3-month Landmark Research Articles

435 Left ventricular reverse remodeling and angiotensin ii receptor blocker neprilysin inhibitor - a real-world data

Abstract BACKGROUND Although sacubitril/valsartan (ARNI) improves the NYHA functional class and prognosis in patients with heart failure with reduced ejection fraction (HFrEF), its impact on reverse remodelling is uncertain. We assessed left ventricular reverse remodeling in a cohort of HFrEF patients treated with ARNI. METHODS We conducted a single-centre, retrospective, observational study of 200 HFrEF patients started on ARNI during 2018. Of these, we analysed 100 patients treated with the maximum, target dose (97/103 mg bid). Baseline clinical, laboratory and demographic characteristics were evaluated and a clinical and echocardiographic follow-up, including left ventricular ejection fraction (LVEF), left ventricular global longitudinal strain (GLS), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV) and mitral valve regurgitation (MR), were conducted from ARNI initiation to a 3-month landmark. RESULTS Mean age was 59 ± 13 years and 85% were male. At baseline, 63% were on NYHA II, 34% in NYHA III and 3% in NYHA IV functional class. Mean systolic blood pressure was 125 ± 16 mmHg, median NT-proBNP was 773 pg/dL (IQR 386-1569) and mean LVEF 27 ± 7%. Median time between initiation of the drug and reaching the target dose was 10 weeks. Functional class significantly improved; at baseline, 37% of patients were in NYHA III-IV; 3 months after target dose, only 6% remained in NYHA III-IV (p = 0.005). Half of patients (48.6%) improved LVEF (from 27 ± 7% to 31 ± 10%, mean increase 4.2 ± 8.8%; 95%CI 2.1 to 6.3, p < 0.001) and in one quarter (24.6%) LVEF improved over 35% (p < 0.001). In a echocardiographic subgroup analysis, including a random sample of 35 patients, we found a significant improvement in GLS 1.5 ± 2.9 (95%CI 0.4 to 2.6%, p = 0.009), a significant decrease in LVESV and LVEDV 29 ± 3 mL (95%CI -42.6mL to -15.4mL, p < 0.001) and 31 ± 47ml (95% CI -48 to -15, p < 0.001), respectively, and a significant improvement in MR severity (p = 0.001). CONCLUSIONS We observed that in an HFrEF patient population treated with ARNI there was a significant clinical improvement, who may be explained by a robust impact on reverse remodelling, even on a short-time of follow-up. An interesting finding was that 24.6% improved LVEF above the 35% cut-off, and therefore lost an indication for a prophylactic implantable cardioverter defibrillator.

The Impact of Allogeneic Hematopoietic Cell Transplantation (alloHCT) on the Outcome of Poor-Risk Non-Hodgkin Lymphoma (NHL): A Retrospective Intent-to-Transplant (ITT) Analysis

Although alloHCT is an accepted salvage treatment in defined settings of poor-risk NHL, its potential benefit in these indications remains controversial because virtually all published studies are uncontrolled and restricted to patients who were actually able to undergo transplantation. Here, we aimed at assessing the impact of alloHCT by measuring its outcome from the time of donor search indication rather than from the time of transplant, thereby taking into account those patients who fail to proceed to allografting for any reason. Study design and patients : In a single centre retrospective analysis, course and outcome of all patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) mantle cell lymphoma (MCL) and peripheral T-cell lymphoma (PTCL) who were considered as having an alloHCT indication according to accepted guidelines between 2004 and 2018 were recorded. Primary endpoint was overall survival (OS) from start of donor search. A key secondary endpoint was comparison of OS from the 3-month landmark by donor availability. Accepted donors were matched related donors (MRD), 10/10 matched unrelated donors (MUD), 9/10 compatible unrelated donors (MMUD), and mismatched related donors (MMRD), with haplo donors being used at our institution only since 2014. Results : Altogether a donor search was initiated in 187 patients (DLBCL 32%, FL 17%, MCL 23%, PTCL 28%). Median age was 54 (19-69) years with 74% being male. Within a median time from diagnosis to search initiation of 1.1 (0.1-19) years, a median of 4 (1-9) treatment lines had been administered, including an autoHCT in 50%. 69% of the patients had active disease at the time of search initiation. Only 2 patients underwent donor search in 1st remission (for Richter transformation and hepatosplenic T cell lymphoma, respectively). With a median follow-up of 6.2 (0.6-15.9) years, OS at 5 years after search initiation for DLBCL, FL, MCL, and PTCL was 25%, 44%, 52%, and 50%, respectively (Fig 1). 171 patients (91%) were alive at the 3-month landmark. For these, an MRD (20%), MUD (44%), MMUD (25%), or MMRD (7%) could be identified in 96% of the cases. AlloHCT was performed in 72% of all 187 patients, and in 79% of the patients alive at the 3-month landmark, with a significantly lower rate in DLBCL (69%) compared to the other entities. In patients who were actually transplanted, 5-year OS from landmark for DLBCL, FL, MCL and PTCL was 32%, 63%, 62%, and 62%, respectively, whereas only 5 of the 36 patients (14%) alive at the 3-month landmark not undergoing alloHCT for any reason survived long term. Due to the low rate of unsuccessful searches, donor vs no-donor landmark survival analyses were not possible. Conclusions: Despite donor search now being successful in virtually all cases, 20-30% of those patients intended for alloHCT for NHL will never proceed to transplant. However, long-term OS by ITT does not seem substantially worse than alloHCT outcome observed in registry studies restricted to patients actually transplanted, with DLBCL appearing inferior to the other 3 entities. Patients surviving the 3-month landmark but not undergoing alloHCT for any reason have a poor outlook. These results may serve as benchmark for novel therapeutic options entering the NHL treatment landscape. Disclosures Luft: Neovii: Research Funding; JAZZ: Research Funding. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support. Dreger:Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy.

