Univariate Hazard Ratio Research Articles

Extended surgical safety margins and ulceration are associated with an improved prognosis in pleomorphic dermal sarcomas.

Pleomorphic dermal sarcomas (PDS) are frequent UV-induced sarcomas of the skin of intermediate grade malignant potential. Despite the fact that PDS have a noteworthy potential to recur (up to 28%) as well as to metastasize (up to 20%), there are no specific clinical guidelines with respect to follow-up these patients. Moreover, little is known about clinical, histological or molecular prognostic factors in PDS. The aim of the present study was to identify risk factors to predict relapse in a large multicentre sample cohort of PDS which could aid to optimize personalized treatment recommendations regarding surgical safety margins and adjuvant radiotherapy. Patients with a diagnosis of PDS were selected from nine European institutions based on the histopathologic criteria described by Fletcher. Clinicopathologic and follow-up data were collected and statistically analysed calculating univariate hazard ratios with 95% confidence intervals by use of the Cox proportional-hazards model and a significance level of P<0.05. Patients with an incomplete excision of the tumour were excluded. Univariate Cox regression analysis of possible prognostic factors for progression-free survival (PFS) performed in 92 patients revealed that an excision margin of <2cm is significantly associated with relapse of PDS [hazard ratio 4.478 (95% CI 1.536-13.055), P=0.006]. Ulceration of the tumour was associated with a significantly better prognosis [0.396 (0.174-0.904), P=0.028] whereas adjuvant radiotherapy did not reach statistical significance to improve prognosis in patients with PDS [0.775 (0.231-2.593), P=0.679]. Gender, age, immunosuppression, intratumoural necrosis, tumour location, vertical thickness or horizontal diameter did not significantly influence PFS in PDS. We identified surgical safety margins of <2cm and absence of ulceration as risk factors for relapse in patients with PDS. These findings may be implemented into both the primary treatment as well as the further monitoring of patients with PDS.

Prognostic Value of 18F-Fluorocholine PET Parameters in Metastatic Castrate-Resistant Prostate Cancer Patients Treated with Docetaxel.

Background and Aim The availability of new treatments for metastatic castrate-resistant prostate cancer (mCRPC) patients increases the need for reliable biomarkers to help clinicians to choose the better sequence strategy. The aim of the present retrospective and observational work is to investigate the prognostic value of 18F-fluorocholine (18F-FCH) positron emission tomography (PET) parameters in mCRPC. Materials and Methods Between March 2013 and August 2016, 29 patients with mCRPC were included. They all received three-weekly docetaxel after androgen deprivation therapy, and they underwent 18F-FCH PET/computed tomography (CT) before and after the therapy. Semi-quantitative indices such as maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) with partial volume effect (PVC-SUV) correction, metabolically active tumour volume (MATV), and total lesion activity (TLA) with partial volume effect (PVC-TLA) correction were measured both in pre-treatment and post-treatment 18F-FCH PET/CT scans for each lesion. Whole-body indices were calculated as sum of values measured for each lesion (SSUVmax, SPVC-SUV, SMATV, and STLA). Progression-free survival (PFS) and overall survival (OS) were considered as clinical endpoints. Univariate and multivariate hazard ratios for whole-body 18F-FCH PET indices were performed, and p < 0.05 was considered as significant. Results Cox regression analysis showed a statistically significant correlation between PFS, SMATV, and STLA. No correlations between OS and 18F-FCH PET parameters were defined probably due to the small sample size. Conclusions Semi-quantitative indices such as SMATV and STLA at baseline have a prognostic role in patients treated with docetaxel for mCRPC, suggesting a potential role of 18F-FCH PET/CT imaging in clinical decision-making.

Impact of Epithelial–Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ

A better definition of biomarkers and biological processes related to local recurrence and disease progression is highly warranted for ductal breast carcinoma in situ (DCIS). Stromal-epithelial interactions are likely of major importance for the biological, clinical, and pathological distinctions between high- and low-risk DCIS cases. Stromal platelet derived growth factor receptor (PDGFR) was immunohistochemically assessed in two DCIS patient cohorts (n = 458 and n = 80). Cox proportional hazards models were used to calculate the hazard ratios of recurrence. The molecular mechanisms regulating stromal PDGFR expression were investigated in experimental in vitro co-culture systems of DCIS cells and fibroblasts and analyzed using immunoblot and quantitative real-time PCR. Knock-out of JAG1 in DCIS cells and NOTCH2 in fibroblasts was obtained through CRISPR/Cas9. Experimental data were validated by mammary fat pad injection of DCIS and DCIS-JAG1 knock-out cells (10 mice per group). All statistical tests were two-sided. PDGFRα(low)/PDGFRβ(high) fibroblasts were associated with increased risk for recurrence in DCIS (univariate hazard ratio = 1.59, 95% confidence interval [CI] = 1.02 to 2.46; P = .04 Wald test; multivariable hazard ratio = 1.78, 95% CI = 1.07 to 2.97; P = .03). Tissue culture and mouse model studies indicated that this fibroblast phenotype is induced by DCIS cells in a cell contact-dependent manner. Epithelial Jagged1 and fibroblast Notch2 were identified through loss-of-function studies as key juxtacrine signaling components driving the formation of the poor prognosis-associated fibroblast phenotype. A PDGFRα(low)/PDGFRβ(high) fibroblast subset was identified as a marker for high-risk DCIS. The Jagged-1/Notch2/PDGFR stroma-epithelial pathway was described as a novel signaling mechanism regulating this poor prognosis-associated fibroblast subset. In general terms, the study highlights epithelial-stromal crosstalk in DCIS and contributes to ongoing efforts to define clinically relevant fibroblast subsets and their etiology.

