Lower Progression Rate Research Articles

Association between enrollment factors and incident cognitive impairment in Blacks and Whites: Data from the Alzheimer's Disease Center

IntroductionWe examined the influence of enrollment factors demonstrated to differ by race on incident mild cognitive impairment and dementia using Alzheimer's Disease Center data. MethodsDifferences in rates of incident impairment between non-Latino Whites and Blacks (n = 12,242) were examined with age-at-progression survival models. Models included race, sex, education, source of recruitment, health factors, and family history of dementia. ResultsNo significant race differences in progression were observed in cognitively unimpaired participants. In those with mild cognitive impairment at baseline, Whites evidenced greater risk for progression than Blacks. Enrollment factors, for example, referral source, were significantly related to progression. DiscussionThe finding that Blacks demonstrated lower rate of progression than Whites is contrary to the extant literature. Nested-regression analyses suggested that selection-related factors, differing by race, may account for these findings and influence our ability to accurately estimate risk for progression. It is potentially problematic to make racial comparisons using Alzheimer's Disease Center data sets.

415 External Validation of the Progression in Barrett’s Score in a Prospective Multicenter BE Cohort

INTRODUCTION: Endoscopic surveillance guidelines in Barrett’s esophagus (BE) to detect progression to high grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) are based solely on dysplasia grade. Given low rates of progression, identification of predictors (and scores) of progression may help to focus surveillance or intervention in those at higher risk. We aimed to assess predictors of progression and externally validate the Progression in Barrett’s (PIB) score in an independent multicenter prospective BE and EAC cohort. METHODS: The EA and Barrett’s esophagus (EABE) registry is a prospective cohort of patients recruited from three medical centers. Progressors were defined as those with the development of HGD or EAC more than 12 months after initial diagnosis. Demographic and clinical variables were abstracted. The annual incidence rate and predictors of progression were assessed using univariate and multivariable Cox proportional hazards analysis. The ability of the PIB score (incorporating weighted scores for male gender, smoking (ever versus never), BE length and confirmed LGD) to risk stratify the cohort into low (0-10 points), intermediate (11-20 points) and high risk (> 20 points) groups was assessed. RESULTS: 429 patients were included. 84% were men, with a mean (SD) age of 61.5 (9.9) years. 65% were ever smokers and most (76.7%), had NDBE at diagnosis. Mean (SD) maximal BE segment length was 5.9 (3.2) cm. Eighty-two patients (19.1%) progressed to HGD (n = 65) or EAC (n = 17) over a median (IQR) follow up of 7.5 (3.7, 12.5) years. Annual incidence rates of progression to EAC and EAC/HGD were 0.5% and 2.0% respectively. Univariate and multivariable predictors of progression are displayed in Table 1. The PIB score divided patients into three groups (Table 2) with progressively increasing rates of progression. The risk in the high risk group was three fold higher than the low risk group (P = 0.024). The risk in the intermediate group was twofold higher but not statistically significantly higher (P = 0.13). The PIB score had a c-statistic score of 0.76 in the original cohort. In this cohort the c-statistic value was lower at 0.64, suggesting moderate performance. CONCLUSION: Male sex and BE length predicted progression in this independent multicenter cohort. The PIB score was also able to risk-stratify patients in this validation cohort with the high risk cohort being 3x more likely to progress compared to the low risk cohort.

P6564Prediction of the progression from paroxysmal to persistent or permanent atrial fibrillation using different scores. Is AF progression mainly atrial aging?