Increasing Rates of Perioperative Chemotherapy are Associated With Improved Survival in Men With Urothelial Bladder Cancer With Prostatic Stromal Invasion

Our objective was to test whether the rates of perioperative chemotherapy (CHT) administration in patients with urothelial bladder cancer (UCUB) with prostatic stromal invasion (pT4a) changed over time. Moreover, we tested the effect of CHT on overall mortality (OM), as well as on cancer-specific mortality (CSM) in this patient population. Within the Surveillance, Epidemiology, and End Results database (2004-2016), we identified 1513 men with non-metastatic UCUB with prostatic stromal invasion who underwent radical cystectomy with lymph node dissection, with or without CHT administration. Estimated annual percentage change analyses, inverse probability of treatment-weighting (IPTW), Kaplan-Meier plots, Cox regression models, and landmark analyses were performed. Overall, 732 (48.4%) patients with pT4a UCUB disease underwent radical cystectomy with perioperative CHT administration between 2004 and 2016. The CHT administration rate increased from 29.0% in 2004 to 64.8% in 2016 (P< .001). In IPTW-adjusted analyses, the 5-year overall survival was 47.7% versus 39.8%, and cancer-specific survival was 53.6 versus 50.1%, for with versus without CHT administration, respectively. After multivariable and IPTW-adjusted Cox regression models, administration of CHT independently predicted lower OM (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.52-0.73), as well as lower CSM (HR, 0.66; 95% CI, 0.55-0.80). even after 3-month landmark analyses (OM HR, 0.64; 95% CI 0.54-0.76; CSM HR, 0.70; 95% CI, 0.58-0.85). The use of CHT in patients with pT4a UCUB increased from low to moderate in the most contemporary era. However, based on its impressive reduction in OM, as well as in CSM, further increases in CHT administration rates should be highly encouraged in this patient population.

OP-42 - Efficacy of therapeutic plasma exchange in the treatment of multiple myeloma patients with hyperviscosity syndrome: a single-centre experience

To summarize the clinical features and outcomes in Chinese patients with immunoglobulin light-chain (AL) amyloidosis with ≥10% bone marrow plasma cells (BMPCs).We retrospectively compared the clinical features and outcomes between patients with ≥10% BMPCs (high-BMPC group; n = 56) and those with <10% BMPCs (low-BMPC group; n = 311).Patients in the high-BMPC group had significantly higher levels of N-terminal pro-brain natriuretic peptide, significantly lower levels of 24 h urine protein, and significantly higher levels of difference between the involved and uninvolved serum free light chains (485.3 versus 121.1 mg/L, P < 0.001). Patients in the high-BMPC group had significantly higher early mortality within 3 months of diagnosis (21.4% versus 10.9%, P = 0.018). In a 3-month landmark analysis, median progression-free survival durations were 17.3 and 34.5 months (P = 0.01), and the median overall survival durations were 24.4 months and not reached in the high- and low-BMPC groups, respectively (P = 0.005).Patients with AL amyloidosis and ≥10% BMPCs have higher mortality within 3 months of diagnosis and poorer prognosis compared with patients with <10% BMPCs.

