuals performing these searches (TKPB and KCX) were blinded to the surgeons’ clinical outcomes.t test. Surgeons were also grouped on the basis of risk-adjusted mortality rate quartile, and online ratings were compared using Student t test. P<.05 was considered statistically significant, and all tests were 2-sided. Statistical analysis was performed using SAS version 9 (SAS Institute Inc).We assessed the association between surgeon online rating and risk-adjusted mortality rate using the Pearson correlation coefficient. In addition, surgeons were grouped on the basis of average online rating, and risk-adjusted mortality rates were compared using the Student There were 614 cardiac surgeons with risk-adjusted mortality rates listed in the 5 state reports . For all states combined, the average 30-day risk-adjusted mortality rate after isolated CABG surgery was 1.68% .We found 96.1% (590/614) of the surgeons to be rated online, including from Healthgrades (n=540) , Vitals P=.13). Risk-adjusted mortality rates were similar for surgeons across categories of average online rating . However, 30-day risk-adjusted mortality is the most commonly accepted measure of quality in the field . In addiFor physicians, who have long argued that online ratings do not reflect clinical competency , the resOur study also has important implications for patients. Consumers are increasingly using online reviews to guide their selection of goods and services, and health care is no exception . Based oIn summary, this study of cardiac surgeons practicing in the 5 US states that publicly report outcomes found no correlation between online rating and risk-adjusted mortality rates. Patients using online rating websites to guide their choice of physician should recognize that these ratings may not reflect actual quality of care as defined by accepted metrics.


Multiple myeloma (MM) has one of the highest risks of venous thromboembolism (VTE) of all cancers due to pathologic changes and treatment-related exposures. This study assessed the one-year incidence of VTE in newly diagnosed MM and to determine the baseline and time-varying treatment-related factors associated with VTE risk in a U.S.-based cohort. MM patients were identified and age, gender, and baseline comorbidities were determined. Treatment-related exposures included thalidomide derivatives (IMIDs), proteasome inhibitors, cytotoxic chemotherapy, steroids, erythropoietin-stimulating agents (ESAs), stem cell transplants (SCT), hospitalizations, infection, and central venous catheters (CVC). Multiple statistical models were used including a baseline competing risks model, a time-varying exposure Cox proportional hazard (CPH) model, and a case-time-control analysis. The overall incidence of VTE was 107.2 per 1000 person-years with one-half of the VTEs occurring in the first 90 days. The baseline model showed that increasing age, heart failure, and hypertension were associated with one-year incidence of VTE. MM-specific IMID treatment had lower than expected associations with VTE based on prior literature. Instead, exposure to ESAs, SCT, CVC, and infection had higher associations. Based on these results, VTE risk in MM may be less straightforward than considering only chemotherapy exposures, and other treatment-related exposures should be considered to determine patient risk. Multiple myeloma (MM) has one of the highest risks of thrombosis among all cancers due to disease-related pathological changes and treatment ,2,3. MalPrevious studies have assessed VTE risk in MM during randomized-controlled trials (RCTs) or in small observational studies with limited information about other risk factors associated with MM-related thrombosis ,9,10,21.The objective of this study was to determine the one-year incidence of VTE in newly diagnosed MM, assess the association of baseline characteristics and thrombosis, and to investigate the acute association between disease-related treatments and exposures with thrombosis. While previous studies have shown increased risks associated with specific treatments, our a priori hypothesis was that other treatment exposures occurring during treatment, such as supportive therapy or hospitalizations, may be attributing the observed increased risk of thrombosis associated with MM.This was a retrospective cohort study utilizing an extract of patients with at least two diagnoses of MM : 203.0x) at least 14 days apart during 2008–2013 from the Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental databases. The MarketScan data are administrative claims data including medical diagnostic and procedural billing information and pharmacy fill records for those with commercial insurance linked to demographic and insurance enrollment information for each individual. The dataset represents patients from all 50 U.S. states and is representative based on demographic and geographic characteristics. The data do not include detailed clinical information  but are a complete record of a patient’s healthcare utilization.For further inclusion, subjects were required to have a minimum of six months of continuous medical and pharmacy insurance coverage prior to the first MM diagnosis and be at least 18 years or older at diagnosis. Subjects also could not have a previous diagnosis of another cancer or a thrombotic outcome event during the six-month, pre-index period. Use of the MarketScan data was approved by the University of Kentucky Institutional Review Board (15-0334-P6A).Age was assessed on the MM index date and gender was linked from the enrollment file. The Charlson Comorbidity Index was used to assess comorbidity burden based on the ICD-9 coding algorithm by Quan et al.  and the Deep vein thrombosis (DVT) and pulmonary embolism (PE) VTE events were assessed based on previously published ICD-9 algorithms ,24,25. DPerson time was calculated correcting for the differential follow-up of each subject. The incidence rate of VTE was reported as the rate per 1000 person-years. Incidence rates were calculated at several intervals  as well as for the complete one-year study period.Due to the high risk of death associated with MM as well as the baseline risk of death in the older population, it was necessary to assess thrombosis alongside the competing risk of death over longer follow-up periods . In a suThe association of VTE with baseline demographic and clinical characteristics at diagnosis was assessed using a competing risks regression model using the complete follow-up time for each individual up to one year of