non-CR Patients Research Articles

Tu1188 EFFICACY OF PHOTODYNAMIC THERAPY WITH A NEW PHOTOSENSITIZER (TALAPORFIN SODIUM) AS A SALVAGE TREATMENT FOR LOCAL FAILURE AFTER DEFINITIVE CHEMORADIOTHERAPY FOR ESOPHAGEAL CANCER.

Esophageal cancer is one of the most common cancers worldwide. Chemoradiotherapy (CRT) is one of the curative treatments for esophageal cancer in patients with unresectable tumors or those who refuse surgery. However, local failure after CRT is a problem. An alternate treatment in such patients is photodynamic therapy (PDT). Talaporfin sodium, a second-generation photosensitizer, is rapidly cleared from the skin and requires a shorter sun-shade period (2 weeks). Furthermore, the depth of effect is expected to extend to deeper layers of the muscularis propria because of the excitation wavelength of the diode laser. In this study, we evaluated the efficacy of PDT with talaporfin sodium for local failure after CRT for esophageal cancer. Patients with histologically proven local failure limited within the muscularis propria after radiotherapy (RT) of 50 Gy or more for esophageal cancer were eligible.The PDT procedure commenced with intravenous administration of a 40 mg/m2-dose of talaporfin sodium, followed by laser irradiation at a 664-nm wavelength 4 to 6 hours after administration. The fluence of the diode laser was set at 100 J/cm2. The local efficacy was classified based on endoscopic evaluation as local complete response (L-CR). The L-CR rate per patients was the primary endpoint of this study. The secondary endpoints were local progression-free survival (L-PFS), and overall survival (OS). 14 patients with a total of 20 lesions received additional laser irradiation. The median total laser exposure dose was 210 (range: 100–800) J. 11 patients with a total of 16 lesions achieved L-CR after PDT (L-CR rate: 80.0%). The L-CR rate of T1 failure lesions was 92.3% (12/13), whereas the L-CR rate of T2 failure lesions was 57.1% (4/7). The median follow up period was 11.6 months (range: 1.3-38). 3 non-CR patients with PDT developed progression and one of them died at 697 days after PDT. 1 CR patient developed local recurrence 94 days after PDT and received salvage surgery. The other 2 patients died due to other cancers at 113 days, and 326 days after PDT. Therefore, 6 events were confirmed for the L-PFS curve at present, and the median L-PFS was 326 days. As for OS, only 3 events described earlier were observed, and thus the median survival is undefined for this follow up period. Chest pain was occurred in 4 patients (28.6%), while fever (38°C) occurred in 2 patients (14.3%). No skin phototoxicity was observed. 2 patients (14.3%) developed an esophageal perforation and were managed with non-surgical measures. There was no case of treatment-related death. PDT using talaporfin sodium and a diode laser is a safe and curative salvage treatment for local failure after CRT for patients with esophageal cancer. The possibility of esophageal perforation after PDT should be considered for longer than 1 month post-therapy.

The role of interim FDG PET-CT after induction chemotherapy as a predictor of concurrent chemoradiotherapy efficacy and prognosis for head and neck cancer

PurposeInduction chemotherapy (ICT) with docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiotherapy (CCRT) has the advantages of organ preservation and systemic control in head and neck cancer (HNC). Early prediction of CCRT efficacy may help identify patients who will benefit more from surgery than from CCRT. We investigated the role of interim 18-fluoro-2-deoxy-glucose positron emission tomography computed tomography (FDG PET-CT) after ICT to predict the efficacy of CCRT and clinical outcomes.MethodsTumor responses were retrospectively reviewed after CCRT based on the Response Evaluation Criteria in Solid Tumors. FDG PET-CT imaging was performed before and after three cycles of TPF. We examined the associations between the metabolic response (percentage decrease in the maximum standardized uptake value [SUVmax] and total metabolic tumor volume [MTV]) after ICT and complete response (CR) to CCRT, progression-free survival (PFS), and overall survival (OS).ResultsWe studied 43 HNC patients with a median follow-up of 32.7 months. Lymph node (LN) SUVmax and total MTV decreases from baseline after ICT were greater in patients with a CR to CCRT than in non-CR patients (LN SUVmax, 88.8% vs. 62.5%, respectively; total MTV, 99.7% vs. 89.9%, respectively). Decreases in total MTV ≥ 78% and LN SUVmax ≥73% after ICT predicted CR to CCRT and longer OS and PFS.ConclusionsUsing interim FDG PET-CT to measure SUVmax and total MTV after three cycles of ICT may be a useful technique for identifying HNC patients who will benefit from CCRT and predicting survival outcomes.