Abstract Reliable prediction of atrial fibrillation (AF) progression from paroxysmal to non-paroxysmal form of AF could help in optimizing follow-up and decision-making regarding the rate and rhythm control management. The HATCH score and others have been proposed to identify AF patients likely to progress to sustained forms of AF, but external validation is limited. We aimed at evaluating these scores in a large series of AF patients and to identify possible factors leading to persistent/permanent AF. Methods All patients with AF seen over a period of 10 years were identified in a database and followed up for AF progression and mortality. Predictors of outcomes were identified using Cox regression model. The values of HATCH, CHA2DS2-VASc, ALARMEc, APPLE, MB-LATER scores and CHARLSON comorbidity index were evaluated with C statistics for prediction of AF progression. Results Among 8962 patients (71±14 years), 4991, 476 and 3495 had paroxysmal, persistent AF, and permanent AF, respectively. During a follow-up of 927±1084 days, 404 paroxysmal AF patients progressed to persistent or permanent AF (yearly rate of 3.0%). Progression was associated with a trend toward increased cardiovascular mortality. Independent predictors of AF progression were heart failure (hazard ratio (HR) 2.07; 95% CI 1.50–2.85, p<0.0001), valvular disease (HR=1.87, 95% CI=1.35–2.58, p=0.0002) and the use of digoxin (HR=2.39, 95% CI=1.75–3.29, p<0.001). Conversely, a history of stroke was associated with a lower rate of progression (HR=0.50, 95% CI=0.28–0.88, p=0.02). Overall, most of the score, particularly the HATCH score, were modest predictors of progression (table). The best score was actually the CHARLSON comorbidity index. The predictive values of all scores were better on patients not treated with antiarrhythmic agent. C-statistics for AF progression All patients (n=4,991) p value* HATCH 0.576 (0.562–0.590) <0.0001 CHA2DS2-VASc 0.532 (0.503–0.560) <0.0001 ALARMEc 0.634 (0.607–0.660) 0.03 APPLE 0.631 (0.605–0.658) 0.03 MB-LATER 0.612 (0.587–0.638) 0.001 CHARLSON 0.667 (0.640–0.693) – *DeLong test vs CHARLSON comorbidity index. Conclusion Most of scores have a modest predictive value to identify the risk of evolution to permanent AF. Among them, the CHARLSON comorbidity index had the best predictive value and outperformed other tools. This suggests that AF progression may actually reflect global aging both at the individual and local atrial level.

Rate of Progression in Activity and Participation Outcomes in Exercisers with Parkinson's Disease: A Five-Year Prospective Longitudinal Study.

Background Rates of progression of motor symptoms and physical performance show declines between 2% and 7% annually in community samples with Parkinson's disease (PD). However, the effects of ongoing exercise behaviors on progression rates have not been considered. Objective The primary purpose of this prospective, longitudinal study was to examine the annual rates of progression in activity and participation measures over five years in community-based exercisers with PD. Methods A cohort of 55 regular exercisers with idiopathic PD was assessed at baseline and 1, 2, and 5 years. Regular exercise was defined as scores of 4-5 on the Stages for Readiness to Exercise Scale and a self-reported average of at least 60 minutes of exercise/week within six months of each testing session. Unadjusted and adjusted annual progression rates for activity and participation measures were calculated with a standardized equation of change from baseline. A linear mixed model with covariates of age at PD diagnosis and PD subtype was used to determine adjusted change scores. Results Annual progression rates for unadjusted and adjusted variables were similar, and none exceeded 1.7% across time points for this group of exercisers with PD. Older age at PD diagnosis significantly contributed to faster progression of walking and balance functions. A nonlinear trajectory of the PD progression was demonstrated across most activity and participation outcomes. Conclusions Annual progression rates demonstrated by this sample of exercisers were lower than those previously reported for motor decline in general samples with PD. Assessing activity and participation outcomes longitudinally at interim time points was important for understanding the trajectory of change over time. The lower rates of progression in this study warrant further investigation into the long-term effects of exercise in PD.

Long-term outcomes in Chinese patients with chronic hepatitis B receiving nucleoside/nucleotide analogue therapy in real-world clinical practice: 5-year results from the EVOLVE study.