follow-up. Post-diagnosis, treatment-related covariates were excluded from this model to avoid the bias of ignoring competing risks. In this model, the dependent outcome has three levels: 0 = censored; 1 = thrombosis; and 2 = death. Subdistribution hazard ratios (HR) and their 95% confidence intervals (CI) for the association between each baseline covariate and thrombotic events were estimated for each baseline covariate included in the model. A post-hoc analysis restricted the model to the first 90 days after diagnosis to explore the association in the early post-diagnosis phase, which showed no significant differences from the main model. The one-year cumulative incidence of thrombotic events was reported for the total cohort.The case-time-control study design incorporates both the case-control and case-crossover study designs. Since it assigns cases by outcome events, it is not sensitive to the bias associated with competing risks. The case-time-control study design assumes that if an exposure causes a transient increase in the risk of an event then it will be more common in the “hazard” period immediately before an event; defined for this study as the 30 days immediately proximal to the event. A washout period was used between days 31–60 and the comparison period consisted of days 61–90 before the event . Cases iExposures were assessed as binary indicators in each exposure period and included: IMIDs ; PIs ; steroids ; cytotoxic chemotherapy ; stem cell transplant (SCT); hospitalization ; colony stimulating factors (CSF); central venous catheter (CVC); ESAs; and infection. Infection was broadly coded to encompass all bacterial, viral, and fungal infections. Because anticoagulation was highly collinear with IMID treatment, it was not assessed in any of the models. Conditional logistic regression was used to estimate the adjusted case-time-control OR and 95% CIs were calculated by bootstrapping the sample with 5000 replications .Sensitivity analyses were conducted varying the hazard, washout, and comparison exposure windows, which showed that the results were not sensitive to the specification. Further, for both Model #2 and Model #3 below, MM-specific treatments were categorized based on typical regimens  as well as separating the IMID group into individual products . The findings were not sensitive to these specifications.Our previous work showed a high rate of thromboembolism associated with MM in the first 90 days after diagnosis . Higher All exposures from the case-time-control analysis were modeled as time-varying exposures by daily intervals. A residual risk period was programmed for each exposure to account for the prolonged increase in risk of thromboembolism event after an exposure occurs. Two models were estimated using 7 and 14 days for this risk window, which was added to the total exposure window. For outpatient prescription products, this included the dispensing date, days supplied, and the 7- or 14-day period. Inpatient chemotherapies and diagnoses included the day of exposure plus the additional risk window. Hospitalizations (SCT and non-SCT) included the day of admission, length of stay, and the risk window.Sensitivity analyses for the CPH model included stratifying by exposure to prophylactic anticoagulation and whether or not MM treatment was initiated within this initial 90-day period. All baseline characteristics were included in the model and the proportionality assumption was tested for each. HRs and 95% confidence intervals were reported for all time-varying exposures. All analyses were conducted using SAS version 9.4 .There were 1050 thrombosis events observed in 13,700 individuals during the one-year follow-up. This included 756 DVTs (72% of events) and 294 PEs (28%). Nearly one-half  occurred within the first 90 days after MM diagnosis. The cohort contributed 9791.4 person-years of follow-up time for a one-year incidence rate of thrombosis of 107.2  events per 1000 person-years. The highest incidence of thrombosis was in the first 30 days with 251 events and an incidence rate of 234.2  per 1000 person-years. The rate of thrombotic events decreased over the 60-, 90-, and 180-day intervals: 196.6 , 171.7 , 140.1 , per 1000 person-years, respectively. There were 384 deaths experienced as a competing risk and a total of 479 deaths during the study period with an incidence rate of 48.9  deaths per 1000 person-years.The one-year cumulative incidence of thrombosis was 9.2%  for the total cohort . The cumCohort baseline characteristics are summarized in After adjustment for treatment exposures, there were no significant baseline characteristics associated with thromboembolism in the first 90 days after diagnosis. Among MM-specific chemotherapy, thalidomide ) and steroids ) had an increased hazard of thromboembolism in the first 90 days after diagnosis . StrongeTreatment advances over the last decade for MM have led to an increase in median survival greater than five years ,33. HoweThis study investigated both baseline and time-varying factors related to thrombosis risk in newly diagnosed MM. There were few baseline factors found to be associated with risk in our study, suggesting that risk may be associated with factors related to treatment of MM instead of pre-existing, patient-related factors. Further, these baseline characteristics were not significant after treatment was included in a time-varying CPH model. We observed that nearly one-half of all thrombotic events occurred within the first 90 days after MM diagnosis. This underscores the need to identify early risk factors at diagnosis to guide the utilization of thromboprophylaxis—especially in the first 90 days of treatment.Treatment-related risks have been investigated in RCTs and small prospective studies using static treatment group assignment, and have not necessarily considered other disease-related exposures that may contribute to risk ,10,11. WOur study is subject to several limitations inherent to claims-based studies ,40. We rThis study found an incidence rate of thrombotic events of 107.2 events per 1000 person-years in a U.S. cohort with multiple myeloma. Nearly one-half of all events occurred in the 90 days after multiple myeloma diagnosis. Other than IMIDs only, additional MM treatment-related risk factors for VTE included stem cell transplants, central venous catheters, ESAs, infection, and all-cause hospitalization. Consideration of high-risk exposures may guide clinicians to periods where increased surveillance or prophylactic interventions may be most impactful.