Optimal Timing of Adjuvant Therapy in Resected Stage I-II Pancreatic Cancer

For resectable pancreatic cancer, surgery followed by adjuvant chemotherapy or chemoradiation is widely used. Although studies suggest initiation of adjuvant therapy within 12 weeks of surgery, the optimal timing remains unclear. The National Cancer Database was queried for primary stage I-II cT1-3N0-1M0 resected pancreatic adenocarcinoma treated with or without adjuvant therapy (2004-2015). Baseline patient, tumor, and treatment characteristics were obtained. The primary endpoint was overall survival (OS). With a 3-month conditional landmark, restricted cubic spline model, Kaplan-Meier analysis, multivariable Cox proportional hazards method, and propensity score matching were used. Among 7548 patients (n=5453 with adjuvant therapy and n=2095 without adjuvant therapy), Cox model with restricted cubic splines identified the lowest mortality risk when adjuvant therapy was started 28 to 59 days after surgery. This was divided into early (n=269, <28 days), reference interval (n=3048, 28-59 days), and late cohorts (n=2136, >59 days). Median follow-up was 38.6 months (interquartile range 24.4-62.0). Compared to the reference interval cohort on multivariable analysis, both early cohort (HR 1.17, p=0.030) and late cohort (HR 1.09, p=0.0078) were associated with worse mortality. Similarly, the reference interval cohort had improved OS compared to the early cohort (2-year OS 52.5% vs 45.1%, p=0.024) and the late cohort (2-year OS 51.3% vs 45.4%, p=0.011) in 268 and 2042 propensity-matched pairs, respectively. Interaction term analysis showed OS benefit of the reference interval compared to the early cohort among patients with more comorbidities (Charlson-Deyo comorbidity score [CDS] 0-1: HR 0.89, p=0.13; CDS ≥2: HR 0.50, p=0.015) and with unplanned readmission within 30 days postoperatively (no readmission: HR 0.91, p=0.22; unplanned readmission: HR 0.32, p=0.0062; others: HR 1.49, p=0.76). Compared to the late cohort, the OS benefit for the reference interval cohort was seen in patients with smaller tumors (<3.1 cm: HR 0.81, p<0.001; ≥3.1 cm: HR 1.00, p=0.94). Patients who received adjuvant therapy >12 weeks after surgery (n=683) had improved OS compared to surgery alone in both multivariable analysis (HR 0.75, p<0.001) and 655 propensity-matched pairs (2-year OS 47.2% vs 38.0%, p<0.001). Patients who commence adjuvant therapy within 28 to 59 days after primary surgical resection have improved survival outcomes compared to those with adjuvant therapy before 28 days or after 59 days. This result is especially significant among patients with worse comorbidities, unplanned readmission postoperatively, and smaller tumors. Patients who recover slowly from surgery may still benefit from delayed adjuvant therapy initiated beyond 12 weeks postoperatively.

SUN-291 PREDICTIVE FACTORS OF ESA HYPORESPONSIVENESS IN PRE-DIALYSIS CKD PATIENTS: SECONDARY ANALYSIS OF THE RADIANCE-CKD STUDY

Erythropoiesis-Stimulating Agents [ESA] hyporesponsiveness is related to poor renal outcome in management of renal anemia; however, it is difficult to predict which patients will be hyporesponsive. We previously reported on the RADIANCE-CKD study, a multicenter, open-label, randomized controlled study to evaluate renal outcome by different target hemoglobin [Hb] levels using epoetin beta pegol [CERA] in pre-dialysis CKD patients with poor response to ESA (ASN 2018). The aim of the present study was to predict the patients with ESA hyporesponsiveness among pre-dialysis CKD patients. Pre-dialysis CKD patients (362 patients) with poor response to ESA were randomly assigned to an intensive treatment group (I-group; target Hb level of ≥11 g/dl) or a conservative treatment group (C-group; target Hb level of baseline Hb ±1g/dl). The primary renal composite endpoint was a transition to renal replacement therapy, reduction of eGFR to <6 ml/min/1.73 m2, or >30% reduction of eGFR. In the 3-month landmark analysis, the incidence of renal outcome was evaluated in 3 categories of Hb levels (<10, 10 to <11, ≥11 g/dl) according to tertiles of ESA dose. ESA hyporesponsiveness patients (HYPO) were defined as achieved Hb level <11 g/dl with high tertile and achieved Hb level <10 g/dl with mid-tertile in I-group. The predictive factors of hyporesponsiveness patients were then assessed using a logistic regression model and estimated area under the receiver operating characteristic (ROC) curve. Mean age was 74.7 years and 58.6% of patients were male. Mean baseline eGFR in I-group and C-group were 15.3 and 15.9 ml/min/1.73 m2, respectively. Kaplan-Meier analysis and Cox proportional hazards analysis showed no significant difference in the primary end point between the two groups (99 and 109 events) during the 21-month observation period. In the 3-month landmark analysis, achieved Hb level and required ESA dose were higher in I-group. The incidence of the renal composite endpoint had a tendency to increase in accordance with decrease of Hb levels regardless of the ESA dose in both groups. A total of 30 (54.5%) HYPO patients had the renal composite endpoint, as compared with 54 (50.9%) non-HYPO. Based on the logistic regression analysis, 19 background characteristics (age, BW, eGFR, Alb, ferritin, Hb, CRP, etc.) and 14 biomarkers (IL-6, Hepcidin, TGFβ, CD147, PTH, 25Vitamin-D, etc.) were evaluated as predictive factors of HYPO. The obtained area under the ROC curve (AUC) was 0.88, with sensitivity of 84% and specificity of 84%. Using a branch-and-bound algorithm to find the highest likelihood score statistic for 6 variables, the selected variables were age, Hb, Hepcidin, TGFβ, CD147, and PTH; then, the estimated AUC was 0.82. The patients with ESA hyporesponsiveness among Japanese CKD patients can be predicted based on clinical characteristics and biomarkers in pre-dialysis.