In China, the optimal management of individuals living with chronic HBV infection (CHB) remains an unmet need. The EVOLVE Study was a 5-year prospective, longitudinal, observational study that compared the clinical outcomes in treatment-naive CHB patients receiving entecavir (ETV) or lamivudine (LAM)-based therapies. Males or females aged ≥18 years, diagnosed with CHB regardless of cirrhosis or hepatitis B e antigen (HBeAg) status were enrolled from tier 2 city hospitals (between 2012-2014). The choice of initial therapy and subsequent treatment modifications was at the discretion of treating physicians. Key outcomes included treatment modifications, virological response (HBV DNA <300 copies/ml) and HBV disease progression. Of the 3,408 patients enrolled, 1,807 and 628 received ETV and LAM-based therapy, respectively. The mean age was 39.5 years, 74% were male and 22.9% had cirrhosis. The rate of treatment modification was higher in the LAM-based versus ETV group (25.9% versus 13.7%); viral breakthrough was the most common reason in the LAM-based group versus financial reasons in the ETV group. At week 240, the virological response rate was 73% in both treatment groups. Compared with LAM-based therapy, ETV was associated with a significantly lower incidence of viral breakthrough (12.6% versus 2.1%) and genotypic resistance (10.1% versus 1.2%; P<0.0001 for both); significantly lower risk of HBV disease progression (14.0% versus 10.7%; P=0.0113); and lower rates of progression to decompensated cirrhosis (9.6% versus 6.4%) and hepatocellular carcinoma (1.9% versus 0.8%). This real-world, longitudinal study demonstrated a significantly lower risk of HBV-related disease progression, viral breakthrough and resistance with ETV versus LAM-based therapy. ClinicalTrials.gov NCT01726439.

Abstract 59: The pioneer transcription factor FOXA2 regulates integrin alpha 1 expression controlling prostate cancer bone colonization

Abstract Introduction. Approximately 30,000 men will die from prostate cancer (PCa) in 2018. When localized and detected early, it has a low rate of progression and metastasis, with successful treatment. However, some patients may progress to a more lethal castrate-resistant PCa. While this occurs, frequent bone metastases will arise, and patient prognosis typically falls to 3-5 years due to lack of therapy available. The purpose of this study was to unveil the mechanisms of PCa bone colonization, allowing us to identify novel targeted therapies to prevent and treat PCa. Methods. Gene expression profiling studies revealed a subset of metastatic PCa samples express the pioneer forkhead transcription factor, FOXA2. Consistently, we found FOXA2 abundance in a sample set of human PCa bone metastases, which may suggest a functional role for FOXA2. Protein analysis of common PCa cell lines revealed high levels of FOXA2 in aggressive bone metastatic PCa PC3 cells. To understand the role of FOXA2 in PCa metastasis, FOXA2 was stably knocked down in PC3 cells. Results. PC3 cells with FOXA2 knocked down (FOXA2-KD) failed to generate in vivo bone destruction following intra-tibial injection contradictory to their parental cell line. To elucidate how FOXA2 is orchestrating these changes, we assessed the expression of all integrins and observed that loss of FOXA2 decreased mRNA and protein expression of the collagen-I binding integrin α1. Furthermore, we found FOXA2-KD decreased PC3 cells’ adhesion, spreading, and downstream Integrin α1 signaling cascades on collagen-I (a major component of bone ECM) coated surfaces. Additionally, a neutralizing antibody to integrin α1 was administered to PC3 Control cells, prompting the same adhesion pattern, solidifying that this integrin is critical to collagen-I adherence. Through ChIP analysis, we learned that FOXA2 directly regulates the ITGA1 gene promoter. Lastly, we overexpressed integrin α1 in PC3 FOXA2-KD cells and rescued the adherence properties. Conclusions. Taken together, the FOXA2-controlled expression of integrin α1 resulted in changes to adherence, spreading, and integrin signaling, providing a mechanism for how PCa cells colonize the bones. Funding: This research is supported by DOD grant (W81XWH-12-1-0212), NIH grants (R03 CA212567 and R01 CA226285), LSUHSC startups (FWCC and Office of Research) to XY, and Carroll Feist Pre-doctoral Fellowship to ZC. Citation Format: Zachary M. Connelly, Shu Yang, Nazih Khater, A. Wayne Orr, Renjie Jin, David Degraff, Colm Morrissey, Eva Corey, Robert Matusik, Xiuping Yu. The pioneer transcription factor FOXA2 regulates integrin alpha 1 expression controlling prostate cancer bone colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 59.