Abstract P4-16-03: Cardiovascular outcomes and long term survival with discontinuation of adjuvant trastuzumab

Abstract Background: Trastuzumab (T) induced cardiomyopathy remains a significant limitation to adjuvant HER2 directed therapy. Recent studies have aimed to reduce cardiotoxicity through combination with non-anthracycline (non-A) chemotherapy or shorter treatment duration. However there is limited data regarding cardiac outcomes and long-term survival with early discontinuation of adjuvant T. Methods: An IRB-approved single-institution retrospective analysis was performed for 401 consecutive patients with non-metastatic HER2+ breast cancer treated at the Ohio State University Comprehensive Cancer Center from 2005-2015. Medical records were reviewed for clinicopathologic features, systemic treatment and survival information. Disease Free Survival (DFS) was defined as time from diagnosis to first recurrence (loco-regional or distant recurrence) including second primary breast cancer or death. Overall survival (OS) was defined as time from diagnosis to death or last known follow up. OS and DFS estimates were generated using Kaplan Meier methods and compared using Log-rank tests. Cox proportional hazard models were used to calculate univariate and multivariate hazard ratios for OS and DFS. Results: A total of 371/401 (92.5%) patients received adjuvant T (n= 401, mean age: 59.4 years; stage 1: 120, 30%; stage II: 194, 48%; stage III: 87, 22%; ER+: 235, 58%); among whom 106/371 (28.6%) patients held adjuvant T for any reason. Median duration of therapy in patients with any interruption with T was 11.3 (0.5-16.9) months and 23/371 (6.9%) received less than 6 months of adjuvant T. Cardiomyopathy (measured as LVEF decline on 2D echocardiogram or MUGA &amp;gt;= 15 points) was the most common reason for withholding T (66/106, 62.3%). The majority of these patients received a cardiology referral (77/ 106, 72.6%) with a 13 day mean time to evaluation in outpatient clinic. Patients receiving non-A chemotherapy and beta blockers or ACE inhibitors during treatment were significantly less likely to experience cardiomyopathy (A vs non-A: 49/190, 25.8% vs. 16/136, 11.8% p=0.002); (Med vs no Med: 7/148, 4.73% vs 59/184, 32.1%; p&amp;lt;0.001). Log-rank tests indicate a significant worsening in OS and DFS for patients who discontinued T (p=0.021, 0.001 respectively). Multivariate analyses confirmed significant worsening in DFS after adjusting for age, stage, ER , node status, and cardiomyopathy (Adjusted HR: 4.0[2.02 – 7.92], p&amp;lt; 0.001) Table 1- Discontinuation of adjuvant trastuzumab Number of patients (%)Initial treatment371Completed therapy with no interruption265 (71.4)Interruption of therapy for minimum of 2 weeks64 (17.2)Permanently discontinued42 (11.3) Conclusion: Discontinuation of adjuvant trastuzumab, most often from cardiomyopathy, is an independent prognostic marker for worse DFS in non-metastatic HER2 positive breast cancer. Non-anthracycline chemotherapy and use of cardio-protective medication is associated with significantly reduced incidence of cardiotoxicity in this population. Future prospective studies should consider optimizing cardiovascular function to avoid interruption in adjuvant HER 2 directed therapy. Citation Format: Sardesai S, Liu J, Palettas M, Stephens J, Stover D, Williams N, Reinbolt R, VanDeusen J, Wesolowski R, Lustberg M, Ramaswamy B. Cardiovascular outcomes and long term survival with discontinuation of adjuvant trastuzumab [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-03.

Abstract P4-14-12: Outcomes in hormone receptor positive, invasive lobular cancer in the era of endocrine monotherapy