MED12 exon 2 mutations, which are more common in fibroadenomas and benign phyllodes tumors. TERT promoter hotspot mutations have been documented in phyllodes tumors, and found to be more frequent in borderline and malignant lesions. Several lines of evidence suggest that a subset of phyllodes tumors might arise from fibroadenomas. Here we sought to investigate the genetic differences between phyllodes tumors with fibroadenoma-like areas vs. those without. We retrieved data for 16 borderline/ malignant phyllodes tumors, including seven phyllodes tumors with fibroadenoma-like areas and nine phyllodes tumors without fibroadenoma-like areas, which had been previously subjected to targeted capture massively parallel sequencing. Whilst MED12 exon 2 mutations were significantly more frequent in tumors with fibroadenoma-like areas (71 vs. 11%), an enrichment in genetic alterations targeting bona fide cancer genes was found in those without fibroadenoma-like areas, in particular in EGFR mutations and amplifications (78 vs. 14%). No significant difference in the frequency of TERT genetic alterations was observed (71% in cases with fibroadenoma-like areas vs 56% in those without fibroadenoma-like areas). Our data suggest that the development of phyllodes tumors might follow two different evolutionary pathways: a MED12-mutant pathway that involves the progression from a fibroadenoma to a malignant phyllodes tumor; and a MED12-wild-type pathway, where malignant phyllodes tumors arise de novo through the acquisition of genetic alterations targeting cancer genes. Additional studies are warranted to confirm our observations and define whether the outcome differs between both pathways.Breast fibroepithelial lesions (fibroadenomas and phyllodes tumors) are underpinned by recurrent  MED12, a gene often altered in benign breast fibroepithelial tumors, whereas PTs without fibroadenoma-like areas more commonly had mutations in EGFR and other known cancer genes. The findings suggest that some PTs arise from fibroadenomas, while others originate anew.Malignant fibroepithelial breast tumors may arise by two distinct pathways: one from progression of benign tumors, and another where normal cells acquire mutations in cancer genes that result directly in the development of a more aggresive lesion. Phyllodes tumors (PTs) are rare breast tumors that start in the connective tissue; most are benign, but they are sometimes malignant. Jorge Reis-Filho from the Memorial Sloan Kettering Cancer Center in New York City, USA, and colleagues compared genetic differences between malignant PTs that resemble a benign tumor, known as fibroadenoma, and those that don’t. They found that PTs with fibroadenoma-like areas were more likely to harbor mutations in exon 2 of  Additional genes, such as FLNA, SETD2 and RARA, are mutated in both entities but at a lower frequency in FAs.11 Importantly, among PTs, a stepwise decrease in the prevalence of MED12 mutations from benign to borderline and to malignant PTs has been demonstrated.10 Moreover, whilst FAs have a less complex genomic landscape and lower mutational burden than PTs,11 somatic genetic alterations in bona fide cancer genes, such as NF1, RB1, TP53, PIK3CA, and EGFR appear to be restricted malignant and few borderline PTs.11 Finally, TERT promoter mutations and gene amplifications are absent or exceedingly rare in FAs, but recurrent in PTs, though significantly more frequent in borderline and malignant PTs than in benign PTs, suggesting that TERT genetic alterations might play a role in the progression from benign to malignant PTs.13FAs and PTs share not only histologic similarities, but also genetic features. Highly recurrent and clonal somatic mutations targeting the exon 2 of 16 Importantly, however, whilst grade progression within PTs is a well-described phenomenon,19 progression from FAs to PTs remains a matter of contention. Recent analyses of synchronous or metachronous ipsilateral fibroepithelial lesions revealed identical MED12 mutations in pairs of FA and PT , providing molecular evidence in support of the clonal relatedness between FAs and PTs from the same patients.20 In one patient with three FAs, one benign PT and one malignant PT in the same breast, we found that only the malignant PT, which was clonally related to one of the three FAs, harbored a TERT promoter mutation.20 These findings support the notion that FAs might constitute the substrate for the development of PTs, and that TERT genetic alterations might drive malignant progression in fibroepithelial lesions.20Malignant PTs are often histologically heterogeneous, displaying areas consistent with benign PTs or even FAs. Some studies have suggested that FAs may rarely progress to malignant PTs.MED12 mutations are significantly more common in benign fibroepithelial lesions than in malignant PTs, that FAs might constitute the substrate for the development of a subset of PTs and that TERT genetic alterations might drive malignant progression in fibroepithelial lesions, we hypothesized that the development of borderline and malignant PTs might follow two distinct evolutionary pathways, according to MED12 status. In the MED12-mutant pathway, a linear progression from FA/ benign PT to borderline/ malignant PT would occur and be likely driven by the acquisition of TERT genetic alterations. By contrast, in the MED12-wild type pathway, borderline and malignant PTs are more likely to develop de novo, and driven by early genetic alterations in TERT and/or other cancer genes. To test this hypothesis, we investigated the differences in the repertoire of somatic genetic alterations of borderline and malignant PTs with FA-like areas, which might presumably have stemmed from a pre-existing FA, vs. that of PTs without FA-like areas, which might have arisen de novo.Taken together, given that 10 which were categorized by six pathologists with expertise in breast pathology  as five borderline PTs and 11 malignant PTs according to WHO criteria.1 Only cases with all histologic slides available for re-review were included in this study. The median number of sections reviewed was 21 (range 8–42). In addition, all histological sections were re-reviewed by two pathologists (FP and FCG) to assess the presence of FA-like areas, defined as intracanalicular, pericanalicular or myxoid areas of low stromal cellularity, lacking cytologic atypia and mitotic activity. Discordant cases were reviewed on a multi-headed microscope together with a third pathologist (JSR-F) to reach a consensus. Based on the criteria above, seven PTs  were classified as having FA-like areas; nine PTs, all of them malignant, had no FA-like areas .Our study cohort consists of 16 PTs, previously described by Piscuoglio et al.,p > 0.05, Mann–Whitney U test). Likewise, the median size of the PTs was similar between the group of PTs with FA-like areas, 9 cm (range 1.6–11), and the group of PTs without FA-like areas, 8.5 cm . With regard to the histopathologic features used for the classification of PTs , only mitotic activity differed significantly between the two groups, with PTs without FA-like areas having