Alpha-Fetoprotein, Des-Gamma-Carboxy Prothrombin, and Modified RECIST Response as Predictors of Survival after Transarterial Radioembolization for Hepatocellular Carcinoma

PurposeTo evaluate the prognostic role of alpha-fetoprotein (AFP), des-gamma-carboxy protein (DCP), and modified Response Evaluation Criteria in Solid Tumors (mRECIST) in patients with hepatocellular carcinoma after transarterial radioembolization (TARE). Materials and MethodsDuring 2009–2016, 63 patients with AFP >20 ng/mL, DCP >20 mAU/mL, and Child-Pugh class A who were treated with TARE were evaluated using landmark and risk-of-death method after TARE. Both resin microspheres (n = 46) and glass microspheres (n = 17) were used. AFP or DCP response was defined as more than 50% decrease from baseline. mRECIST response was defined as complete or partial response. Median age was 60 years, and the proportion of male sex was 77.8% (n = 49). The proportions of patients with Barcelona Clinic Liver Cancer stages A, B, and C were 7.9% (n = 5), 46.0% (n = 29), and 46.0% (n = 29), respectively. ResultsAt the 3-month landmark, AFP, DCP, and mRECIST responders lived longer than nonresponders (median overall survival, 75.8 vs 7.6 months for AFP; 75.8 vs 7.1 months for DCP; and 75.8 vs 10.0 months for mRECIST; all P < .05). The 6-month risk of death at the 3-month landmark was statistically different only between DCP responders and nonresponders (P = .002). In multivariate analysis, age less than 70 years (P = .024), absence of distant metastasis (P = .049), DCP response (P = .003), and mRECIST response (P = .003) were independent predictors for overall survival at the 3-month landmark after TARE. ConclusionsAFP, DCP, and mRECIST responders showed better prognosis than nonresponders after TARE, and DCP response was a more potent predictor than AFP response. Tumor marker response, as well as radiologic response, may be useful to predict post-TARE survival.

Clinical presentation and prognosis of immunoglobulin light-chain amyloidosis with high percentage of bone marrow plasma cells

ObjectiveTo summarize the clinical features and outcomes in Chinese patients with immunoglobulin light-chain (AL) amyloidosis with ≥10% bone marrow plasma cells (BMPCs). MethodsWe retrospectively compared the clinical features and outcomes between patients with ≥10% BMPCs (high-BMPC group; n = 56) and those with <10% BMPCs (low-BMPC group; n = 311). ResultsPatients in the high-BMPC group had significantly higher levels of N-terminal pro-brain natriuretic peptide, significantly lower levels of 24 h urine protein, and significantly higher levels of difference between the involved and uninvolved serum free light chains (485.3 versus 121.1 mg/L, P < 0.001). Patients in the high-BMPC group had significantly higher early mortality within 3 months of diagnosis (21.4% versus 10.9%, P = 0.018). In a 3-month landmark analysis, median progression-free survival durations were 17.3 and 34.5 months (P = 0.01), and the median overall survival durations were 24.4 months and not reached in the high- and low-BMPC groups, respectively (P = 0.005). ConclusionPatients with AL amyloidosis and ≥10% BMPCs have higher mortality within 3 months of diagnosis and poorer prognosis compared with patients with <10% BMPCs.

One-year clinical outcome of biodegradable polymer sirolimus-eluting stent in patients needing short dual antiplatelet therapy. Insight from the ULISSE registry (ULtimaster Italian multicenter all comerS Stent rEgistry)

BackgroundThis study aimed to evaluate real-world clinical outcome of patients needing short dual antiplatelet therapy (S-DAPT) following PCI with Ultimaster® thin-strut, biodegradable polymer sirolimus-eluting stent (BP-SES), which was supposed to induce faster stent endothelialization and reduce device thrombogenicity. MethodsIn this sub-group analysis of patients enrolled in the ULISSE registry, two groups were identified: 1) patients discharged with S-DAPT (≤3-month) due to high bleeding risk or need for urgent major non-cardiac surgery and 2) patients discharged with recommended DAPT (R-DAPT) duration (≥6-month). The primary ischemic-safety and bleeding-safety endpoints were TLF (composite of cardiac-death, target vessel MI, and clinically driven target lesion revascularization), and BARC major bleedings (≥type-3a) at 1-year follow-up. To account for events occurring before DAPT discontinuation we performed 3-month landmark analysis. Results82 patients (5%) were discharged with ≤3-month DAPT (57 ± 27 days), and 1558 patients (94%) were discharged with ≥6-month DAPT (318 ± 75 days). No significant differences between S-DAPT and R-DAPT group were observed in TLF at 1-year (7.9% vs. 4.6%). The rate of BARC major bleeding resulted significantly higher in S-DAPT group (3.9% vs. 0.3%; p = 0.001), with the majority of bleeding events occurring within 3 months. The landmark analysis showed no significant differences in BARC major bleedings between groups (1.4% vs. 0.3%; p = 0.142). ConclusionsAs compared to those treated with R-DAPT (≥6-month), patients needing -S-DAPT (≤3-month) after PCI with Ultimaster® BP-SES had similar rates of 1-year TLF and BARC major bleedings following early DAPT discontinuation.