Abstract 2782: MicroRNAs response to concurrent chemoradiotherapy predicts oligo- and polymetastatic progression in patients with Stage IV colorectal adenocarcinoma

Abstract Colorectal cancer (CRC) is the third most common cancer and an important contributor to cancer mortality and morbidity worldwide. The survival rate (11%) in patients with stage IV CRC remain suboptimal. Among these, an intermediate state of distal metastasis termed oligometastasis(es) is characterized by a less aggressive biology with limited tumor progression. Oligometastases are amenable to metastasis-directed local treatments; however, a significant portion of these progresses to polymetastases. The purpose of this study is to identify predictors of oligometastatic progression that could improve patient selection and survival for metastasis-directed localized therapy. microRNAs (miRs) classifiers have previously been shown to predict oligometastatic progression in smaller studies with a heterogeneous primary tumor. Here, we focus on a larger and first study comprising exclusively stage IV CRC to determine CRC-specific classifier of oligometastic progression. We analyzed microRNAs microarray expression patterns from initial oligometastatic patients (≤5 initial metastases) with metastatic CRCs resected with curative intent. 96 stage IV CRC Korean subjects (70 males, 26 females; mean age 60 years) were stratified into subgroups based on their rate of recurrent metastatic progression over a follow-up period. The criteria for these subgroups were previously validated (PloS one, 7(12), p.e50141): (i) patients with no and/or low rate of progression (LRP; &amp;lt;0.6 new metastases/year) and (ii) patients with a high rate of progression (HRP; &amp;gt;3.6 new metastases/year). microRNA expression (Affymetrix GeneChip microRNA 4.0) was analyzed with quantile normalization, COMBAT, and LIMMA, and then validated using PAM. 47 microRNAs were prioritized (FDR&amp;lt;5%) between HRP (n=22) and LRP (n=60) and were associated with the rate of metastatic progression and survival in the current dataset. Six miroRNAs of this study were previously shown to discriminate between HRP vs LRP among lung metastases of heterogeneous primary tumor types (miR-127-5p, miR-154-5p, miR-199b-5p, miR-485-5p, miR-491-5p, and miR-502-5p). In addition, we observe an overrepresentation of microRNAs from the 14q32.31 locus and members of the miR-154 family from this loci that had previously been implicated in oligo- vs poly- metastasis progression (miR-154-5p, miR-337-5p, miR-381-3p, miR-382-5p, miR-409-5p, and miR-487a-3p). These results further corroborate the hypothesis that HRP and LRP are distinct entities at both clinical and molecular levels. Citation Format: Sung Hak Lee, Nima Pouladi, Colleen Kenost, Francesca Vitali, Yves A. Lussier. MicroRNAs response to concurrent chemoradiotherapy predicts oligo- and polymetastatic progression in patients with Stage IV colorectal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2782.

Long-term observational approach in women with histological diagnosis of cervical low-grade squamous intraepithelial lesion: an Italian multicentric retrospective cohort study

ObjectiveTo evaluate the risk of progression to high-grade squamous intraepithelial lesion (HSIL) (CIN2-3) or invasive cancer in women with histopathological diagnosis of low-grade squamous intraepithelial lesion (LSIL) (CIN1), managed in...

PS1237 DOSE DENSE ABVD (DD‐ABVD) AS FIRST LINE THERAPY IN EARLY‐STAGE UNFAVOURABLE HODGKIN LYMPHOMA (CHL): RESULTS OF A PHASE II, PROSPECTIVE, MULTI‐CENTER STUDY BY FONDAZIONE ITALIANA LINFOMI