Abstract Background:Invasive lobular carcinoma (ILC) accounts for up to 15% of all breast cancers and is clinically and biologically distinct from invasive ductal carcinoma (IDC). Despite that, women with early stage ILC are often treated similarly to IDC. However, several retrospective studies suggest that patients (pts) with ILC may not derive survival benefit from the addition of chemotherapy to endocrine therapy relative to pts with IDC. The purpose of our study was to compare outcomes of pts with ILC treated with chemotherapy with those who received endocrine monotherapy. Methods: A retrospective review of pts with ILC or pleomorphic lobular carcinoma treated at the Ohio State University James Cancer Center from 2004-2014 was performed. Clinico-pathologic characteristics, treatment summary and clinical outcomes were collected. Distant disease-free survival (DDFS) was defined as time from diagnosis to the first distant metastases or death and overall survival (OS) was the time from diagnosis to death or last known follow up. DDFS and OS curves were created using Kaplan-Meier methods and compared using log-rank tests. Cox proportional hazard models were used to calculate univariate and multi variable hazard ratios (HR) for OS and DDFS. Results: We identified 379 pts with early stage ILC (stage I: 43% (162/379), stage II: 34% (127/379), stage III: 22% (84/379), unknown: 1% (6/379)). The majority of pts were post-menopausal (79%), Caucasian (92%) and ER+/PR+ (87%) and HER2 negative (96%). One hundred seventy six pts (46%) received chemotherapy and 189 (50%) pts received endocrine therapy alone. Pts who received chemotherapy had stage II or III disease, positive lymph nodes and grade 2 or 3 tumors; while pts who received endocrine monotherapy had stage I disease, negative lymph nodes and grade 1 or 2 tumors. We found a 51% decrease in chemotherapy (from 63% to 31%) and an increase in endocrine monotherapy use (from 34% to 65%) between 2004-2010 and 2011-2014. One hundred thirty two pts were evaluated with Oncotype DX, of which 76% (100/132) were node negative with the majority having a low recurrence score (low: 64%; intermediate: 33%; high: 3%). The use of Oncotype DX increased from 21.1% in 2004-2010 to 47.9% in 2011-2014. We found that 112 of 149 pts with at least 5 years follow up (75.2%) successfully completed five or more years of endocrine therapy. Univariate cox models showed worse DDFS HRs for type of therapy and node status (HR: 2.36, p=0.005, HR: 4.16, p&amp;lt;0.001, respectively). However, the HR for therapy was no longer significant when adjusting for age, grade, and nodal involvement (HR = 1.19, 95% CI: 0.56 – 2.52, p=0.646). Nodal involvement remained significant (HR= 3.56, 95% CI: 1.64-7.70, p=0.001) after adjusting for therapy, age and grade. No significant difference in OS was found between endocrine monotherapy and chemotherapy (p=0.426, log-rank test). Conclusion: We found no difference in DDFS between endocrine monotherapy and chemotherapy after adjusting for age, grade, and nodal involvement in pts with early stage ILC. This supports the hypothesis that ILC may not derive a significant benefit from the addition of chemotherapy. We need more prospective clinical trials considering histology to better understand how best to treat ILC. Citation Format: Williams N, Liu J, Stephens J, Palettas M, Boutrid H, Sardesai S, Reinbolt R, Stover D, VanDeusen J, Noonan A, Wesolowski R, Lustberg M, Ramaswamy B. Outcomes in hormone receptor positive, invasive lobular cancer in the era of endocrine monotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-12.

U-shaped association of central pulse pressure with long-term prognosis after ST-segment elevation myocardial infarction.

The relationship between central pulse pressure (CPP) measured at the time of primary percutaneous coronary intervention (PPCI) and long-term prognosis after ST-segment elevation myocardial infarction (STEMI) has not been investigated. CPP measurements were performed in 1348 patients with STEMI (327 women; mean age 62.5 ± 12.1years) undergoing PPCI. Aortic systolic and diastolic blood pressure was measured before intervention. The primary outcome was 8-year all-cause mortality. The median [25-75th percentile] CPP value was 55.0 [43.0-70.0] mmHg. CPP correlated negatively with heart rate (P < 0.001), body mass index (P = 0.007), Killip class (P < 0.001) and initial area at risk (P < 0.001) and positively with age (P < 0.001), female sex (P < 0.001), diabetes (P = 0.012), arterial hypertension (P < 0.001) and glomerular filtration rate (P = 0.004). There were 181 deaths over the follow-up. In patients with CPP within the 1st, 2nd and 3rd tertiles, the Kaplan-Meier estimates of mortality were 17.3%, 10.8% and 24.2%, respectively; univariable hazard ratio [HR] =1.52, 95% confidence interval [CI] 0.99 to 2.32; P = 0.055 for tertile 1 vs. tertile 2 and HR =2.09 [1.36-3.21]; P < 0.001 for tertile 3 vs. tertile 2. For CPP values lower than 35mmHg and higher than 71mmHg, the association between CPP and all-cause mortality was significant (HR =1.276 [1.004-1.621] for the 35mmHg value and HR =1.289 [1.003-1.657] for the 71mmHg value) compared with the CPP reference value (54mmHg). After adjustment, the association between CPP and all-cause mortality was attenuated (P = 0.304). In patients with STEMI undergoing PPCI there is a U-shaped association between CPP and mortality up to 8years after PPCI.

Risk factors for subsequent work disability in patients with acute myocardial infarction.

Scientific knowledge on risk factors for work disability in terms of long-term sickness absence (SA) and disability pension (DP) following acute myocardial infarction (AMI) is limited. The study aimed to investigate socio-demographic, work-related and medical characteristics as risk factors for long-term SA (>90 days) and DP in patients with a first AMI. This is a population-based cohort study of 8199 individuals aged 19-60 years who had a first AMI during 2008-10 and were alive 30 days after AMI. Univariate and multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) with regard to long-term SA and DP with a 3-year follow-up were estimated by Cox regression. We found a higher risk of long-term SA and DP after AMI in women, those with lower education and previous SA (range of HRs: 1.29-7.34). Older age and being born in non-European countries were associated with a 2- to 3-fold higher risk of DP. Moreover, ST-elevation myocardial infarction (STEMI), musculoskeletal and common mental disorders (CMDs) were risk factors for long-term SA and DP, while diabetes mellitus and stroke were associated with a higher risk of DP (range of HRs: 1.12-2.98). Coronary artery bypass grafting (CABG) compared with percutaneous coronary intervention was associated with a 2-fold higher risk of work disability. Older women, those with lower education and non-European immigrants had a higher risk of work disability after AMI, particularly permanent work disability. STEMI, CABG, diabetes mellitus, stroke, musculoskeletal disorders and CMDs provide important clinical information for work disability after AMI.