Isolated limb perfusion for locally advanced angiosarcoma in extremities: A multi-centre study

BackgroundAngiosarcomas are rare and aggressive soft-tissue sarcomas. The only potential curative treatment is complete surgical excision. This study reports the outcome of isolated limb perfusion (ILP) with high-dose melphalan and tumour necrosis factor α for locally advanced angiosarcoma. Material and methodsAll patients who underwent an ILP for angiosarcomas between 1991 and 2016 in three tertiary referral centres were identified from prospectively maintained databases. ResultsA total of 39 patients were included, with a median follow-up of 18 months (interquartile range 6.1–60.8). Of these patients, 23 (58.9%) patients had a complete response (CR) after ILP, 10 (25.6%) had a partial response, 4 (10.3%) had stable disease and 2 (5.1%) patients had progressive disease immediately after ILP. A total of 22 patients developed local progression (56.4%), whereas nine (23.1%) developed distant metastases. The patients with CR had a significantly prolonged median local progression-free survival (PFS) (15.4 versus 7.3 months, p = 0.015) when compared with non-CR patients, and a trend towards better median overall survival (81.2 versus 14.5 months, p = 0.054). Six patients underwent multiple ILPs, whereby the CR rate of the first, second and third ILPs were 60%, 80% and 67%, respectively. Thirteen (33.3%) patients needed further surgical intervention, consisting of resection in eight patients (20.5%) and amputation in five patients (12.8%). ConclusionILP is an effective treatment option for patients with locally advanced angiosarcoma in the extremities, resulting in a high number of CRs, a high limb salvage rate and prolonged local PFS.

Biological Characteristics and Therapeutic Efficacy of 103 Patients with Acute Erythroleukemia

To investigate the biological characteristics and therapeutic efficacyt of acute erythroleukemia (AEL,AML-M6). Blood cell count, liver function, lactate dehydrogenase level, coagulation, morphology, immunology, cell genetics and molecular biology were retrospectively analyzed in 103 cases of acute erythroleukemia patients admitted in our department from May 2016 to June 2009. The therapeutic efficacy was observed by means of remission rate, relapse rate, relapse-free survival and overall survival. The medians of white blood cells, granulocyte, hemoglobin and platelet were 3.04×109/L, 0.67×109/L, 66 g/L, and 45×109/L,respectively. Nucleated red blood cells were found in the peripheral blood smears from 71.1% of AEL patients. None of the patients showed abnormal coagulation function. Flow cytometry analysis indicated that CD13 (93.5%),CD117(89.1%), HLA-DR(87.0%), and CD34 (80.0%) were highly expressed in AEL, and lymphoid antigens of CD4 (42.9%) and CD7(28.9%) were expressed in partial patients. Karyotype analysis in 82 patients showed 52.4% (43/82) normal karyotype, 41.5% (34/82) abnormal karyotype, and 6.1% (5/82) failed tests. In the 34 cases with abnormal karyotype, there were 14(41.2%) cases with simple chromosomal abnomality and 20(58.8%) cases with complex karyotype. The positive rate of fusion gene accounted for 16.7% in 60 patients, and the gene mutations accounted for 77.8% in 27 patients. Among 103 cases of AEL, 81 cases were treated with chemotherapy, but 66 cases can be used for therapeutic analysis, as a results the total complete remission rate derived from 2 courses of treatment was 45.5% (30/66). The relapse rate was 36.7% (11/30), and the median relapse time was 15.5 months (6.2-50 months). The median survival time of 66 patients for therapeutic analysis was 29 months. The median survival time of CR patients was very significantly longer than that of the non-CR patients(P=0.001). The 5 year survival rate of CR patients was 65%, the median time of relapse-free survival (RFS) was 46.2 months and 3-years RFS was 58%. AEL is characterized by the highly expressed CD34 antigen, and complex karyotype. Although AEL has lower CR rate and poor prognosis, CR patients can achieve long-term survival and have good quality of life.

Cell surface GRP78 expression on T and NK cell sub-populations of breast cancer patients.

11561 Background: The targeting of unfolded protein response (UPR) in tumor cells has received much attention. However, data are sparse on the impact of UPR on T and NK cells. The master regulator of UPR is the glucose-regulated protein 78 (GRP78) that is expressed in some tumor cells or normal stressed cells. There are few studies concerning GRP78 expression on T and NK cells in cancer and its relationship to stress induction by chemotherapy. We aimed to reveal the effect of UPR activation on the peripheral T and NK cells of breast cancer patients by the evaluation of cell surface GRP78 expression on T and NK cells before and after neoadjuvant chemotherapy. Methods: Forty-seven patients with triple negative, ER positive/Her2 negative and Her2 positive breast cancer were included. FACS analysis of their blood specimens before and after neoadjuvant treatment was performed. For multicolor FACS analysis, anti-CD3, CD4, CD8, CD56, CD16, NKG2D, CD45RA, CD45RO, CCR7 CD62L and anti-GRP78 antibody (AF488) were added to one of the tubes. A second tube was incubated with IgG-AF488 as isotype control. Analysis of the different T and NK subpopulations that expressed cell surface GRP78 were analyzed with the Gallios Flow cytometer and Kaluza Flow Analysis Software (Beckman Coulter, Inc.). Results: The percentage of cell surface GRP78 baseline expression in CD3 (1.8±0.9), CD8 (2.9±1.5), NKG2D (4.8±2) and CD45RO/CD62L/CCR7 active T memory cells (2.1±0.5) in Her2 positive patients were significantly higher than in triple negative and ER positive/Her2 negative patients. GRP78 expression on CD56, CD16 and NKG2D cells measured after neoadjuvant treatment was significantly higher in patients with complete response (CR) compared to patients without CR. 89% of the CR patients presented with Her2+ subtype. The non-CR patients include triple negative and Her2 negative subtypes. Conclusions: GRP78 was found to be expressed in the different T and NK sub-populations. The level of expression changed with each breast cancer subtype and response to chemotherapy. These novel findings suggest that GRP78 may be used as a new predictive biomarker. It sets the stage for understanding the mechanism of UPR activation on the immune system in breast cancer.