more mitoses than PTs with FA-like areas  in regards to their clinico-pathological features. The median age of the patients with PTs with FA-like areas was 43 years (range 28–55), younger but not significantly different from that of patients with PTs without FA-like areas . Analysis of the MSK-IMPACT data revealed a similar number of non-synonymous somatic mutations in the PTs regardless of the presence of FA-like areas (medians of 4 (range 3–7) and 4 (range 2–8)) in PTs with FA-like areas and PTs without FA-like areas, respectively  platform,MED12 exon 2 mutations were significantly more frequent in PTs with FA-like areas  than in PTs without FA-like areas  in all PTs with FA-like areas cases  in PTs with FA-like areas and 5/9 (56%) in PTs without FA-like areas . Conversely, somatic genetic alterations affecting EGFR, including amplifications and likely pathogenic missense mutations, were significantly more frequent in PTs without FA-like areas  than in PTs with FA-like areas , ERBB2 (V777L), ERBB3 (V104L), NRAS (Q61K), and PIK3CA (H1047R) were found to be exclusive to PTs without FA-like areas  as biomarkers predictive of therapeutic response, these genetic alterations could be potentially targetable. EGFR amplifications and the V774M tyrosine kinase mutation are known to be oncogenic,32 and the L62R, G63R, and E84V mutations have been recently identified as new functional variants,33 and target the ligand domain of EGFR, which plays a crucial role in its dimerization and activation, and is currently the target of anti-EGFR monoclonal antibodies such as cetuximab and panitumumab.34Although there is currently no compelling clinical evidence supporting the role of FLNA) might be drivers not recognized in our study. Finally, we cannot exclude the possibility that at least a subset of PTs without FA-like areas could have originated from a pre-existing FA, in which the malignant component outgrew and obliterated a pre-existing FA.Our study has important limitations. First, our series did not include borderline PTs without FA-like areas. However, our findings may be a reflection of the fact that PTs that stem from pre-existing FAs might be of lower grade than those developing de novo. Second, the assessment of the differences in clinical behavior between PTs with FA-like areas and those without FA-like areas was not possible due to the small size of our cohort, low recurrence rate of the lesions and short follow-up time. Third, sampling of specimens included in the study was performed for clinical purposes and not tailored for the assessment of the presence of FA-like areas. Nonetheless, we only included cases for which all histologic sections were available for re-review. Fourth, the cases in our study were analyzed using the MSK-IMPACT platform, which interrogates a limited number of genes; therefore it is possible that genes not included in this platform  using the MSK-IMPACT sequencing assay, which interrogates all coding regions and selected intronic regions and promoters of up to 410 key cancer genes. Detection of somatic mutations was performed as detailed in Piscuoglio et al.40 Allele-specific copy number alterations were identified using FACETS.41 Targeted massively parallel sequencing of cases MaPT19 and MaPT20 had been performed using MSK-IMPACT v.3, which interrogates all coding exomes and selected non-coding regions of 275 genes. Detection of somatic mutations and copy number alterations for these cases had been performed as described in Cheng et al.21 The 227 genes common to MSK-IMPACT (410 genes) and MSK-IMPACT v.3 were considered in the re-analysis described here and are listed in the Supplementary Table 45 and the presence of the mutated gene in the cancer gene lists by Kandoth et al.46 the Cancer Gene Census47 or Lawrence et al.48 as detailed in Piscuoglio et al.10 The cancer cell fraction (CCF) of each mutation was defined using ABSOLUTE (v1.0.6)50 as inferred in Piscuoglio et al.10 Mutations were considered clonal if their probability of being clonal was >50%50 or if the lower bound of the 95% confidence interval of its CCF was >90%, otherwise the mutations were considered subclonal.A detailed description of tissue microdissection, DNA extraction and sequencing is provided in the original publication.U test. Differences in the frequency of genetic alterations affecting single genes were assessed using Fisher’s exact test. Two-tailed p-values < 0.05 were considered statistically significant.Comparisons of depth of coverage and mutation rates were performed using the Mann–Whitney Sequencing data is available at the National Center for Biotechnology Information Sequence Read Archive under the accession SRP062618. All relevant data are available from the authors.Supplementary LegendsSupplementary Figure 1Supplementary Table 1Supplementary Table 2Supplementary Table 3Supplementary Table 4


Interest is growing in the use of non-invasive techniques for complementing liver biopsy for liver fibrosis assessment. We aimed to prospectively evaluate liver histology in chronic hepatitis B (CHB) patients with e-antigen positivity, and develop and validate a novel scoring system—e-antigen-positive CHB liver fibrosis (EPLF) score—for noninvasively predicting the fibrosis stages.We identified the baseline variables associated with fibrosis stage  in 212 CHB patients with e-antigen positivity. These significant variables were used to develop the EPLF scoring system. The EPLF score equation was developed based on the prediction of fibrosis stages via multivariate ordered logistic regression analysis. The diagnostic powers of the EPLF score and several non-invasive markers were assessed through an area under the receiver operating characteristic curve (AUROC) analyses. This EPLF score model was validated in another set of 208 similar patients.The natural logarithms of serum albumin, HBeAg, and HBsAg levels were selected as significant independent variables for the EPLF score equation. The EPLF score had good diagnostic power  and good diagnostic accuracy (72–85%), with a high positive predictive value (80.8–92.8%) for each fibrosis stage in the test group. Similar results were observed in the validation group . The EPLF score exhibited a strong correlation with fibrosis stage , and was the preferable non-invasive marker for staging liver fibrosis.In e-antigen-positive patients with CHB, the EPLF score could serve as a potential non-invasive marker of liver fibrosis stage. Chronic Hepatitis B (CHB) virus infection is a public health problem. The characterization of patients with CHB is often divided into the hepatitis B e antigen (HBeAg) positive and HBeAg negative patients. It is known that HBeAg seropositive patients are at increased risk for development hepatocellular carcinoma (HCC). The severity of hepatic fibrosis is a key role for determining disease prognosis in chronic hepatitis B (CHB) patients , 2. TherHepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) are two routine used markers to determine condition of chronic HBV infection, which were found to have inverse relationship with the severity of fibrosis in HBeAg-positive