Background:Four cycles of ABVD followed by 30 Gy involved site radiotherapy (ISRT) is the standard of care for patients with early unfavourable classical Hodgkin lymphoma (cHL). Since dose‐density might represent an important factor to achieve complete remission and longterm survival, we designed a prospective, multicenter, phase II trial to investigate feasibility, safety and efficacy of dose‐dense ABVD (dd‐ABVD) in patients with early unfavourable HL. This prospective, multicentric, phase 2 study enrolled patients aged 18–70 years with newly diagnosed cHL, unfavourable stage I or II, according to EORTC prognostic criteria. Patients with stage IIB bulky were excluded.Aims:Aims of the study were to investigate feasibility, safety and efficacy of dd‐ABVD in patients with early unfavorable cHL.Methods:Dd‐ABVD consists of Doxorubicin, Bleomycin, Vinblastine and Dacarbazine used at the same doses of conventional ABVD but is administered on days 1 and 8 every 3 weeks instead of days 1 and 15 every 4 weeks. In the absence of progressive disease (PD) or unacceptable toxicity, 4 cycles of dd‐ABVD followed by ISRT were administered. Interim PET was mandatory after 2 courses (PET‐2). Patients experiencing PD were shifted to second‐line salvage therapy. Feasibility and activity of dd‐ABVD regimen were the primary endpoints of the study. By design, the study was considered feasible if ≤5 out of 52 patients required a dose reduction below 85% of the planned dose. The percentage of interim PET negativity was chosen as the parameter to evaluate its activity.Results:Between February 2012 and June 2015, 96 patients were enrolled and evaluated. The feasibility endpoint was achieved with only 4 out of 52 patients requiring a dose reduction greater than 15%. The mean dose intensity in the 96 patients who started dd‐ABVD treatment was 93.7% with only 3 patients unable to complete ddABVD chemotherapy due to toxicity. The activity analysis was performed in all 96 patients. PET‐2 was available for 92/96 (95.8%) patients, of whom 79 were PET‐2 negative (85.9%) and 13 PET‐2 positive (14.1%). In 3 cases PET‐2 was not performed due to logistic reasons and in 1 patient because of switch to standard ABVD following a SAE at cycle 1. Considering the global outcome of the 96 patients who received at least 1 dd‐ABVD course: 90 patients achieved CR (93.8 %), 1 PR (1%), 4 PD (4.2 %) and 1 (1%) was without a known disease assessment. With a median follow‐up of 39.9 months (range: 2.1‐ 57.6 months), median PFS and OS were not reached, at 24 months PFS and OS were 91.5% and 97.9%, respectively. No statistically significant differences were observed for PET‐2 negative and PET‐2 positive patients for both 2 years PFS (94.9% vs 84.6%, p: 0.260) and OS (98.7% vs 100% a, p: 0.560) (figure 1). Most frequent toxicities were haematological. The infection rate was low (infection 8.3% and febrile neutropenia 6.25%); no patient developed cardiac toxicity until now. There was one toxic death after cycle 4; 3 patients were discontinued from the study due to toxicity and were switched to standard ABVD or AVDSummary/Conclusion:The study demonstrates the feasibility of the dd‐ABVD regimen in early unfavourable cHL which also allows a reduction in overall treatment duration without a significant increase in toxicity. Moreover, the dose‐dense strategy translated in excellent data of outcome in term of CR rate, PFS, and OS with a low rate of progression at 2 years. Dd‐ABVD deserves further comparison with conventional ABVD in early unfavourable as well in advanced cHL.image

Follicular lymphoma genomics.

Follicular lymphoma genomics.

Predictive factors for progression of patients with carcinoma in situ of the bladder at long-term follow-up: pure versus non-pure CIS.

The aim of this study was to identify the predictive factors for progression defined as any event that shifted the management of the disease from a bladder sparing approach, by comparing patients with pure versus non-pure carcinoma in situ (CIS) of the bladder. A retrospective analysis was carried out in consecutive patients affected by newly-diagnosed pure CIS and non-pure CIS (excluding cases with concomitant muscle invasive cancer). All patients were enrolled a in our institution from 1998 to 2010. Data was prospectively collected. Main end point was progression-free survival. Overall, 149 patients with CIS were identified for the analysis. A total of 98 patients had pure CIS (66%). Median follow-up was 103 months (range: 40-206 months). Progression occurred in 29 patients (19%). A total of 30 patients died during the follow-up (20%). In 13 cases (9%), the death was cancer specific. Progression-free survival estimate was 181 months (95% CI: 169-193 months) and 154 months (95% CI: 133-176 months) respectively for pure and non-pure CIS population (P=0.03). Among examined variables (age, gender, symptoms, smoking habit, ASA score, number of bacillus Calmette-Guérin [BCG] instillations), multivariate analysis disclosed that only CIS type was an independent predictor of progression (P=0.03) with a relative risk of 0.37 in favor of pure CIS. Pure and non-pure CIS are efficiently treated by BCG therapy combined with trans-urethral resection and/or radical cystectomy, with relatively low rate of progression. CIS type was the only significant predictor of progression.