Expression of lymphoid enhance factor 1 in acute myelogenous leukemia patients with intermediate-risk and its clinical significance

Objective To quantitatively analyze the mRNA expression level of lymphoid enhance factor 1 (LEF-1) in bone marrow mononuclear cells of patients with acute myeloid leukemia (AML) at intermediate-risk after initial diagnosis and chemotherapy, and to analyze its clinical significance. Methods The real-time fluorescence quantitative polymerase chain reaction (RT-PCR) was used to measure the expression level of LEF-1 gene in AML patients at intermediate-risk after initial diagnosis and chemotherapy, and its relationship with effectiveness and survival were analyzed. Results The LEF-1 mRNA level in preliminarily diagnosed patients with AML was significantly higher than that in control arm [0.005 19 (0.000 15-0.092 07) vs. 0.001 01 (0.000 09-0.002 33)], and the difference was statistically significant (u= 134.50, P < 0.01). The LEF-1 mRNA level in patients after chemotherapy was significantly declines as compared to that in patients before chemotherapy [0.001 07 (0.000 08-0.007 44) vs. 0.005 19 (0.000 15-0.092 07)], and the difference was statistically significant (u= 317.00, P < 0.01) and LEF-1 mRNA expression level before chemotherapy in complete remission (CR) patients was significantly higher than that in non-CR patients [(0.011 08 (0.001 64-0.092 07) vs. 0.001 10 (0.000 15-0.009 16)], and the difference was statistically significant (u= 19.00, P < 0.01). High LEF-1 expression predicted a significantly better overall survival in AML patients with intermediate-risk cytogenetics (χ2= 4.549, P= 0.033). Conclusions LEF-1 may be involved in the development and progression of AML at intermediate-risk patients and is closely related to tumor burden and treatment efficacy. LEF-1 may be a good predictor of better prognosis and a novel target for therapeutic effect. Key words: Leukemia, myeloid, acute; Polymerase chain reaction; Lymphoid enhance factor 1; Prognosis

Does residual microscopic disease after chemoradiotherapy for locally advanced rectal cancer translate into a good clinical outcome?

This study aimed to assess the progression-free and overall survival of patients with residual microscopic disease following neoadjuvant chemoradiotherapy and rectal resection for locally advanced rectal cancer. Two-hundred and thirty-four consecutive rectal cancer patients who had neoadjuvant chemoradiotherapy followed by radical resection (from May 2000 to April 2012) were divided according to pathological tumour response: residual microscopic disease (MIC), complete response (pCR) and partial/no response (non-CR). Data on the neoadjuvant regime, treatment-to-surgery interval, final pathology, type of operation, operative time, postoperative complications, length of hospital stay, disease recurrence and mortality were compared between the groups. There were 13 (5.5%) MIC patients, 48 (20.5%) with pCR and 173 (73.9%) with non-CR group. The groups were demographically comparable. MIC patients had more retrieved lymph nodes compared with the non-CR and pCR patients (median 13 compared with 8 and 10, respectively, P=0.0086). The 5-year overall survival rates were 93.4% for the pCR and MIC patients vs 82.1% for the non-CR patients (P=0.0324). The 5-year progression-free survival was 85.2% for the pCR and MIC patients vs 73.8% for the non-CR patients (P=0.086). We have identified and assessed a new pathological subgroup of rectal cancer patients who had residual microscopic disease after neoadjuvant therapy. The survival analysis aligned them closely with pCR patients.