CHB patients , 18. HigTo address the gap in knowledge, the purpose of this study was to establish a model based on serum levels of HBeAg and HBsAg, named e-antigen-positive CHB liver fibrosis (EPLF) score to predict the stage of fibrosis for HBeAg-positive CHB patients. Additionally, we evaluated its predict value in assessment fibrosis progression and comparison the predict value with that of other non-invasive fibrosis markers, including FIB-4 and APRI in validation.A total of 212 patients (144 men and 68 women) met the inclusion criteria and were included in the analysis. The baseline data of the test set used in for the development of the EPLF score, stratified by histological fibrosis stage, are summarised in Table The results of the ordered logistic regression analysis are presented in Table e[HBeAg (PEIU/mL)]—4.55×Loge[Albumin (g/dL)]—0.34×Loge[HBsAg (IU/mL)].EPLF score=20.28—0.42×LogTable From July 2014 and July 2016, 215 liver biopsies were performed. Seven patients were excluded from the study, including 3 with prior antivirus therapy, 2 with concomitant liver disease, and 2 with insufficient liver tissue for analysis. The characteristics of the validation set were similar to those of the training set, as showed in Table The status of the initial liver biopsy and histological examinations three years later for 12 patients are shown in Table Figure In the present study, we sought to develop a model (EPLF) that employed a single point measurement of HBsAg, and HbeAg levels and liver function test results to predict the degree of liver fibrosis in a consecutive series of e-antigen-positive treatment-naïve CHB patients. We found that serum albumin., HBsAg, and HbeAg levels were independent predictors of liver fibrosis stage. A one-time baseline measurement of HBsAg, HbeAg levels and albumin levels could be used to predict liver fibrosis stage in CHB patients with HbeAg seropositive. The EPLF model including these three variables was simple to use and had comparable accuracy in staging liver fibrosis and might to be used to predict fibrosis progression in e-antigen-positive treatment-naïve CHB patientsThe major finding of this study was that combined serum levels of HBeAg and HBsAg could correctly stage liver fibrosis in e-antigen-positive CHB patients with high accuracy, although the mechanisms underlying this correlation remain unclear. At some points, chronic hepatitis B infection is an immunologic tolerance disease. HBV itself has non-cytopathic towards infected hepatocytes . Liver iAnother finding of our study is that there is no relationship between ALT values and histologic finding in e-antigen-positive treatment-naïve CHB patients. Elevation of ALT levels is the hallmark of hepatocyte inflammation that has long been used as the best diagnostic marker for hepatitis associated with viral, drug, alcohol, or other etilogies. Because CHB patients show wide fluctuations in biochemical activities, patients with significant liver injury may experience spontaneous normalization of ALT levels for a long time. CHB patients with persistently normal ALT levels may experience severe histologic liver damage. Our results based on 420 patients found that among patients with normal ALT levels, 36%have fibrosis scores greater than F2. Our data support the reports of Kumar et al,  who statConceptually, serum aminotransferase level is much less important as a predictor of fibrosis progress in CHB patients during immune active phase as it fluctuated widely. As comparison, the levels of HBsAg and HBeAg change slowly, presumably as a result of long time of hepatic inflammation. The EPLF regression equation suggests that long-term liver fibrosis progression in HBeAg positive CHB patients is the results of immune control, represented by the levels of HBsAg and HBeAg. In a subpopulation of the current study, 10 of the 12 patients experienced fibrosis progress that can be found by the EPLF score change. The EPLF score appears to be suitable not only for staging liver fibrosis, but for evaluating fibrosis progress in treat-naïve HBeAg positive CHB patients.Although the current study contains one of the largest series of HBeAg-positive, treat-naive CHB patients, there are several limitations to be noted. First, the current study used liver histology findings, obtained from liver biopsies, as reference parameters. Since biopsies are limited by sampling errors and exhibit variability,  the histIn conclusion, in the present study, we developed and validated a potential fibrosis marker for HBeAg-positive CHB patients, which was non-invasive, practical, and easily accessible. The use of this prediction score may help guide clinical decision making and potentially reduce the need for invasive liver biopsies in the management of HBV genotype B- or C-associated HBeAg-positive patients with CHB. The prediction score can be used to stage the liver fibrosis with high accuracy. This non-invasive prediction score approach may be of particular benefit in low-resource settings.We conducted a prospective study atZhe Jiang Provincial People's Hospital between December 1, 2012, and December 1, 2015. The study protocol was reviewed and approved by the ethics committee of the hospital. Informed consent was obtained from each patient prior to participation.4 copies/mL); and no previous or concomitant anti-HBV therapy. We excluded patients with liver comorbidities, such as hepatitis delta superinfection, hepatitis C virus co-infection, chronic alcohol consumption , Wilson disease, human immunodeficiency virus co-infection, and auto-immune hepatitis. The scoring system was developed based on the data of the patients in the test group.A total of 212 patients with CHB were enrolled in the study from the Liver Center of Zhe Jiang Provincial People's Hospital between December 1, 2012, and December 1, 2014. All the patients who fulfilled the following inclusion criteria were enrolled: age≥18 years; diagnosis of CHB based on HBsAg positivity for >6 months; HBeAg positivity; detectable HBV-DNA level , bilirubin, and albumin, as well as complete blood count, were performed in the clinical laboratory of the hospital using commercially available assays. The levels of hepatitis antibodies, including HBsAg, HBsAb HBeAg, HBeAb, HBcAb, and anti-hepatitis C virus, were measured using Clinical Laboratory Improvement Act-approved systems, in accordance with AASLD practice guidelines. The serum HBV-DNA levels were assessed using a real-time polymerase chain reaction system . The lower limit of detection was set at 200 copies/mL, and the linearity range was set from 200 to 20,000 copies/mL.The levels of HBsAg were quantified using the Architect HBsAg assay  after 1:100 dilutions. Samples with HBsAg levels of >250 IU/mL at 1:100 dilutions were retested at final dilutions of 1:1,000. Samples with HBsAg levels <0.05 IU/mL at 1:100 dilutions were retested in an undiluted condition. The serum level of HBeAg was determined by using a microparticle-based enzyme immunoassay with a commercially available kit . The dynamic range of the assay is 0.15–300 PEIU/mL; the samples with concentrations