Strides Toward Improving Post-Hematopoietic Progenitor Stem Cell Transplant Vaccination Compliance

Topic Significance & Study Purpose/Background/Rationale Hematopoietic stem cell transplant (HCT) recipients are at risk for losing natural and acquired immunities, that can lead to post-HCT infectious complications. Post-HCT re-vaccination is considered a standard of care by FACT and NMDP. The current work is a quality improvement project to improve vaccination compliance. Programmatic deficiencies were identified and a Plan Do Study Act (PDSA) was implemented. Methods, Intervention, & Analysis A retrospective audit of recipient charts was performed for vaccination schedule completion and compliance by September 30, 2016. The audit is a snapshot of patients that have received vaccines at the scheduled intervals or completed the full vaccination schedule. Compliance was defined as completion of scheduled vaccination within 3 months of target date unless otherwise documented. Relapse, delayed, held for GVHD/immunosuppressant's or steroids, and refusal with proper documentation are considered complaint. Deceased patients within 3 months of target date were excluded. Overall compliance is defined as: at the 24-month landmark, which patients have received vaccinations at all landmarks based on the compliance guidelines. 21-months after implementing the PDSA, recipient charts were audited for vaccination schedule completion and compliance by June 30, 2018. Findings & Interpretation Identified deficiencies included an infrastructure that did not allow for vaccinations to be given in the same clinic as the patient's appointment with their transplant physician, lack of communication between the clinics, inconsistent orders and documentation, and a lack of knowledge with staff and patients. The PDSA interventions included a standardized vaccination order sheet, appointment identification, staff and patient education, reminder cards, and policy updates. After implementing the PDSA, the overall compliance has increased from 56.7% to 72% and overall completion has increased from 76% to 83.8% over a 21-month period. Discussion & Implications Vaccination compliance requires standardization of practices, effective communication, and adequate documentation when caring for post-transplant patients. Success of a post transplantation vaccination program requires unwavering commitment to provide support and oversight for effective vaccination strategies. Retrospective vaccination chart audits continue quarterly to achieve an 80% compliance rate.

Viral and other therapies for recurrent glioblastoma: is a 24-month durable response unusual?

A phase I trial of an engineered poliovirus for the treatment of recurrent glioblastoma (GBM) has attracted attention due to 8 survivors reaching the 24-month and 5 reaching the 36-month survival landmarks.1 Genetically engineered viruses (oncolytic viruses) have been in trials for GBM for almost two decades.2 These replication-competent (tumor-selective, oncolytic, replication-conditional) viruses or replication-defective viral vectors (gene therapy) deliver cytotoxic payloads to tumors, leading to immunogenic death and intratumoral inflammatory responses. This transforms the tumor microenvironment from immunologically naïve ("cold") to inflamed ("hot"), increasing immune cell recognition of tumor antigens and the durable responses observed in virotherapy.3,4 Several current and past virotherapy trials have reported a "tail" of apparent responders at the 24-month landmark. Other modalities have also reported a "tail" of seemingly long-term survivors. These trials seem to show that these responder "tails" characterize a defined subset of GBM patients.

Evaluating Nationwide Practice Patterns in Chemoradiotherapeutic Regimens and Relative Efficacy of Chemoradiation Versus Adjuvant Radiation for Grade III Gliomas

For newly diagnosed Grade III gliomas including anaplastic oligodendrogliomas (AO), anaplastic astrocytomas (AA) and anaplastic oligoastrocytomas (AOA), combined chemoradiotherapy (CRT) remains the current standard of care. Two landmark trials established multiagent (MA) chemoradiotherapy using PCV as first-line for 1p/19q-codeleted tumors. However, single-agent (SA) CRT using temozolomide is an alternative off-label option. Recently, interim analysis of CATNON confirmed that temozolomide-based SA-CRT offers significant survival benefit for 1p/19q-noncodeleted tumors. Here, we evaluated nationwide patterns in receipt of CRT and relative treatment efficacies for Grade III gliomas using the National Cancer Database (NCDB). Patients with a first primary diagnosis of AO, AA or mixed glioma treated from 2006-2014 were identified from the NCDB. WHO Grade III glioma patients were identified whose initial treatment courses involved surgery with or without adjuvant RT (55-63 Gy in 25-34 fractions) or CRT. Factors examined included facility type, location, age, sex, race, Charlson-Deyo score, median income, insurance and extent of resection (EoR). Overall survival was assessed by Kaplan-Meier and Cox proportional hazards modeling. Potential predictors of MA- vs SA-CRT were examined using multivariate logistic regression. Adjusted survival comparison was performed using propensity score matching. From a total of 21,877 AO, AA and mixed gliomas, 4,553 WHO Grade III glioma patients were identified that met inclusion criteria. Median age was 47. Most patients (72.5%) received combined chemoradiotherapy, while a minority received only adjuvant RT (8.1%). At a median follow-up of 4.6 years, median survival was 88.3, 59.1, and 32.5 months for patients treated with chemoradiation, adjuvant RT or surgery alone, respectively (p<0.001), which remained significant on 1- and 3-month landmark analyses. On multivariate analysis, factors associated with improved survival included EoR, adjuvant RT and receipt of chemotherapy along with AO or mixed glioma histology, younger age, non-Medicare status, lower Charlson-Deyo score and higher median income. Among 3200 patients who received chemoradiation using known number of chemotherapeutic agents, 3,088 (96.5%) received SA chemotherapy while only 112 (3.5%) received MA chemotherapy. Only EoR was associated with receipt of multi-agent chemotherapy (OR: 3.22 for STR vs. biopsy). Propensity score matched analysis detected no significant median survival difference between patients receiving SA vs. MA CRT (44.0 months vs. 53.6 months, p=0.36). Independent of WHO Grade III histology, chemoradiation was associated with improved survival. Interestingly, despite only recent randomized data confirming its efficacy, SA-CRT was much more frequently offered than MA-CRT nationwide. Further study is needed regarding relative efficacy, particularly for 1p/19q-codeleted tumors.