P.3.027 - Norepinephrine transporter gene and protein expression of the human brain investigated with postmortem data and PET

IL-22 is an IL-10-family cytokine that regulates chronic inflammation. We investigated the role of IL-22 and its receptor, IL-22R1, in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP).IL-22 and IL-22R1 protein and mRNA expression in NP and in uncinate tissues (UT) from CRS and non-CRS patients was examined using immunohistochemistry and real-time PCR, respectively. Dispersed NP and UT cells were cultured with the Staphylococcus aureus exotoxins, staphylococcal enterotoxin B and alpha-toxin, following which exotoxin-induced IL-22 levels and their association with clinicopathological factors were analyzed. Effects of IL-22 on MUC1 expression and cytokine release in NP cells were also determined.IL-22 and IL-22R1 in NP were mainly expressed in infiltrating inflammatory cells and in epithelial cells, respectively. IL-22 mRNA levels in NP were significantly higher than those in UTs from non-CRS patients whereas IL-22R1 levels were conversely lower in NPs. NP cells produced substantial amounts of IL-22 in response to exotoxins. Exotoxin-induced IL-22 production by NP cells significantly and negatively correlated with the degree of local eosinophilia and postoperative computed tomography (CT) score, whereas conversely it positively correlated with the forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC) ratio. IL-22 significantly enhanced MUC1 mRNA expression in NP cells. IL-22-induced MUC1 mRNA levels were significantly and positively correlated with IL-22R1 mRNA levels in NPs.These data suggest that imbalance of IL-22/IL-22R1 signaling regulates the pathogenesis of CRSwNP, including local eosinophilia, via alteration of MUC1 expression.

B-cell Function Gene Mutations in Diffuse Large B-cell Lymphoma: A Retrospective Cohort Study

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous subtype of non-Hodgkin lymphoma. In addition to clinical and immunophenotypic characteristics, recurrent gene mutations have recently been identified in patients with DLBCL using next-generation sequencing technologies. The aim of this study is to investigate the clinical relevance of B-cell function gene mutations in DLBCL. Clinical analysis was performed on 680 Chinese DLBCL patients (146 non-CR and 534 CR cases) treated with six cycles of 21-day R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), alone or followed by two additional doses of rituximab consolidation on patients' own intention. Somatic mutations of B-cell function genes were further screened on 275 (71 non-CR and 204 CR) cases with available tumor samples by targeted sequencing, including genes involved in B-cell receptors (BCRs) pathway (CARD11, LYN, CD79A, and CD79B), Toll-like receptors (TLRs) pathway (MYD88), and tumor necrotic factor receptor (TNFR) pathway (TRAF2 and TNFAIP3). B-cell function gene mutations occurred in 44.0% (121/275) of DLBCL patients. The TLRs and TNFR related gene mutations were more frequently observed in non-CR patients (p=0.019 and p=0.032, respectively). BCRs related gene mutations, as well as revised IPI (R-IPI) and double BCL-2/MYC expression, were independently related to short progression-free survival in DLBCL after CR. The adverse prognostic effect of BCRs related gene mutations could be overcome by two additional doses of rituximab consolidation. These results highlight the molecular heterogeneity of DLBCL and identify a significant role of B-cell function gene mutations on lymphoma progression and response to rituximab in DLBCL.

Genetic Determinants of Response to Guadecitabine (SGI-110) in AML

Background: Guadecitabine is a second generation hypomethylating drug with improved pharmacokinetics and pharmacodynamics compared to decitabine and demonstrated clinical activity in both treatment naïve (tn) and relapsed-refractory (rr) AML. Previous studies reported similar response rates to guadecitabine in different cytogenetic subsets but it remains unknown whether this extends to genetic changes.Methods: Pre-treatment blood or bone marrow derived DNA was available for analysis from a total of 220 patients with AML enrolled on guadecitabine phase I-II trials (121 rrAML and 99 tnAML). We included only patients treated at therapeutic doses. Mutations in a panel of 54 genes was studied by the TruSight Myeloid Sequencing Panel (Illumina) and deep sequencingon the Illumina HiSeq platform. FLT3 mutations were separately determined by PCR analysis. The sequence data was analyzed for mutations using the TruSeq Amplicon Application in the Illumina BaseSpace Suite. Putative mutation calls were further filtered by sequencing read quality, minimum variant allelic fraction, and presence in the dbSNP and COSMIC databases.Results: In aggregate, responses to guadecitabine in rrAML were 15 CR (12%), 12 PR/CRi/CRp and 94 non responders (NR) and in tnAML, responses were 34 CR (34%), 21 PR/CRi/CRp and 44 NR. Overall, a median of 1 (range 0 - 5) mutation was present in each patient, with no significant differences between tn and rr AML. The most frequently mutated genes were ASXL1 (16.8%), TET2 (14.1%), IDH2 (10.9%), NPM1 (10%), RUNX1 (9.5%), DNMT3A (9.1%), NRAS (9.1%), FLT3-ITD (8.6%), U2AF1 (8.2%), IDH1 (6.8%), TP53 (5%), and KRAS (4.5%). The distribution of mutations was as expected for a group of patients with rrAML and elderly tnAML. We used Fisher's exact tests to compare mutation frequencies between patients who achieved CR and those who did not achieve CR. When we evaluated rrAML and tnAML separately, none of the genes showed a significantly different mutation rate between response subgroups. We then examined the population as a whole (N=220) and found that mutations in NRAS were significantly lower in patients who achieved CR (0/49) compared to those who did not (20/171, p=0.009). NRAS and KRAS mutations were inversely correlated, and when we considered the two genes together, mutations were present in 1/49 CR patients compared to 28/171 non-CR patients (p=0.007). Overall, CR rate was 3.4% in patients with RAS mutations compared to 25.1% in patients without such mutations. There was a similar significant trend for IDH2 mutations to be lower in CR patients (1/48) compared to non-CR patients (23/172, p=0.02) but this was not seen for IDH1. None of the mutations in other epigenetic regulators (DNMT3A, ASXL1, EZH2, TET2, U2AF1 or WT1) were significantly different between CR and non-CR patients individually or when we considered mutations in any of 8 epigenetic regulators (mutated in 22/49 CR patients vs. 93/171 non-CR patients, p=0.26). RAS mutations were higher in rrAML (22/121, 18.2%) than in tnAML (7/99, 7.1%, p=0.017) which may explain the lower CR rate in this group. Patients with PR/CRi/CRp were genetically similar to NR.Conclusions: In patients with AML treated with guadecitabine, RAS pathway mutations and IDH2 mutations are associated with a lower likelihood of achieving a CR. DisclosuresKropf:Celgene: Consultancy; Takeda: Consultancy. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Taverna:Astex Pharmaceuticals: Employment. Naim:Astex Pharmaceuticals: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Teva Pharmaceutical Industries: Consultancy; Astex Pharmaceuticals: Consultancy.