En bloc re-resection of high-risk NMIBC after en bloc resection: results of a multicenter observational study.

To investigate the role of en bloc re-resection (EBRS) in patients who had undergone previous en bloc resection for high-risk non-muscle-invasive bladder cancer (NMIBC). An international, multicenter, observational retrospective analysis of prospectively collected data. Patients with a high-risk NMIBC who had previously undergone en bloc resection were scheduled for EBRS of the resected area after 40days. The primary outcome was the presence of residual tumor or recurrence-free survival. Overall, 78 patients underwent EBRS. Only five (6.41%) residual cancers were found: one patient had a pTa G3 (1.28%) cancer and four (5.13%) had a pTis. The detrusor muscle was preserved in all samples. Only one patient had a positive margin on EBRS. No procedure called for a conversion to traditional re-TURBT. No patient experienced bladder perforation or other intra-operative complications. The recurrence rate at the first follow-up cystoscopy (RRFF-C at 3months) was 3.85% (three patients). The median follow-up period was 30.8months (range 6.9-76.0months). In univariate analysis, the only predictor of recurrence was grade. Overall we observed 11 recurrences. Only one tumor progressed to T2 MIBC. The low rates of residual tumor, recurrence, and progression seem to raise doubts about the efficacy of EBRS in patients who have previously undergone en bloc resection. EBRS appears to be a feasible and safe procedure with a low rate of complications. However, further data will be needed before EBRS can be used in clinical trials or recommended as a treatment modality.

Low rates of radiographic progression of structural joint damage over 2 years of baricitinib treatment in patients with rheumatoid arthritis

ObjectivesTo evaluate radiographic progression of structural joint damage over 2 years in patients with rheumatoid arthritis from baricitinib clinical trials who were disease-modifying antirheumatic drug (DMARD)–naïve or had an inadequate...

Efficacy of therapeutic soft contact lens in the management of gelatinous drop-like corneal dystrophy

Background/AimsTo investigate the efficacy of therapeutic soft contact lenses (SCLs) in gelatinous drop-like corneal dystrophy (GDLD) management.MethodsThis was a retrospective, consecutive, observational case series, including 20 patients (40 eyes) with...

Stepping-Stone or Dead End: To What Extent Does Part-Time Employment Enable Progression Out of Low Pay for Male and Female Employees in the UK?

AbstractUsing data from Understanding Society and the British Household Panel Survey, this article explores the relationship between working part-time and progression out of low pay for male and female employees using a discrete-time event history model. The results show that working part-time relative to full-time decreases the likelihood of progression out of low pay, defined as earning below two-thirds of the median hourly wage. However, part-time workers who transition to full-time employment experience similar rates of progression to full-time workers. This casts doubt on the idea that part-time workers have lower progression rates because they have lower abilities or work motivation and reinforces the need to address the quality of part-time jobs in the UK labour market. The negative effect of working part-time is greater for men than for women, although women are more at risk of becoming trapped in low pay in the sense that they tend to work part-time for longer periods of time, particularly if they have children. Factors such as childcare policy and Universal Credit (UC) incentivise part-time employment for certain groups, although in the right labour market conditions UC may encourage some part-time workers to increase their working hours.

The role of the renal biopsy and surveillance in the management of small renal masses

Cross-sectional imaging shows a limited diagnostic accuracy for the histological discrimination of small renal masses (SRM). In this scenario, a renal tumor biopsy is a safe, feasible and effective diagnostic tool that can guide treatment strategy by providing the histological characterization of a SRM. Although nephron-sparing surgery is still considered the gold standard treatment for patients with SRM, more and more evidence suggests that active surveillance (AS) is a reasonable alternative option, especially in old and comorbid patients. Indeed, owing to the relatively slow growth and favorable biology of SRM, AS followed up by, if necessary, a delayed intervention provides an optimal oncological outcome with low rates of systemic progression or death.