beyond this range were diluted with foetal bovine serum to ensure linearity.9/L). Moreover, the FIB-4 results were calculated using the formula: age (years)×AST (U/L)/platelet count (109/L)×(ALT (U/L)1/2).The values of 2 non-invasive fibrosis markers, APRI and FIB-4, were also determined. APRI values were calculated using the formula: AST (U/L)/upper normal limit×100/platelet count . The specimens were fixed, paraffin-embedded, and stained with haematoxylin and eosin (HE). A minimum of 1.5 cm of liver tissue with at least 9 portal tracts was required for appropriate diagnosis. All liver biopsies were reviewed by 1 pathologist (G.Q.R), who was blinded to the clinical characteristics of the study subjects. Liver fibrosis was evaluated according to the MATAVIR scoring system  as folloTo predict the histological fibrosis stage, ordered logistic regression analyses were performed, by using the histological fibrosis stages as ordinal data  and as dependent variables; the independent variables included standard biochemical and haematological test results, gender, viral markers, and age. The independent variables with strong correlations (r>0.7) in the multivariate logistic regression analyses were excluded to avoid multicollinearity. The scoring system equation was developed by adding a minus sign to the regression equation for the logit of F0 probability in the multivariate analysis.After developing the scoring system equation, we measured the score in the test group during each histological examination. The diagnostic value of the EPLF score, APRI, and FIB-4 were calculated and evaluation in the validation set, and the discrimination performance was also evaluated using the validation dataset.Among the 212 patients involved in this study, 12 patients had a second histological examination after 36 months. The EPLF score and other non-invasive markers were calculated at time of each histological examination.Quantitative variables are expressed as means (standard deviation) in the case of normal distribution; otherwise, the data are presented as medians (interquartile range). Categorical data are presented as frequencies and percentages. The correlations between the ordinal and continuous data were assessed using the Spearman correlation coefficient. For logistic regression analysis, the p value of each independent variable was determined by the Wald chi-square value . The diagnostic powers of the EPLF score and other fibrosis markers were evaluated based on the area under the receiver operating characteristic curve (AUROC); the cut-off values were determined by maximising the sum of the sensitivity and specificity, according to Youden's index . Moreove


Omega-3 fatty acids play critical roles during fetal growth and development with increased intakes associated with improved maternal-fetal outcomes. Omega-3 fatty acid intake in Western diets is low, and the impact of socioeconomic factors on omega-3 fatty acid intake in pregnant women and women of childbearing age has not been reported. We used the National Health and Nutrition Examination Survey (NHANES) cycles 2003–2012 to assess the relationship between omega-3 fatty acid intake and socioeconomic factors in women of childbearing age. Out of 7266 eligible participants, 6478 were women of childbearing age, while 788 were identified as pregnant at the time of the survey. Mean EPA+DHA intake of the population was 89.0 mg with no significant difference between pregnant and non-pregnant women. By univariate and multivariate analyses adjusting for confounders, omega-3 fatty acid intake was significantly associated with poverty-to-income ratio, race, and educational attainment. Our results demonstrate that omega-3 fatty acid intake is a concern in pregnant women and women of childbearing age in the United States, and that socioeconomically disadvantaged populations are more susceptible to potential deficiencies. Strategies to increase omega-3 fatty acid intake in these populations could have the potential to improve maternal and infant health outcomes. Maternal diet is critical for a successful pregnancy, as well as fetal health outcomes ,2,3. TheDespite the importance of these fatty acids in maternal-fetal health, omega-3 fatty acid intake is typically very low in the Western diet ,13. Socihttp://wwwn.cdc.gov/Nchs/Nhanes/ [Women who were 14–45 years of age and women who were identified as pregnant from NHANES cycles 2003–2012 were included in the analysis . Waves The main outcome variable was the dietary intake of omega-3 fatty acids DHA and EPA. The average EPA and DHA intakes for each participant were used to calculate a sum value of the two estimates (EPA+DHA). In other studies, average EPA, DHA, and their summation have been shown to be highly correlated ,21. HoweDietary intake in the NHANES survey was determined from two interviewer-administered 24-h recalls using methodology developed and validated by the U.S. Department of Agriculture. The dietary recalls were conducted in English or Spanish in study participants who were 12 years and older. Three to 10 days later, all participants were asked to complete a second 24-h dietary recall interview by telephone.Use of dietary supplements or prenatal vitamins containing omega-3 fatty acids was evaluated through the NHANES supplement files. Supplements containing the ingredient codes matching “alpha-linolenic acid (ALA), omega-3, docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA)” from the Dietary Supplement Ingredient Database (Release 3) were identified. The identified omega-3 supplements were then matched to the individual’s file to create a dichotomous (Y/N) variable for supplement intake in the last 30 days.Poverty-to-income ratio (PIR) was used as an index of socioeconomic status. The PIR is the ratio of household income to the poverty threshold after accounting for inflation and family size ,25. The Race/ethnicity was categorized as Hispanic, non-Hispanic white, non-Hispanic Black, and Other . Education level was categorized as less than high school, high school diploma recipient, or GED , and greater than high school education.Food insecurity was measured with the 18-item US Food Security Survey Module . Questiop-values for the comparisons of continuous data between groups  were obtained from “PROC SURVEYREG”, a SAS procedure that performs regression analysis for sample survey data. Potential confounding variables were chosen based on prior associations in the literature and significance in the univariate models. The final multivariate model included age, energy intake, race/ethnicity, PIR, NHANES wave, education level, and pregnancy status. A p-value of < 0.05 was considered statistically significant.Descriptive statistics (counts and percentages and means and standard deviations) are shown for all participants. SAS version 9.4  was used for all statistical analyses. Survey procedures in this software package incorporate sample weights and adjust analyses for the complex sample design of the survey. Survey sample weights were used in all analyses to determine estimates that were representative of the U.S. civilian, non-institutionalized