Analysis of Long-Term Survival in Multiple Myeloma Patients after First-Line Autologous Stem Cell Transplantation: Impact of Clinical Risk Factors and Duration of Response

Background: In the last decade, the introduction of novel agents into multiple myeloma (MM) therapy has significantly improved response rates and enabled long-term survival in a subset of patients. Yet, clinical characteristics of these long-term survivors as well as the exact impact of depth and sustainment of response still remain a matter of debate.Methods: MM patients treated at our center with high-dose melphalan supported by autologous stem cell transplantation (ASCT) as part of their first-line therapy between June 1992 and July 2014 were retrospectively analyzed. Response assessment was performed 100 days after ASCT according to EBMT criteria, since 2008 response according to IMWG criteria was also available. Overall survival (OS) and progression-free survival (PFS) were calculated from day of first ASCT. Additionally, landmark analyses regarding OS were performed at 1, 2, 3, and 5 years after ASCT. Impact of variables on PFS and OS were analyzed using multivariate Cox regression models. Furthermore, in order to assess evolution of prognosis over time, the conditional survival CS(t|s), which expresses the conditional probability of surviving further t years, was calculated as the ratio of two Kaplan-Meier estimates Ŝ(t) with .Results: 865 patients were included in this analysis, median age was 57.0 years (range 24-74), 509 were male. New agents based induction therapy was administered in 358 patients, 258 patients underwent tandem ASCT. Following ASCT, 386 patients received maintenance therapy, mainly with interferon or thalidomide. 75 patients proceeded to allogeneic transplantation and were censored at that time. Median PFS was 2.1 years, median OS was 6.4 years.Analysis of clinical influence factors revealed novel agent based induction therapy (p<0.01), maintenance therapy (p<0.01) and achievement of complete response (CR) (p=0.01) to be significantly associated with prolonged PFS, while older age (p=0.01) and thrombocytes at diagnosis < 150/nl (p=0.02) were identified as risk factors; a negative trend was seen for ISS stage 3 (p=0.067). With regard to OS, novel agent based induction therapy (p<0.01), maintenance therapy (p<0.01) and duration of time to progression (p<0.01) showed a highly significant positive impact, older age (p<0.01) and renal insufficiency at diagnosis (p=0.048) exerted a negative influence.To assess the importance of duration of response, landmark analyses were performed at 1, 2, 3, and 5 years after ASCT evaluating OS of patients with sustained CR, sustained inferior responses (non-CR), lost CR and lost non-CR at these respective time points. Remarkably, sustainment of any response showed a highly significant impact on survival at each of these time points (p<0.01) with no discernable difference between sustained CR and sustained non-CR patients. Landmark analysis at 1 year is shown in Figure 1. Administration of maintenance therapy independently improved outcome (p<0.01).Conditional survival regarding the probability to survive further three years CS(3|s) was calculated starting from the time of first ASCT stratified for the different response cohorts (see Figure 2). No significant differences could be found between patients with complete and partial response. In contrast, patients with progressive disease (PD) at day 100 after ASCT had a much lower probability of surviving the following three years after ASCT compared to patients responding to ASCT. However, those patients with PD that did survive the first year after ASCT, achieved a similar conditional three-year survival to that of patients responding initially.Conclusions: In this large retrospective study, sustainment of response after first-line ASCT was revealed as a major impact factor for OS independent of the depth of response. Administration of maintenance therapy further improved outcome, supporting the hypothesis that interventions prolonging responses achieved after ASCT are essential to reach long-term survival. [Display omitted] [Display omitted] [Display omitted] DisclosuresHillengass:Amgen: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Research Funding; Sanofi: Research Funding. Goldschmidt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Raab:Amgen: Consultancy, Research Funding; BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Research Funding.