Overall and disease-specific survival of Hodgkin lymphoma survivors who subsequently developed gastrointestinal cancer.

BackgroundHodgkin lymphoma (HL) survivors have an increased risk of gastrointestinal (GI) cancer. This study aims to evaluate whether survival of patients who survived HL and developed GI cancer differs from survival of first primary GI cancer patients.MethodsOverall and cause‐specific survival of GI cancer patients in a HL survivor cohort (GI‐HL, N = 104, including esophageal, gastric, small intestinal, and colorectal cancer) was compared with survival of a first primary GI cancer patient cohort (GI‐1, N = 1025, generated by case matching based on tumor site, gender, age, and year of diagnosis). Cox proportional hazards regression was used for survival analyses. Multivariable analyses were adjusted for GI cancer stage, grade of differentiation, surgery, radiotherapy, and chemotherapy.ResultsGI‐HL cancers were diagnosed at a median age of 54 years (interquartile range 45‐60). No differences in tumor stage or frequency of surgery were found. GI‐HL patients less often received radiotherapy (8% vs 23% in GI‐1 patients, P < 0.001) and chemotherapy (28% vs 41%, P = 0.01) for their GI tumor. Compared with GI‐1 patients, overall and disease‐specific survival of GI‐HL patients was worse (univariable hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.03‐1.65, P = 0.03; and HR 1.29, 95% CI 1.00‐1.67, P = 0.049, respectively; multivariable HR 1.33, 95% CI 1.05‐1.68, P = 0.02; and HR 1.33, 95% CI 1.03‐1.72, P = 0.03, respectively).ConclusionsLong‐term overall and disease‐specific survival of GI cancer in HL survivors is worse compared with first primary GI cancer patients. Differences in tumor stage, grade of differentiation, or treatment could not explain this worse survival.

Associations Between Migraine and Type 2 Diabetes in Women

Little is known about the associations between migraine and type 2 diabetes and the temporality of the association between these 2 diseases. To evaluate the association between migraine and type 2 diabetes incidence as well as the evolution of the prevalence of active migraine before and after type 2 diabetes diagnosis. We used data from the E3N cohort study, a French prospective population-based study initiated in 1990 on a cohort of women born between 1925 and 1950. The E3N study participants are insured by a health insurance plan that mostly covers teachers. From the eligible women in the E3N study, we included those who completed the 2002 follow-up questionnaire with information available on migraine. We then excluded prevalent cases of type 2 diabetes, leaving a final sample of women who were followed up between 2004 and 2014. All potential occurrences of type 2 diabetes were identified through a drug reimbursement database. Statistical analyses were performed in March 2018. Self-reported migraine occurrence. Pharmacologically treated type 2 diabetes. From the 98 995 women in the study, 76 403 women completed the 2002 follow-up survey. Of these, 2156 were excluded because they had type 2 diabetes, leaving 74 247 women. Participants had a mean (SD) age of 61 (6) years at baseline, and all were free of type 2 diabetes. During 10 years of follow-up, 2372 incident type 2 diabetes cases occurred. A lower risk of type 2 diabetes was observed for women with active migraine compared with women with no migraine history (univariate hazard ratio, 0.80 [95% CI, 0.67-0.96], multivariable-adjusted hazard ratio, 0.70 [95% CI, 0.58-0.85]). We also observed a linear decrease in active migraine prevalence from 22% (95% CI, 16%-27%) to 11% (95% CI, 10%-12%) during the 24 years prior to diabetes diagnosis, after adjustment for potential type 2 diabetes risk factors. A plateau of migraine prevalence around 11% was then observed for 22 years after diagnosis. We observed a lower risk of developing type 2 diabetes for women with active migraine and a decrease in active migraine prevalence prior to diabetes diagnosis. Further targeted research should focus on understanding the mechanisms involved in explaining these findings.

Recipient Outcomes From Nondirected Live Kidney Donors: A UK-based Cohort Study.

BackgroundIncreasing numbers of patients with end-stage renal failure are receiving kidneys from nondirected kidney donors (NKDs), also known as altruistic donors. Transplant outcomes for recipients of such kidneys are largely inferred from studies on specified kidney donors (SKDs), which may be inaccurate due to differences in donor, recipient and transplant specific factors. We report the outcomes for recipients of NKD in the United Kingdom.MethodsOutcomes for 6861 patients receiving a living donor kidney transplant between January 2007 and December 2014 were analyzed using both the National Health Service Blood and Transplant and the UK Renal Registry datasets. Graft and patient outcomes were compared for patients receiving NKD and SKD organs using univariable and multivariable analyses.ResultsThere was significant discordance between the NKD and SKD donors and recipients. These included increased donor age (median, 58 years vs 47 years; P < 0.001) and higher rates of hemodialysis and previous transplants in the NKD group (both P < 0.001). Despite such markers of increased risk among both donors and recipients of NKD kidneys, there was no difference in graft survival on univariable (hazard ratio, 1.20; 95% confidence interval, 0.77-1.86; P = 0.419) or multivariable analysis (hazard ratio, 1.13; 95% confidence interval, 0.65-1.95; P = 0.665).ConclusionsDespite some markers of transplant complexity, nondirected kidney donor organs are an excellent source of organs for transplantation.