Investigating Nationwide Usage Trends and Relative Efficacy of Combined Modality Treatments for Elderly Glioblastoma Patients

For well-functioning glioblastoma (GBM) patients under 65 years old, long-course chemoradiotherapy (LC-CRT) remains standard of care. For elderly patients, early trials established efficacy of hypofractionated radiation alone. More recent data demonstrated that short-course chemoradiation (SC-CRT) improves survival over short-course RT alone. Here, we investigated nationwide treatment patterns and relative outcomes for SC- vs. LC-CRT using the National Cancer Database (NCDB). Patients aged ≥65 with a first primary diagnosis of GBM treated from 2006-2014 who underwent surgery with or without adjuvant LCRT (58-63 Gy in 28-34 fractions) or SCRT (34-42 Gy in 10-15 fractions) were identified from the NCDB. Factors examined included facility type, location, age, sex, race, Charlson-Deyo score, median income, insurance, tumor size, extent of resection (EoR) and chemotherapy. Overall survival was assessed using Kaplan-Meier and Cox proportional hazards modeling. Multivariate logistic regression was used to characterize predictors of SC-CRT versus LC-CRT. Propensity score matching was performed for adjusted survival comparison. From 107,956 GBM cases, 12,688 elderly patients were identified that met inclusion criteria. Median age was 72 with median follow-up of 48.3 months. A total of 7358 (58%) received chemotherapy. 7187 (56.6%) and 433 (3.4%) received LCRT and SCRT, respectively. Median survivals were 11.9, 6.9 and 3.0 months for patients who received LCRT, SCRT or no RT (p<0.001), respectively, which remained significant on 1- and 3-month landmark analyses. On multivariate regression, age, Charlson-Deyo score, tumor size, EoR, receipt of RT, receipt of chemotherapy, median income, race and treatment at academic facility were significantly associated with survival. Notably, LCRT was associated with lower mortality risk than SCRT (HR: 1.261 for SCRT vs. LCRT, 95% CI: 1.135-1.402). Among 6935 patients who underwent chemoradiation, 96.2% received LC-CRT and 3.8% received SC-CRT. Factors associated with receipt of SC-CRT included treatment at academic facility (OR: 2.6), old age (OR: 3.3 for 75-84 years old, OR: 8.9 for age ≥85), insurance status (OR: 0.232 for private vs. uninsured), lower median income, EoR (OR: 0.42 for undocumented) and brainstem involvement (OR: 14.1 vs. supratentorial). On propensity score matched analysis, long-course CRT was associated with significant survival benefit over short-course CRT (11.4 months vs. 9.1 months, p < 0.005). In this registry-based study of elderly GBM patients, factors associated with receipt of long-course over short-course CRT included younger age, supratentorial location, treatment at a non-academic facility, facility location, greater median income and private insurance. Even after adjustment for covariates, LC-CRT was associated with improved survival over SC-CRT.

Comparison of Early and Long-Term Outcomes After Transcatheter Aortic Valve Implantation in Patients with New York Heart Association Functional Class IV to those in Class III and Less

Our aim was to investigate the impact of a baseline New York Heart Association (NYHA) class IV on clinical outcomes of a large real-world population who underwent transcatheter aortic valve implantation (TAVI). The primary end points were all-cause mortality, cardiovascular mortality, and re-hospitalization, evaluated at the longest available follow-up and by means of a 3-month landmark analysis. The secondary end points were: change in NYHA class, left ventricular ejection fraction, pulmonary pressure and mitral regurgitation. Out of 2,467 patients, 271 (11%) had a NYHA functional class IV at the admission. The latter had higher Society of Thoracic Surgeons (STS) score (9.2% vs 5.5%; p < 0.001) compared to NYHA ≤ III patients, owing to more comorbidities (prior myocardial infarction, severe long-term kidney disease, atrial fibrillation, left ventricular dysfunction, significant mitral regurgitation, pulmonary hypertension). Device success was similar between the two groups (93.7% vs 94.5%; p = 0.583). At a median follow-up of 15 months (interquartile range 4 to 36 months) a lower freedom from primary end points was observed among NYHA IV versus NYHA ≤ III group (survival from all-cause death: 52% vs 58.4%; p = 0.002; survival from cardiovascular death: 72.5% vs 76.5%; p = 0.091; freedom from re-hospitalization: 81.5% vs 85.4%; p = 0.038). However, after adjustment for baseline imbalance, NYHA IV did not influence the relative risk of long-term primary end points. A 3-month landmark analysis showed that NYHA IV independently predicted 3-month all-cause and cardiovascular mortality (hazard ratio: 1.77; 95% CI [1.10 to 2.83]; p = 0.018 and hazard ratio: 1.64; 95% CI [1.03 to 2.59]; p = 0.036, respectively). Instead, after 3-month follow-up NYHA IV did not affect the risk of primary end points. A significant improvement of the secondary end points was noted in both NYHA IV and NYHA ≤≤ III groups. In conclusion, the presence of NYHA class IV in TAVI candidates was associated to a significant increased risk of mortality within 3 months. Patients with baseline NYHA IV who survived at 3 months had a long-term outcome comparable to that of other subjects. Left ventricular systolic function, pulmonary pressure, and mitral insufficiency significantly improved after TAVI regardless of baseline NYHA class IV.