Oral maintenance metronomic vinorelbine versus best supportive care in advanced non-small-cell lung cancer after platinum-based chemotherapy: The MA.NI.LA. multicenter, randomized, controlled, phase II trial

BackgroundOral vinorelbine administered at the maximum tolerated dose has already showed activity and a good safety profile in advanced non-small-cell lung cancer (NSCLC). The MA.NI.LA study was a phase II, multicenter, randomized, controlled trial that aimed to assess the effects of a ‘switched maintenance’ regimen with oral metronomic vinorelbine (OMV) in patients with NSCLC who had not progressed after first-line platinum-based chemotherapy. Patients and methodsPatients were randomly assigned in a 1:1 ratio to either OMV (50 mg three-times weekly) as maintenance treatment or best supportive care (BSC). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective disease control rate (DCR, CR + PR + SD), safety and quality of life. ResultsIn total, 61 and 59 patients were assigned to OMV and BSC, respectively. At a median follow-up of 23.9 (IQR 10.2–38.2) months, patients treated with OMV reported a significantly lower progression rate compared to patient in the BSC arm (89% [54/61] vs 96% [56/58]; HR 0.73; 90% CI 0.53-0.999, p = 0.049). Median PFS for patients treated with vinorelbine was 4.3 months (95% CI 2.8–5.6) vs 2.8 months (95% CI 1.9–4.5) for patients receiving BSC. This benefit was specifically evident in patients aged ≥70 years, in current smokers, and in those who reported disease stabilization as best response to induction chemotherapy. OS and response rate and quality of life were similar in the two arms. Drop-out rate for major toxicity with OMV was unexpectedly high (25%, 14/61) mainly due to grade 3–4 neutropenia (11%, 7/61).Conclusions In patients with unselected NSCLC achieving disease control after platinum-based chemotherapy switch maintenance therapy with OMV prolonged PFS compared to BSC; however, the optimal dose of OMV requires further investigation.

Value of Tumor Growth Rate (TGR) as an Early Biomarker Predictor of Patients' Outcome in Neuroendocrine Tumors (NET)-The GREPONET Study.

Tumor growth rate (TGR; percent size change per month [%/m]) is postulated to be an early radiological biomarker to overcome limitations of RECIST. This study aimed to assess the impact of TGR in neuroendocrine tumors (NETs) and potential clinical and therapeutic applications. Patients (pts) with advanced grade (G) 1/2 NETs from the pancreas or small bowel initiating systemic treatment (ST) or watch and wait (WW) were eligible. Baseline and follow-up scans were retrospectively reviewed to calculate TGR at pretreatment (TGR0), first follow-up (TGRfirst), and 3(±1) months of study entry (TGR3m). Out of 905 pts screened, 222 were eligible. Best TGRfirst (222 pts) cutoff was 0.8 (area under the curve, 0.74). When applied to TGR3m (103 pts), pts with TGR3m <0.8 (66.9%) versus TGR3m ≥ 0.8 (33.1%) had longer median progression-free survival (PFS; 26.3 m; 95% confidence interval [CI] 19.5-32.4 vs. 9.3 m; 95% CI, 6.1-22.9) and lower progression rate at 12 months (7.3% vs. 56.8%; p = .001). WW (vs. ST) and TGR3m ≥ 0.8 (hazard ratio [HR], 3.75; 95% CI, 2.21-6.34; p < .001) were retained as factors associated with a shorter PFS in multivariable Cox regression. TGR3m (HR, 3.62; 95% CI, 1.97-6.64; p < .001) was also an independent factor related to shorter PFS when analysis was limited to pts with stable disease (81 pts). Out of the 60 pts with TGR0 data available, 60% of pts had TGR0 < 4%/month. TGR0 ≥ 4 %/month (HR, 2.22; 95% CI, 1.15-4.31; p = .018) was also an independent factor related to shorter PFS. TGR is an early radiological biomarker able to predict PFS and to identify patients with advanced NETs who may require closer radiological follow-up. Tumor growth rate at 3 months (TGR3m) is an early radiological biomarker able to predict progression-free survival and to identify patients with advanced neuroendocrine tumors who may require closer radiological follow-up. It is feasible to calculate TGR3m in clinical practice and it could be a useful tool for guiding patient management. This biomarker could also be implemented in future clinical trials to assess response to therapy.