Diffuse Large B-Cell Lymphoma, Not Otherwise Specified: Discordance between Histology and Flow Cytometry in Bone Marrow Examination at Diagnosis

Background: Bone marrow (BM) examination is essential in the staging of diffuse large B-cell lymphoma (DLBCL). The assessment of BM involvement includes both histology (gold-standard) and flow cytometry (FC), but few studies have compared BM biopsy (BMB) histologic findings with results of FC analysis of BM aspirate. Discordance between both techniques generates debate about the staging and the prognostic significance in these cases.Methods: We performed a retrospective single-center analysis of patients with DLBCL, not otherwise specified (NOS) diagnosed during a 4-year period (2014-2017). Patients were divided in three groups according to BM findings of BMB and FC at diagnosis. Standard FC was performed by 4-color flow panel until 2016 and by 8-color FC since then. We described main characteristics of each group at diagnosis and analyzed survival outcomes. We applied means of descriptive statistics and Pearson's chi-squared test, and analyzed survival outcomes according to Kaplan-Meier, using Cox regression for comparisons.Results: We analyzed 59 cases, which were divided in three groups: 40 cases (67.8%) presented both negative histology and FC (BMB-/FC-), 10 (16.9%) showed BM involvement using both histology and FC (BMB+/FC+) and 9 cases (15.3%) presented discordant results, all of them with negative histology and positive FC (BMB-/FC+). Clinical and biological characteristics of each group at diagnosis are presented in Table 1. Median infiltration by FC analysis of the BMB-/FC+ group was 0.8% (0.1-2.9) and 3/9 patients presented discordant immunophenotype of lymphoma cells between BM and node biopsy. If we considered BM infiltration as positive in all BMB-/FC+ cases, 4/9 (6.8% of all patients) would be upstaged. First-line treatment was homogeneous in all patients. With a median observation time of 18 months, progression-free survival (PFS) after 2 years was 67%, 22% and 22% with BMB-/FC-, BMB-/FC+ and BMB+/FC+, respectively (Figure 1A), with a multivariate hazard ratio (HR) of 1.9 (95% CI 1.2-2.9, p=0.004) and an univariate HR for FC+ (BMB-/FC+ and BMB+/FC+) vs FC- (BMB-/FC-) of 3.3 (95% CI 1.5-7.3, p=0.003). Two-year overall survival (OS) was 68%, 41% and 33% with BMB-/FC-, BMB-/FC+ and BMB+/FC+, respectively (Figure 1B); multivariate HR was 1.6 (95% CI 1.1-2.6, p=0.042) and univariate HR for FC+ vs FC- was 2.5 (95% CI 1.1-5.9, p=0.035). We found no significant difference between BMB-/FC+ and BMB+/FC+ in survival outcomes.Conclusions: In our series, the group with discordant BM infiltration (BMB-/FC+) presented worsen survival outcomes than BMB-/FC-. Such results should be validated in prospective studies because published series are retrospective and not focused specifically on DLBCL. BM infiltration detected by FC analysis but not by BMB could be considered as extranodal involvement at DLBCL NOS diagnosis. [Display omitted] DisclosuresGarcía Gutiérrez:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau.

1551. The Impact of Recurrent CMV Disease on Long-Term Survival in Solid Organ Transplant Recipients

BackgroundCytomegalovirus (CMV) remains a significant contributor to morbidity and mortality following solid-organ transplantation (SOT). While relapse after treatment completion can occur in up to 30% of patients, the effect of this on mortality is not clear. The aim of this study was to explore the impact of recurrent CMV disease on long-term survival in SOT recipients.MethodsWe performed a retrospective cohort study of heart, liver and kidney transplant recipients who completed treatment for an episode of CMV disease. Data on potential confounders were collected from the time of CMV treatment completion. Censoring occurred at the time of death, loss to follow-up or 10 years. Univariable and multivariable hazard ratios (HR) were calculated using a Cox model, treating relapse and rejection following CMV as time-varying covariates.ResultsSeventy-nine kidney, 52 heart, 34 liver and five liver-kidney transplant recipients were included. Sixty-two of 170 died, at a median of 3.8 years (interquartile range [IQR] 0.8–6.6 years). Median follow-up amongst the 108 survivors was 7.4 years (IQR 3.7–10 years) although 22 (13%) were censored before 3 years. CMV relapse occurred in 49/170 (29%), 67% within 6 months of treatment completion. Overall mortality amongst those who relapsed was 39% (19/49) vs. 36% (43/121) in those who remained relapse free. On univariable analysis, CMV relapse was not associated with a significantly increased risk of death (unadjusted HR 1.59, 95% CI 0.92–2.75, P = 0.10). After controlling for age and transplanted organ type, findings were similar (adjusted HR 1.68, 95% CI 0.93–3.04, P = 0.09).ConclusionMortality rates following CMV remain high even in the valganciclovir era. In our study, we did not identify a significant relationship between the development of recurrent CMV disease and death. However, the complex nature of these patients, multiple layers of potential confounding and limited statistical power of our cohort make detection of small effects difficult. Future prospective studies evaluating the clinical efficacy of strategies to reduce recurrence are needed to further assess this relationship.Disclosures D. Snydman, Merck: Board Member, Consulting fee and Grant recipient; Shire: Board Member, Consulting fee; Takeda: Board Member, Consulting fee; Chimerix: Board Member, Consulting fee; Seres Therapeutics: Grant Investigator, Grant recipient; Actelion: Grant Investigator, Grant recipient; Moderna: Board Member, Consulting fee; Summit: Grant Investigator, Grant recipient; Tetraphase: Grant Investigator, Grant recipient.