Long-Term Survival of Young Patients Surviving ICU Admission With Severe Sepsis.

Sepsis remains a disease with a high mortality rate. The study goal was to assess long-term survival of severe sepsis in young patients. Retrospective cohort study. Patients admitted with sepsis to ICUs in seven tertiary hospitals between 2003 and 2011. A total of 409 patients less than 45 years who survived to hospital discharge were age and sex matched with 818 patients with infectious disease without sepsis selected from internal medicine or surgical department admissions. None. The median age in sepsis patients and the comparison group was 31 and 32 years, respectively. The proportions of patients surviving after hospital discharge were significantly lower in the sepsis group compared with the control group; among survivors, 6-month, 1-year, and 3-year mortality rates were 0.7% versus 0%, 4.5% versus 0.7%, 7.9% versus 1.2%, and 10.8% versus 1.8%, respectively (p < 0.001 for all). In a multivariate Cox proportional hazards regression model, sepsis was associated with an increased risk of mortality (hazard ratio, 3.79; 95% CI, 2.27-6.32), while controlling for age, Charlson Comorbidity Index, history of stroke, and congestive heart failure. Past the 24-month landmark, sepsis was not found to be an independent risk for mortality (hazard ratio, 1.79; 95% CI, 0.67-4.79). Based on cause of death analysis, chronic underlying comorbidities might explain the excess mortality in patients with sepsis. Young patients experiencing an episode of severe sepsis continue to be at higher risk of long-term mortality. The highest mortality rates were observed during the first 24 months following discharge.

Time to Surgery: a Misguided Quality Metric in Early Stage Pancreatic Cancer

BackgroundLonger time to surgery is associated with worse outcomes in several cancers. We sought to identify disparities in time from diagnosis to surgery in pancreatic cancer and whether delays to surgery correlated with worse survival. MethodsThe US National Cancer Database (2003–2011) was reviewed for patients with clinical stages I–II pancreatic adenocarcinoma who underwent surgical resection. Patients who received neoadjuvant therapy were excluded. Linear regression, Kaplan-Meier analyses, and Cox regression were performed as 3-month landmark analyses. ResultsOf the 14,807 patients included, 37.8% underwent resection ≤ 1 week, 13.7% 1–2 weeks, 25.4% 2–4 weeks, 19.5% 4–8 weeks, and 3.7% 8–12 weeks. Older age, Medicare coverage, greater distance from hospital, treatment at an academic center, and greater comorbidities were associated with increased time. After excluding patients treated within 1 week of diagnosis and controlling for patient, disease, and treatment characteristics, greater time was not associated with worse survival (2–4, HR 1.03, P=0.399; 4–8, HR 0.98, P=0.529; 8–12, P=0.123). ConclusionsFor patients with stages I–II pancreatic adenocarcinoma, there are disparities in surgical wait times. However, earlier initiation of surgical resection within 12 weeks of diagnosis is not associated with a survival benefit. This suggests that allowing time for confirmatory testing and optimization in preparation for surgery may not negatively impact survival.

Abstract No. 541 Radiologic response as a potential surrogate endpoint to overall survival in hepatocellular carcinoma patients undergoing radioembolization

To study the ability of post-radioembolization imaging response to predict overall survival in hepatocellular carcinoma (HCC). With IRB approval, we searched our prospectively acquired HCC database. 948 patients with HCC were treated with radioembolization (Y90) from 2003-2016. Patients with baseline metastases, vascular invasion, multifocal disease, Child-Pugh (CP) >B7, and transplanted/resected were excluded. This created our homogeneous study cohort of 134 patients with CP ≤B7 and solitary HCC. Response (using European Association for Study of the Liver [EASL] and Response Evaluation Criteria in Solid Tumors 1.1 [RECIST 1.1] criteria) was correlated with survival using Landmark and risk-of-death methodologies after reviewing 960 scans. Patients who showed complete or partial response to treatment at specific landmarks were considered as responders. In a subanalysis, survival times of responders were compared to those of patients with stable disease (SD) and progressive disease (PD). Uni/multivariate survival analyses were performed at each Landmark. At the 3-month landmark, responders survived longer than nonresponders by EASL (hazard ratio [HR], 0.46; confidence interval [CI], 0.26-0.82; P = 0.002) but not RECIST 1.1 criteria (HR, 0.70; CI, 0.37-1.32; P = 0.32). At the 6-month Landmark, responders survived longer than nonresponders by EASL (HR, 0.32; CI, 0.15-0.77; P< 0.001) and RECIST 1.1 criteria (HR, 0.50; CI, 0.29-0.87; P = 0.021). At the 12-month Landmark, responders survived longer than nonresponders by EASL (HR, 0.34; CI, 0.15-0.77; P< 0.001) and RECIST 1.1 criteria (HR, 0.52; CI 0.27-0.98; P = 0.049). At 6 months, risk of death was lower for responders by EASL (P< 0.001) and RECIST 1.1 (P = 0.0445). In subanalyses, responders lived longer than patients with SD or PD. EASL response was a significant predictor of survival at 3-, 6-, and 12-month Landmarks on uni/multivariate analyses. Response to Y90 in patients with solitary HCC can prognosticate improved survival. EASL necrosis criteria outperformed RECIST 1.1 size criteria in predicting survival. The therapeutic objective of radioembolization should be radiologic response and not solely to prevent progression.