population. The SAS procedures PROC SURVEYFREQ, PROC SURVEYMEANS, PROC SURVEYLOGISTIC, and PROC SURVEYREG were used in computing descriptive analysis and doing regression analysis, because these procedures accounted for the weighted data and complex design of the sample. The results of the descriptive analysis for categorical variables are represented by counts, percentages and weighted frequencies. Means, standard errors and 95% confidence intervals were used for continuous variables. Associations between categorical variables were determined using the Wald chi-square test that accounts for the complex survey design. The The final number of eligible participants was 7266. Of these, 6478 were women of childbearing age, while 788 were identified as pregnant at the time of the survey. The demographic characteristics of the sample by pregnancy status are given in p = 0.79, 0.71, and 0.75 for DHA, EPA, and DHA+EPA respectively), therefore these populations were combined for analysis of relationships with socioeconomic factors. In the univariate analysis, a statistically significant association was seen between omega-3 fatty acid intake and PIR . Omega-3 fatty acid intake also differed significantly by NHANES wave  or SNAP use .There was no association between omega-3 fatty acid intake and food security . While we did find statistically significant differences in DHA and EPA intake based on NHANES wave , and women with educational attainment beyond a high school diploma have an average EPA+DHA intake of 103 mg/day, while women with a high school diploma as highest degree or not achieving a high school diploma had average intakes of 66 mg/day and 83 mg/day, respectively (p = 0.0004). Race was also significantly associated with omega-3 fatty acid intake (p < 0.0001); non-Hispanic white women of childbearing age had the lowest intake of EPA+DHA, averaging 78 mg/day compared to Hispanic women (94 mg/day), non-Hispanic Black women (112 mg/day), and women of other races, including multi-racial (142 mg/day). These findings indicate numerous risk factors for insufficient omega-3 fatty acid intake in pregnant women and women of childbearing age when compared to suggested intake values [Furthermore, our data indicate that socioeconomically disadvantaged populations are particularly at risk for even lower levels of omega-3 intake. With increasing poverty, our data indicate decreased omega-3 fatty acid intake in women of childbearing age, regardless of pregnancy status (k women 1 mg/day, e values .Omega-3 supplementation in mothers and infants is associated with numerous positive health outcomes in mother and child ,28. HighThe mechanisms underlying the beneficial effects of omega-3 fatty acids are not completely understood. Although, emerging research reveals the role of these lipids in the biosynthesis of bioactive signaling molecules . FollowiRecent studies have raised concerns regarding nutrient intake in the United States, especially with nutrients that are of concern during pregnancy. Data from 2003–2008 NHANES cycles demonstrate that women of childbearing age in the United States are not meeting nutrient guidelines for several nutrients, with distinct differences present between ethnic groups and socioeconomic strata ,45,46. LMultiple factors contribute to low-income individuals having high risk of poor quality diet, including lack of access to grocery stores and high cost of healthy foods . IndividUse of prenatal vitamins may not be a contributing factor toward closing the gap by socioeconomic group, as pre-conception use of multivitamins in the United States is often poor. Our findings indicate only 1.8% of non-pregnant women of childbearing age use omega-3 fatty acid-containing supplements. Furthermore, the inclusion of omega-3 fatty acids in prenatal vitamins is not standard, despite being identified as an important nutrient in pregnant women ,23. FurtOur study has several limitations. The cross-sectional nature of NHANES makes it difficult to infer any causation, and it is also possible that confounding occurred from variables not considered in our analysis. Additionally, dietary intake in NHANES is based on two 24-h recalls, which may not be representative of usual intake, as day-to-day intake of specific food items like fish can be highly variable. However, a single 24-h recall is considered adequate for estimates of group means .Our results demonstrate that omega-3 fatty acid intake in pregnant women and women of childbearing age may be a concern in socioeconomically disadvantaged populations of the United States. More research is needed to determine what type of interventions will be best for specific populations, especially the low-income populations that bear a greater burden of poor diet quality and adverse maternal-child outcomes. As the population of the United States becomes more diverse, issues regarding health and disparities in diet become even more salient.


Lung transplant (LTx) waitlists continue to grow internationally. Consequently, more patients are progressing to require mechanical circulatory support (MCS) as a bridge to transplantation (BTT). MCS strategies include interventional lung assist (iLA) and venovenous (VV) and venoarterial (VA) extracorporeal membrane oxygenation (ECMO). We review our series of patients bridged with MCS while listed for LTx. All consecutive patients, listed for LTx requiring MCS as a BTT at the University of Alberta from 2004 to 2015, were included. Patient demographics and outcomes were compared for the 3 groups .n = 6) were bridged with VA-ECMO, 54% (n = 13) with VV-ECMO, and 21% (n = 5) with iLA. Overall, 71% of patients were bridged successfully to LTx. The 1-year survival posttransplantation was 88%. Of the 24 patients supported with MCS devices, 17 were successfully transplanted and 7 died waiting. In total, 25% ( We have demonstrated the feasibility of utilizing the MCS modalities of VA-ECMO, VV-ECMO, and most recently iLA, as a BTT. MCS is a viable strategy for BTT, offering improved survival outcomes for decompensating adult patients awaiting LTx, resulting in excellent survival posttransplantation. Over the past several decades, lung transplantation (LTx) has increased significantly as a treatment for end-stage lung disease . As repoThe University of Alberta is the largest tertiary care transplant centre in Western Canada, servicing a catchment size of over 6-million km and approximately 7-million people. Over the past decade, the University of Alberta has seen a significant increase in the number of lung transplantations performed, from 42 in 2010 to 61 in 2015. The average waitlist time at our centre has decreased over the last two decades, with times now comparable with other North American centres at 200 days and an average waitlist mortality of 32%. Survival has been respectable in our experience, with 88% 1-year survival overall posttransplantation.Mechanical circulatory support (MCS) devices were first introduced in 1950 for cardiac failure, later to be used in pulmonary failure. MCS strategies previously regarded as rescue therapies are more commonly