Outcome-based interpretation of early interim PET in advanced-stage Hodgkin lymphoma

AbstractThe HD18 study for patients with newly diagnosed advanced-stage Hodgkin lymphoma (HL) used positron emission tomography (PET) after 2 cycles (PET-2) of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses (eBEACOPP) to guide further treatment. Here, we analyzed the impact of PET-2 results in the context of eBEACOPP according to the Deauville score (DS) in patients treated within the HD18 trial. Residual tissue was visually compared with reference regions according to DS. We analyzed the association between PET-2 uptake and baseline characteristics, progression-free survival (PFS), and overall survival (OS). One thousand five patients (52%) had DS1 or DS2, 471 (24%) had DS3, and 469 (24%) DS4. PET-2 uptake was associated with baseline risk factors large mediastinal mass, extranodal disease, and high International Prognostic Score (P < .0001 each). Among 722 patients receiving standard therapy with 6 cycles of eBEACOPP, 3-year PFS rates were 92.2%, 95.9%, and 87.6% with DS1-2, DS3, and DS4, respectively. Univariate hazard ratio (HR) for PFS in patients with DS4 vs DS1-3 was 2.3 (1.3-3.8; P = .002). DS4 was the only factor remaining significant for PFS in a multivariate analysis including the associated baseline risk factors. Three-year OS rates were 97.6% for DS1-2, 99.0% for DS3, and 96.8% for DS4, with a univariate HR for DS4 vs DS1-3 of 2.6 (1.0-6.6; P = .04). Residual uptake above that in the liver at PET-2 (ie, DS4) is an important risk factor regarding survival outcomes for patients treated with eBEACOPP upfront. We thus recommend DS4 as the cutoff value for PET-2 positivity. This trial was registered at www.clinicaltrials.gov as #NCT00515554.

Utility of DNA Flow Cytometric Analysis of Paraffin-embedded Tissue in the Risk Stratification and Management of 'Indefinite for dysplasia' in Patients With Inflammatory Bowel Disease.

The clinical significance of 'indefinite for dysplasia' [IND] in patients with inflammatory bowel disease remains unclear. Currently, no biomarker can reliably differentiate reactive changes from true dysplasia and/or risk stratify IND. A total of 52 IND colon biopsies were analysed by DNA flow cytometry. The follow-up result of each biopsy was determined by reviewing all subsequent biopsies and endoscopic reports for the occurrence of high-grade dysplasia [HGD] or colorectal cancer [CRC] at the site of previous biopsy or in the same segment of colon. The overall 1-, 3-, 5-, and 7-year detection rates of HGD or CRC in all 52 IND cases were 4.6% (95% confidence interval [CI], 0.0%-10.6%), 18.2% [95% CI, 3.5%-30.7%], 26.3% [95% CI, 8.4%-40.7%], and 31.6% [95% CI, 11.2%-47.4%], respectively. More interestingly, 10.6% of IND cases with aneuploidy were subsequently found to have HGD or CRC within 1 year [95% CI, 0.0%-23.7%], with 36.4% [95% CI, 7.1%-56.5%], 51.7% [95% CI, 16.1%-72.2%], and 59.8% [95% CI, 21.4%-79.5%] detected within 3, 5, and 7 years, respectively. By comparison, in the setting of normal DNA content, 1-, 3-, 5-, and 7-year detection rates of HGD or CRC were 0.8% [95% CI, 0.0%-2.7%], 3.3% [95% CI, 0.0%-9.6%], 5.2% [95% CI, 0.0%-14.7%], and 6.5% [95% CI, 0.0%-18.1%], respectively. Only the presence of aneuploidy was found to be a significant predictor of HGD or CRC with the estimated univariate and multivariate hazard ratios of 13.8 [p = 0.016] and 50.3 [p = 0.010], respectively. IND may not be a low-risk condition for HGD or CRC. In this regard, the presence of aneuploidy can identify a subset of IND cases that are at increased risk for subsequent detection of HGD or CRC.

Predictors of time to death after distant recurrence in breast cancer patients.

After experiencing a distant recurrence, breast cancer patients have a poor prognosis; fewer than 5% survive for ten or more years. However, the time to death is highly variable, ranging from a few months to many years. The purpose of this study is to identify, in a large hospital-based series of patients with early-stage breast cancer, factors which predict survival after distant recurrence. We studied a cohort of 2312 women diagnosed with invasive breast cancer at Women's College Hospital between 1987 and 2000 (stages I-III). For each patient, we abstracted information on age at diagnosis, the initial presentation of the cancer (tumour size, lymph node status, tumour grade, ER status, PR status, HER2 status), treatment (surgery, radiotherapy, chemotherapy, hormone therapy), the dates of all tumour recurrences (local, regional, distant) and the dates and causes of death. The Cox proportional hazards model was used to estimate the univariate and multivariate hazard ratios for death from breast cancer following distant recurrence associated with the various tumour features. After a mean follow-up of 12.8years from diagnosis, 523 distant recurrences were recorded among women in the cohort (23% of 2312) and 604 women (26%) died of breast cancer. For the 484 women who had a distant recurrence on record and died of breast cancer, the mean time from distant recurrence to death was 2.0years (range 0-11.9years). In a multivariate analysis, only two factors were significantly associated with time to death after distant recurrence: ER status (positive vs. negative, HR 0.56; 95% CI 0.43-0.71; p < 0.0001) and tumour grade (high vs. low, HR 1.87; 95% CI 1.16-3.01; p = 0.01). Among ER-negative patients (N = 175), high tumour grade and a short time from diagnosis to distant recurrence were associated with a rapid time to death. Among ER-positive patients (N = 336), there was no significant independent predictor of time from recurrence to death. Among ER-negative breast cancer patients, the time to death after distant recurrence was predictable to some extent; women with a short time from diagnosis to recurrence and/or with high-grade tumours were more likely to succumb to breast cancer within 3years. Among ER-positive breast cancer patients who experience a distant recurrence, the time to death varies substantially and between patients could not be predicted by tumour factors or treatment. This suggests that for ER-positive patients, the factors that determine the time from diagnosis to distant recurrence do not predict the course of the cancer post-recurrence.