Delivering trauma mastery with an international trauma masters

IntroductionTrauma is a global problem. The goal of optimising multidisciplinary trauma care through speciality education is a challenge. No single pathway exists to educate care providers in trauma knowledge, management and skills.Queen Mary University of London (QMUL) devised an online electronic learning (e-learning) Master’s degree (MSc) in Trauma Sciences in 2011. E-learning is increasingly popular however low progression rates question effectiveness. The further post-graduate impact is unknown.Our goal was to establish whether this program is a successful method of delivering multidisciplinary trauma education to an international community. We hypothesized that graduating students make a global impact in trauma care, education and research. MethodsThe Trauma Sciences MSc programs launched in 2011. Electronic surveys were distributed worldwide to students who successfully completed the program between 2013–2016. Graduation rates, degree/qualification awarded, clinical involvement in trauma management, presentation of MSc work, academic progression and roles in trauma education were explored. Supporting demographics were extracted from the QMUL student database. ResultsA total of 176 students, of 29 nationalities, enrolled in the two year course between 2011 and 2014. Clinical backgrounds included multi-speciality physicians (83.5%), nurses (9.6%) and paramedics (6.8%). 119 (67.6%) graduated within the study period, 108 (60.8%) with the full masters award. Completion was independent of clinical background (p = 0.20) and age (p = 0.99). Highest completion rates were seen in students from Australia and New Zealand, Asia and Europe (p = 0.03).All survey responders were currently providing regular clinical care to trauma patients. 73% (n = 36) were delivering trauma education, many at national or international level. 49% (n = 24) had presented work from the MSc and 23% (n = 11) published their dissertation.12% (n = 6) subsequently enrolled in a PhD program. ConclusionCompared with other e-learning courses this Masters program has an enviable completion rate. Graduates go on to make an international multidisciplinary impact with diverse roles in clinical management, research and trauma education.This programme provides a robust trauma education curriculum. The QMUL Trauma Sciences MSc program is an excellent resource for clinicians participating in any form of trauma care or who wish to augment sub-speciality training in trauma.

Chemotherapy Modulates Endocrine Therapy-Related Resistance Mutations in Metastatic Breast Cancer

PURPOSE: Accumulation of PIK3CA, ESR1, and GATA3 mutations results in resistance to endocrine therapy in breast cancer patients; however, the response of these genes to chemotherapy is unclear. Therefore, we sought to evaluate the genetic response of circulating tumor DNA (ctDNA) to chemotherapy in metastatic breast cancer patients. METHODS: The mutation frequency of 1021 genes was examined prior to chemotherapy in ctDNA of 44 estrogen receptor–positive metastatic breast cancer patients. These genes were evaluated again in a subset of patients (n=24) following chemotherapy. Mutation frequency was defined as the percentage of mutations found in ctDNA compared to total cell-free DNA. RESULTS: Prior to chemotherapy, PIK3CA was the most commonly mutated gene, with mutation found in 22 of the metastatic breast cancer patients. Following chemotherapy, 16 patients exhibited progressive disease (PD), and 8 patients experienced no progression (non-PD). PIK3CA mutation frequency increased in 56.25% (9/16) of the PD patients but decreased in 62.5% (5/8) of the non-PD patients. As a result, more PD patients exhibited increased PIK3CA mutation frequency than non-PD patients (56.25% vs 0%, P=.002). Further, ESR1 and GATA3 mutations correlated with PIK3CA mutation. Interestingly, patients receiving the mTOR inhibitor everolimus exhibited a lower progression rate (0% vs 62.5%, P=.001), and the combination of everolimus and chemotherapy effectively suppressed PIK3CA, ESR1, and GATA3 gene mutations. CONCLUSION: Together, these results suggest that mTOR inhibition may be a useful chemotherapy adjuvant to suppress chemotherapy-induced gene mutations that render tumors resistant to endocrine therapy in metastatic breast cancer patients with PD.