Sonographic and cyst fluid cytologic changes after EUS-guided pancreatic cyst ablation

The effect of EUS-guided pancreatic cyst ablation (PCA) on sonographic morphology and cyst fluid cytology is unknown. The aim of this study was to evaluate morphologic, cytologic, and change in cyst fluid DNA after PCA. In a prospective single-center study, consecutive patients with suspected benign 10- to 50-mm pancreatic cysts underwent baseline EUS-FNA and EUS-PCA followed 2 to 3 months later by repeat EUS, cyst fluid analysis, and possible repeat PCA. Surveillance imaging after ablation was performed at least annually and classified as complete response (CR), partial response, or persistent, with<5%, 5% to 25%, and 25% of the original cyst volume, respectively. Thirty-six patients underwent EUS-PCA with ethanol alone (n= 8) or ethanol and paclitaxel (n= 28), and CR occurred in 19 patients (56%). After EUS-PCA, EUS showed an increase in wall diameter in 68%, decreased number of septations in 24%, increased debris in 24%, loss of mural nodule or novel calcification in 21%, and alteration of fluid viscosity in 48%. Follow-up cytology showed increased epithelial cellularity in 27%, loss or decreased cellular atypia in 15%, increased or appearance of macrophages in 24%, and inflammatory cells in 15%. Postablation DNA amount increased and quality decreased in 71% each. Between the CR and non-CR patients, there was no significant difference in frequency of sonographic or cytologic features. In the CR group, mean DNA quantity was significantly increased after ablation (P= .023) without a change in quality (P= .136). EUS-PCA induces morphologic and cytologic changes of pancreatic cysts, none of which appears to predict overall imaging-defined response to ablation. (Clinical trial registration numbers: NCT00233038 and NCT01643460.).

IL-22/IL-22R1 signaling regulates the pathophysiology of chronic rhinosinusitis with nasal polyps via alteration of MUC1 expression

BackgroundIL-22 is an IL-10-family cytokine that regulates chronic inflammation. We investigated the role of IL-22 and its receptor, IL-22R1, in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP). MethodsIL-22 and IL-22R1 protein and mRNA expression in NP and in uncinate tissues (UT) from CRS and non-CRS patients was examined using immunohistochemistry and real-time PCR, respectively. Dispersed NP and UT cells were cultured with the Staphylococcus aureus exotoxins, staphylococcal enterotoxin B and alpha-toxin, following which exotoxin-induced IL-22 levels and their association with clinicopathological factors were analyzed. Effects of IL-22 on MUC1 expression and cytokine release in NP cells were also determined. ResultsIL-22 and IL-22R1 in NP were mainly expressed in infiltrating inflammatory cells and in epithelial cells, respectively. IL-22 mRNA levels in NP were significantly higher than those in UTs from non-CRS patients whereas IL-22R1 levels were conversely lower in NPs. NP cells produced substantial amounts of IL-22 in response to exotoxins. Exotoxin-induced IL-22 production by NP cells significantly and negatively correlated with the degree of local eosinophilia and postoperative computed tomography (CT) score, whereas conversely it positively correlated with the forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC) ratio. IL-22 significantly enhanced MUC1 mRNA expression in NP cells. IL-22-induced MUC1 mRNA levels were significantly and positively correlated with IL-22R1 mRNA levels in NPs. ConclusionsThese data suggest that imbalance of IL-22/IL-22R1 signaling regulates the pathogenesis of CRSwNP, including local eosinophilia, via alteration of MUC1 expression.

Group 2 Innate Lymphoid Cells Directly Induce B Cell Activation in Humans

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation and increased group 2 innate lymphoid cells (ILC2). We have also found elevated B cells and overexpression of the extrafollicular B cell marker Epstein-Barr virus-induced protein 2 (EBI2). We investigated whether B cells in polyps expressed EBI2, indicating an extrafollicular phenotype, and whether ILC2s could regulate B cell activation. EBI2 expression on cells from polyps of CRSwNP patients or tonsils from non-CRS patients was assessed by flow cytometry. Antibody production by tissue B cells was assessed by Luminex assay. In other experiments, B cells and ILC2s were isolated from peripheral blood by magnetic bead- and flow cytometry-based methods, respectively. B cells were cultured for 5 days under IgG-promoting conditions (IL-2 and R848 (a TLR7/8 agonist)), or IgE-promoting conditions (IL-4 and anti-CD40), or with autologous ILC2s at a 1:1 ratio, or with IL-2 alone. Polyps contained elevated levels of plasmablasts (PB) and EBI2+ PB compared to tonsil (>5 fold, p<0.001 and >2.5 fold, p<0.01, respectively). In vitro, polyps also produced significantly higher levels of antibodies (p<0.01). IL-4 and anti-CD40 increased B cell survival and EBI2 expression (>5 fold), indicating in vitro development of extrafollicular PB, while IL-2 and R848 had no effect on EBI2. Co-culture of B cells with ILC2s increased B cell survival and promoted a significant increase of EBI2+ B cells (>5 fold, p<0.05). These findings suggest that type 2 inflammation, particularly ILC2s, may play an important role in B cell activation during chronic airway inflammation.