being employed in transplant medicine, specifically in cardiothoracic transplantation as a bridge to transplant (BTT) , 5.It is now recognized that the use of MCS devices can produce satisfactory 1-year survival outcomes for patients requiring MCS bridging prior to their LTx , 7. MCS Herein, we report our single-centre experience with bridging patients using MCS while listed for LTx.From January 1, 2004, to December 31, 2015, twenty-four consecutive patients were bridged to double-lung transplantation using MCS with either VV-ECMO, VA-ECMO, or iLA at the UAMHI. The present study involved a single-institution retrospective cohort with the intention of evaluating the overall outcomes of patients bridged to transplant with MCS.The lungs used in these cases were all donated after neurological declaration of death. They were provided through the Human Organ Procurement and Exchange (HOPE) program. All recipients were deemed eligible for LTx due to end-stage pulmonary disease. All recipients gave informed consent and the study protocol was approved by the local Research Ethics Board. Recipient charts were evaluated for baseline clinical characteristics and followed for survival.Allocation of MCS strategy was based on institutional evidence and best practice. The decision to institute MCS was based on institutional knowledge in patients with end-stage respiratory failure refractory to maximal medical therapy. Modality selection was based on a multidisciplinary team conference involving transplant respirologist, transplant surgeons, critical care extracorporeal life support (ECLS) team, social work team, dietary team, and the infectious disease team.The study sample included 24 consecutive patients undergoing MCS bridging while awaiting double LTx from January 1, 2004, to December 31, 2015. Baseline demographic data is summarized in n = 13), VA-ECMO 25% (n = 6), and ILA 21% (n = 5). Based on the small sample size, there were not any significant differences in age or gender, though females were more likely to be bridged compared to patients undergoing transplantation over the same time-period (p < 0.05). Further demographics, including diagnosis and rates of successful bridge to transplant, are described in Of the patients bridged with MCS, the distribution of modality of MCS was VV-ECMO 54% (p < 0.05). Donor age was greatest in the VA-ECMO recipients (43.2-years) compared to VV-ECMO (29.1-years) and iLA (36.8-years). Actuarial survival to transplantation is shown in p > 0.05). Primary graft dysfunction (PGD) Grade 3 occurred in 29% (n = 2) of VV-ECMO recipients, 25% of VA-ECMO recipients, and none of the iLA recipients at 72-hour posttransplantation. Survival at 1-year posttransplantation is shown in Outcomes for patients who had MCS bridging instituted are summarized in As there is a growing population of potential recipients that may benefit from lung transplantation, there is an increasing need for bridging strategies in patients that develop end-stage respiratory failure while awaiting lung transplantation. The use of mechanical circulatory support (MCS) bridging remains controversial with limited reported outcomes in the literature. Our experience has also been limited, though similar in size to current reported results , 7. MasoThe outcomes from the use of MCS as a BTT have improved over time from prior reports. Our results lend support to the feasibility of MCS bridging with an excellent overall 1-year survival of 88% in those patients requiring MCS bridging. This study provides a contemporary analysis of data at a centre with lung transplant volumes within the top 10% of the ISHLT registry database  and signThe consideration for the use of MCS strategies as BTT has evolved over time. In recent guidelines, initiation of MCS in hemodynamically marginal patients is recommended to prevent posttransplant outcomes that may be adversely affected by the development of irreversible end-organ dysfunction . Patientn = 7; 53%) despite providing 100% posttransplantation 1-year survival. By comparison, all patients bridged with VA-ECMO underwent LTx; however, only 67% of recipients were alive at 1 year. This finding likely reflects the acute, poor functional status of those patients requiring VA-ECMO support, leading to variability in organ allocation. The poor survival posttransplantation of those bridged with VA-ECMO highlights the importance of ensuring appropriate organ allocation to recipients with the greatest chance of a good outcome. This may require further reevaluation of suitability for transplantation with weekly discussions of the multidisciplinary team. This approach has now been developed at our program for patients bridged on MCS.There were differences in rates of successful BTT based on type of MCS modality. VV-ECMO portended the worst likelihood of a successful bridge (Patients undergoing BTT with the iLA device endured the longest amount of time on the waitlist (mean 830 days) and underwent the longest bridge time (mean 44.8 days). This is likely due to the prevalence of PPH in these patients and difficulty in finding suitable donor organs, especially when combined heart-lung transplantation is indicated. In fact, our centre has recently reported the longest such successful bridge using iLA in a PPH recipient undergoing combined heart-lung transplantation . We antiThe previously described pumpless iLA has the potential for expanded use, potentially in patients with secondary pulmonary hypertension, as well as its indicated use in patients with specified primary pulmonary hypertension. We believe that the shift towards iLA use over ECMO may improve pre-, peri-, and posttransplant outcomes, as the pumpless iLA theoretically eliminates some of the consequences associated with pump-dependent ECMO systems.This study is not with limitations. Weaknesses include the modest sample population size of 24. These moderate numbers can be attributed to the select population of patients awaiting transplant who are eligible based on device inclusion criteria, to be initiated on one of the previously described MCS modalities. As well, our results represent the retrospective Western-Canadian experience of the past decade. However, with improved technologies, the potential for expansion of indications for different modalities of MCS may improve outcomes with further experience and refinement within the field. We expect this to be particularly true for the iLA device, which offers a pumpless system, theoretically ameliorating some of the drawbacks of the pump-dependent ECMO systems.In the University of Alberta experience, MCS as a BTT offers a viable strategy for improving survival outcomes of decompensating adult patients awaiting lung transplantation. The use of MCS technologies at this institute over the past decade has led to a reduction in waitlist mortality, with very good 1-year posttransplant survival rate of 88%, for those who underwent pretransplant MCS. We believe the utilization of MCS bridging devices, based on our institutional evidence, to be a viable strategy to decrease waitlist mortality in high acuity patients awaiting LTx.