Pulmonary Arterial Hypertension-Related Morbidity Is Prognostic for Mortality

BackgroundRegistry data suggest that disease progression in pulmonary arterial hypertension (PAH) is indicative of poor prognosis. However, the prognostic relevance of PAH-related morbidity has not been formally evaluated in randomized controlled trials. ObjectivesThe purpose of these analyses was to assess the impact of morbidity events on the risk of subsequent mortality using the landmark method and data from the SERAPHIN and GRIPHON studies. MethodsFor each study, the risk of all-cause death up to the end of the study was assessed from the landmark time point (months 3, 6, and 12) according to whether a patient had experienced a primary endpoint morbidity event before the landmark. Each analysis was conducted using data from all patients who were available for survival follow-up at the landmark. ResultsIn the SERAPHIN study, on the basis of the 3-month landmark time point, patients who experienced a morbidity event before month 3 had an increased risk of death compared with patients who did not (hazard ratio [HR]: 3.39; 95% confidence interval [CI]: 1.94 to 5.92). In the GRIPHON study, on the basis of the 3-month landmark time point, there was also an increased risk with a HR of 4.48; (95% CI: 2.98 to 6.73). Analyses based on 6-month and 12-month landmarks also showed increased risk in patients who experienced morbidity events, albeit with a reduced HR. ConclusionsThese results demonstrate the prognostic relevance of PAH-related morbidity as defined in the SERAPHIN and GRIPHON studies, highlighting the importance of preventing disease progression in patients with PAH and supporting the clinical relevance of SERAPHIN and GRIPHON morbidity events. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension [SERAPHIN]; NCT00660179; Selexipag [ACT-293987] in Pulmonary Arterial Hypertension [GRIPHON]; NCT01106014)

Immune-Related Tumor Response Dynamics in Melanoma Patients Treated with Pembrolizumab: Identifying Markers for Clinical Outcome and Treatment Decisions.

Purpose: Characterize tumor burden dynamics during PD-1 inhibitor therapy and investigate the association with overall survival (OS) in advanced melanoma.Experimental Design: The study included 107 advanced melanoma patients treated with pembrolizumab. Tumor burden dynamics were assessed on serial CT scans using irRECIST and were studied for the association with OS.Results: Among 107 patients, 96 patients had measurable tumor burden and 11 had nontarget lesions alone at baseline. In the 96 patients, maximal tumor shrinkage ranged from -100% to 567% (median, -18.5%). Overall response rate was 44% (42/96; 5 immune-related complete responses, 37 immune-related partial responses). Tumor burden remained <20% increase from baseline throughout therapy in 57 patients (55%). Using a 3-month landmark analysis, patients with <20% tumor burden increase from baseline had longer OS than patients with ≥20% increase (12-month OS rate: 82% vs. 53%). In extended Cox models, patients with <20% tumor burden increase during therapy had significantly reduced hazards of death [HR = 0.19; 95% confidence interval (CI), 0.08-0.43; P < 0.0001 univariate; HR = 0.18; 95% CI, 0.08-0.41; P < 0.0001, multivariable]. Four patients (4%) experienced pseudoprogression; 3 patients had target lesion increase with subsequent response, which was noted after confirmed immune-related progressive disease (irPD). One patient without measurable disease progressed with new lesion that subsequently regressed.Conclusions: Tumor burden increase of <20% from the baseline during pembrolizumab therapy was associated with longer OS, proposing a practical marker for treatment decision guides that needs to be prospectively validated. Pseudoprogressors may experience response after confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluations. Evaluations of patients without measurable disease may require further attention. Clin Cancer Res; 23(16); 4671-9. ©2017 AACR.

Novel pathologic scoring tools predict end-stage kidney disease in light chain (AL) amyloidosis

Background and objectives: Light chain (AL) amyloidosis frequently involves the kidney, causing significant morbidity and mortality. A pathologic scoring system with prognostic utility has not been developed. We hypothesized that the extent of amyloid deposition and degree of scarring injury on kidney biopsy, could provide prognostic value, and aimed to develop pathologic scoring tools based on these features.Methods: This is a case-control study of 39 patients treated for AL amyloidosis with biopsy-proven kidney involvement at a large academic medical center. Our novel scoring tools, composite scarring injury score (CSIS) and amyloid score (AS) were applied to each kidney biopsy. The primary outcome was progression to dialysis-dependent end-stage kidney disease (ESKD) using a 12-month landmark analysis.Results: At 12 months, nine patients had progressed to ESKD. Patients with an AS ≥7.5 had a significantly higher cumulative incidence of ESKD than those with AS <7.5 (p = .04, 95% CI 0.13–0.64).Conclusions: Using a 12-month landmark analysis, AS correlated with progression to ESKD. These data suggest that a kidney biopsy, in addition to providing diagnostic information, can be the basis for a pathologic scoring system with prognostic significance.