Posttreatment FDG-PET-CT response is predictive of tumor progression and survival in anal carcinoma

PurposeWe hypothesize that posttreatment F-18 fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) metabolic response predicts clinical outcomes in patients with anal cancer treated with chemoradiation. Methods and MaterialsThis was a single-institution retrospective review of 148 patients treated definitively for anal squamous cell carcinoma between 2005 and 2012. All patients were followed with posttreatment PET-CT scans and clinical examinations. Progression-free survival (PFS), cause-specific survival, and overall survival (OS) estimates were calculated using the Kaplan-Meier method. ResultsThe median follow-up was 34 months (range, 5-89 months). Pretreatment PET was successful in detecting the primary tumor in 140 cases (95%). Computed tomography (CT) alone was able to detect primary tumors in 78 of 122 patients who had pretreatment CT scans (64%). Inguinal or pelvic lymph nodes were FDG avid in 68 patients, with only 41 of these patients having enlarged lymph nodes by CT criteria (60.3%). Initial posttreatment PET-CT was obtained on average 12.7 ± 4.3 weeks after the last day of radiation (range, 5-25 weeks). Overall complete metabolic response (CR) on initial PET-CT was found in 82 patients (58%). Partial metabolic response was noted in 52 (36.9%) and progression in 7 patients (5%). Only 12/82 patients (14.6%) with a FDG-PET CR eventually recurred. The negative predictive value of a PET-CT scan performed between 13 and 25 weeks posttreatment was 92.9%. The 2-year PFS for patients with CR versus non-CR was 89.8% and 69.2%, respectively (P = .004). The 2-year OS for CR versus non-CR patients was 94.8% and 79.3% (P = .036). ConclusionsComplete metabolic response on posttreatment FDG PET-CT is highly predictive of increased PFS and OS in patients treated with chemoradiation for anal carcinoma. In addition to close clinical surveillance, we recommend obtaining posttreatment PET-CT scans >12 weeks following definitive treatment for anal cancer.

An Absolute Standardized Uptake Value Is More Useful than the Decreased Rate of Uptake of FDG-PET to Predict Responses to Neoadjuvant Chemoradiotherapy for Esophageal Cancer

Background: Neoadjuvant chemoradiotherapy (CRT) is frequently performed for esophageal squamous cell carcinoma. In this study, we retrospectively assessed the standardized uptake value (SUV) of FDG-PET against decreased rates of SUV to assess the response of advanced esophageal squamous cell carcinoma patients to neoadjuvant CRT, and the correlation of this response with histopathological findings. Patients and Methods: Thirty-three patients receiving CRT followed by surgery were analyzed. Results: Using the decreased rate of maximum SUV, the sensitivity and specificity in distinguishing complete responders (CR) from non-CR patients was 63% and 44%. Using the maximum SUV before surgery, the sensitivity and specificity for distinguishing pathological CR from non-CR was 88% and 56%. Conclusions: To identify complete responders of CRT for esophageal cancer, absolute maximum SUV value is a better predictor than decreased rate of the maximum SUV.

Impact of postoperative endoscopy upon clinical outcomes after endoscopic sinus surgery.

After endoscopic sinus surgery (ESS), endoscopy is used to gauge surgical success and clinical outcomes. Prior studies have not examined this topic prospectively using validated outcome metrics across multiple institutions. A multi-institutional, prospective study of patients with chronic rhinosinusitis (CRS) who underwent ESS completed the 22-item Sino-Nasal Outcome Test (SNOT-22), missed productivity, and medication usage questionnaires 6 months postoperatively. Lund-Kennedy endoscopy scoring (LKES) was performed with reviewers blinded to patient-reported data. A control cohort of non-CRS patients was recruited for comparison. Complete data was available on 183 CRS patients and 48 non-CRS control patients. Approximately 50% of patients achieve perfect or near perfect endoscopy (LKES 0 to 2) after ESS. Postoperative endoscopy correlated with total SNOT-22 scores (r = 0.278, p < 0.001), with the strongest correlations to rhinologic and extranasal subdomains in the nasal polyp cohort. Improved postoperative endoscopy was associated with decreased antibiotic and oral steroid usage, but had little association with missed productivity. Among patients who achieved near perfect postoperative endoscopy, those with nasal polyps had SNOT-22 scores that were similar to non-CRS control patients (mean SNOT-22 scores 17.7 and 16.3, respectively). However, CRS patients without nasal polyps remained more symptomatic than non-CRS controls and CRS with nasal polyps patients despite nearly perfect endoscopy (mean SNOT-22 score 21.6). Postoperative endoscopy correlates with SNOT-22 and medication usage in CRS patients. Polyp patients who achieve near perfect endoscopy have similar symptoms to healthy controls; however, nonpolyp patients with near perfect endoscopy still have rhinologic and extranasal symptoms that are worse than healthy controls.