Psychosocial Distress and Health Service Utilization in Patients Undergoing Hemodialysis: A Prospective Study

End-stage renal disease is associated with significant morbidity, high-symptom burden, and health care use. Studies have not yet assessed psychosocial distress and health care utilization in this population. This study examines psychosocial distress and its association with hospitalization and emergency room (ER) visits in patients on maintenance hemodialysis (HD). The Distress Assessment and Response Tool (DART) was administered to 80 adults on HD in a single treatment center. The DART assessed for anxiety, depression, and social distress. Health care utilization data were extracted prospectively from electronic medical charts. The time between psychosocial distress and hospitalization or ER visits during 12-month follow-up was examined using Cox proportional hazard models. Overall 46% of the sample reported psychosocial distress, with 33% screening above the threshold for depression, 14% for anxiety, and 36% for significant social distress. In multivariable regression adjusting for age, sex, and comorbidity, the presence of psychosocial distress was associated with shorter time to hospitalization (hazard ratio: 2.4 [1.1, 5.0], p = 0.03) during 12-month follow-up. Psychosocial distress was not significantly associated with ER visits in either univariable (hazard ratio: 1.3 [0.7, 2.3], p = 0.5) or multivariable (hazard ratio: 1.4 [0.8, 2.6], p = 0.3) analyses. Psychosocial distress is frequent in patients undergoing maintenance HD and is associated with shorter time to hospitalization. Future longitudinal studies should examine if health service use can be reduced through routine distress screening and psychosocial distress intervention.

Liquid biopsy prediction of axillary lymph node metastasis, cancer recurrence, and patient survival in breast cancer: A meta-analysis.

Liquid biopsies using circulating tumor DNA (ctDNA) and cell-free DNA (cfDNA) have been developed for early cancer detection and patient monitoring. To investigate the clinical usefulness of ctDNA aberrations and cfDNA levels in patients with breast cancer (BC), we conducted a meta-analysis of 69 published studies on 5736 patients with BC. The relevant publications were identified by searching PubMed and Embase databases. The effect sizes of outcome parameters were pooled using a random-effects model. The ctDNA mutation rates of TP53, PIK3CA, and ESR1 were approximately 38%, 27%, and 32%, respectively. High levels of cfDNA were associated with BCs rather than with healthy controls. However, these detection rates were not satisfactory for BC screening. Although the precise mechanisms have been unknown, high cfDNA levels were significantly associated with axillary lymph node metastasis (odds ratio [OR] = 2.148, P = .030). The ctDNA mutations were significantly associated with cancer recurrence (OR = 3.793, P < .001), short disease-free survival (univariate hazard ratio [HR] = 5.180, P = .026; multivariate HR = 3.605, P = .001), and progression-free survival (HR = 1.311, P = .013) rates, and poor overall survival outcomes (HR = 2.425, P = .007). This meta-analysis demonstrates that ctDNA mutation status predicts disease recurrence and unfavorable survival outcomes, while cfDNA levels can be predictive of axillary lymph node metastasis in patients with BC.

72P - Leukocyte telomere length and recurrence risk after EGFR-TKIs therapy in patients with advanced lung adenocarcinoma

Background: Gefitinib is currently one of the mostly used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) recommended for treating non-small cell lung cancer. However, the factors that predict treatment prognosis and drug resistance to EGFR-TKIs remain elusive. The objective of this study is to exam the association between leukocyte relative telomere length (RTL) and prognosis or drug resistance of advanced lung adenocarcinoma to gefitinib treatment. Methods: In this study, three hundred and sixty-nine patients with stage IIIB or IV lung adenocarcinoma were recruited between January 2009 and June 2013. All patients were treated with gefitinib orally at a daily dose of 250 mg as first-line monotherapy. Leukocyte RTL of each patient was measured using quantitative polymerase chain reaction (qPCR) protocol on an ABI PRISM 7900HT Sequence Detection System (Applied Biosystems) and calculated according to Cawthon’s formula. Differences in patients’ characteristics were calculated by Pearson’s χ2 tests or Student’s t test. Cox proportional hazard regression analyses were used to calculate univariate and multivariate hazard ratios (HRs). Survival differences were examined using the log-rank test. Two-sided P < 0.05 indicated a significant difference. Results: Among 369 patients, EGFR mutations were positive in 181 patients (49.1%). Compared to long RTL, short leukocyte RTL was significantly associated with poor prognosis in all patients after gefitinib treatment (overall survival: 12.9 months vs. 17.8 months, P = 1.2 × 10-4; progression free survival: 7.8 months vs. 13.0 months, P = 0.043). Additionally, statistically significant association between short leukocyte RTL and shorten OS still existed among the EGFR mutant patients with gefitinib treatment (HR = 1.65, 95% CI = 1.28-2.12; P = 0.006). Besides EGFR mutation status, short RTL also contributed to significantly elevated risk of gefitinib primary resistance (HR = 1.50, 95% CI = 1.05-2.15, P = 0.027). Conclusions: Our results highlight the potential of leukocyte RTL as a novel biomarker in advanced lung adenocarcinoma treated with EGFR-TKIs and the possibility of patient-tailored decisions based on leukocyte RTL. Legal entity responsible for the study: Ming Yang. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Neoadjuvant Therapy for Locally Advanced Esophageal Cancer Should Be Targeted to Tumor Histology

Controversy exists over the optimal neoadjuvant therapy in patients with locally advanced esophageal cancer (EC). Although most groups favor neoadjuvant chemoradiation (nCRT), some prefer preoperative chemotherapy (nCT) without radiation. The objective of this study was to compare outcomes in EC patients undergoing either regimen, followed by surgery. We reviewed a prospectively collected database of EC patients undergoing esophagectomy after nCTor nCRT from 1989 to 2016. Choice of therapy was atthe discretion of the multidisciplinary team. Disease-free survival (DFS) and cancer-specific survival (CSS) were compared by the Kaplan-Meier log-rank test. Independent predictors of CSS were estimated by Cox regression analysis. Among 700 EC patients 338 patients were treated with nCRT (n= 112) or nCT (n= 226) followed by surgery. Patients were well matched for age, gender, and clinical stage, although patients with squamous cellcarcinoma were more likely to receive nCRT (49% vs 26%, p < 0.001). At surgery 90% and 91% of nCRT and nCTpatients, respectively, underwent transthoracic esophagectomy. nCRT, in comparison with nCT, was associated with similar rates of Calvien-Dindo grade III/IV complications (34% vs 33%, p= 0.423) but with a trend toward higher perioperative mortality (5% vs 1%, p= 0.064). Among adenocarcinoma patients (n= 239) theuse of nCRT was associated with higher rates of complete clinical response (18% vs 7.4%), pathologically negative lymph nodes (52% vs 30%, p= 0.001), and complete pathologic response (21% vs 5.1%, p < 0.001). However, there was no difference between nCRT and nCT for 5-year DFS (28% vs 31%, p= 0.636) or CSS (51% vs 52%, p= 0.824) among adenocarcinoma patients. For patients with squamous cell carcinoma (n= 98), nCRT and nCT had similar rates of complete clinical response (31% vs 26%, p= 0.205), but the rates of negative nodes (65% vs 46%, p= 0.064) and of complete pathologic response (42% vs 12%, p < 0.05) were higher with nCRT. For these patients nCRT was associated with no statistical difference in 5-year DFS (57% vs 40%, p= 0.595) but with improved 5-year CSS (87% vs 68%, p= 0.019) compared with nCT. On multivariable analysis for CSS, nCRT predicted improved survival for patients with squamous cell carcinoma (hazard ratio, 0.242; 95% confidence interval, 0.071-0.830) but not for those with adenocarcinoma (univariate hazard ratio, 0.940; 95% confidence interval, 0.544-1.623). For adenocarcinoma patients undergoing surgery for EC, nCRT leads to increased local tumor response compared with nCT alone but with no difference in survival. For squamous carcinoma patients nCRT appears to improve CSS compared with nCT. For patients with locally advanced EC targeted neoadjuvant regimens should be used depending on tumor histology.

The Effect of Pregnancy on the Long-term Risk of Graft Loss, Cardiovascular Disease, and Death in Kidney Transplanted Women in Norway: A Retrospective Cohort Study.

Kidney transplant recipients have now conceived for almost 50 years. Nevertheless, few studies have evaluated long-term health outcomes for kidney transplanted women after pregnancies. We conducted a retrospective cohort study of all Norwegian women receiving a kidney transplant before the age of 50 years between 1969 and 2013, with graft loss, cardiovascular disease, and death as outcomes. Baseline characteristics for all women were ascertained at first transplantation, with information about exposure, outcomes, and potential confounders collected from medical records. To account for changes in pregnancy status, data were analyzed using proportional hazard Cox regression with pregnancy status as a time-dependent covariate changing at the time of pregnancy. Of 650 women studied, 124 had a pregnancy after kidney transplantation. During the study period, graft loss, cardiovascular disease, and death occurred in 237, 73, and 274 women, respectively. Pregnancy was associated with 54% lower risk of graft loss (95% confidence interval [CI]: 25% to 71%) and 72% lower risk of death (95% CI, 53%-84%). Adjusting for possible confounders had a minimal impact on estimated values. There were considerable uncertainties and no statistically significant results regarding the estimated risk of cardiovascular disease after pregnancy (univariate hazard ratio, 0.91; 95% CI, 0.43-1.92; multivariate hazard ratio, 0.71; 95% CI, 0.32-1.60). Kidney transplanted women with pregnancies have a low risk of subsequent graft loss or death. These results are reassuring for the current clinical practice.