Association between colchicine resistance and vitamin D in familial Mediterranean fever

Although colchicines are the only effective treatment of familial Mediterranean fever (FMF), resistance to colchicines (CR) which is observed in up to 30% of the patients is still a problem. Clinically, resistance to colchicine is defined as three or more attacks within the last 6 months period while using ≥2 mg/day colchicine. Previous studies have shown decreased vitamin D levels in FMF patients compared with healthy controls. The aim of this study is to evaluate whether vitamin D levels differ between CR and non-CR FMF patients. This study included 64 FMF patients who were being followed in Nephrology Clinic of Samsun Research and Education Hospital for at least 1 year. FMF was diagnosed according to the criteria defined by Livneh et al. Serum 25-hydroxy vitamin D (25-OHD) concentration (ng/mL) was detected in all FMF patients who were not in an acute attack period. From 64 patients 29 were accepted as CR. Mean 25-OHD level was 9.39 ± 1.00 ng/mL in CR patients and 18.48 ± 1.09 ng/mL in colchicine responsive patients (p < 0.001). Plasma vitamin D levels were significantly lower in colchicine resistant patients. Vitamin D deficiency may be a factor in etiopathogenesis of CR. Studies in larger patient samples that particularly evaluate the response to vitamin D replacement in CR FMF patients are needed.

Abstract 341: Cost of Care Implications for Unstable Angina and Coronary Revascularization Readmissions Following Acute Myocardial Infarction

Objectives: While mortality following acute myocardial infarction (AMI) has decreased over time, subsequent hospitalizations due to unstable angina (UA) and coronary revascularization (CR) continue to be a great source of burden both from a patient’s and a societal perspective. It is unknown, however, how AMI patients who experience these additional readmissions value their health and what the associated costs are, beyond the hospitalization itself. Methods: From TRIUMPH, a 24-center observational AMI registry, we identified patients readmitted for unstable angina (UA) or unplanned CR ≥1 month following index AMI discharge. Propensity matching was used to compare (1) patients who were vs. were not readmitted for UA and (2) patients who were vs. were not readmitted for CR. We examined one-year quality-adjusted life-years (QALYs) using the EQ-5D measurements at 1, 6 and 12 months, as well as post-discharge costs (office visits, cardiac rehabilitation and cardiovascular readmissions, excluding costs for the UA/CR event). Confidence intervals were calculated via bootstrap analysis. Results: A total of 140 (4.26%) were readmitted for UA and 112 (3.41%) patients underwent CR after their AMI. Unadjusted mean 1-year QALYs for UA and non-UA patients were 0.743 and 0.821 [propensity-matched difference -0.076 (95% CI -0.100, -0.042)]. Unadjusted mean 1-year QALYs for CR and non-CR patients were 0.798 and 0.828 [propensity-matched difference -0.032 (95% CI -0.063, -0.003]. Mean differences in costs were $8009 (95% CI $3997, $14229) for UA vs. non-UA patients and $4498 (95% CI $4046, $4966) for CR vs. non-CR patients. Cardiovascular rehospitalizations contributed most to these costs (Table) . Conclusion: In this study, over the year following AMI, patients experiencing UA or unplanned coronary revascularization were challenged in maintaining their health status as compared with those not experiencing the respective event and had significantly higher health care costs.

Abstract 214: Determinants of Cardiac Rehabilitation Referral Following Acute Myocardial Infarction In Australia

Background: Despite the known benefits of cardiac rehabilitation (CR) and widespread endorsement of its use, CR is vastly underutilised, with less than 30% of eligible patients participating in a CR program after a cardiac event. The current study assessed the factors independently associated with referral to CR following acute myocardial infarction (AMI). Methods: The CR referral rate and factors associated with referral were assessed among all consecutive patients undergoing coronary angiography for AMI and surviving to hospital discharge, attending South Australian public hospitals from January 2012 [[Unable to Display Character: &amp;#8211;]] December 2013. Data was maintained by the Coronary Angiogram Database of South Australia (CADOSA), a comprehensive registry compatible with the NCDR ® CathPCI ® Registry. Results: Among 3,212 patients undergoing angiography for AMI, CR referral occurred in 1,530 patients (48%). Compared to patients without CR referral, these patients were younger (62±13 vs. 64±14, p&lt;0.01) and less likely to be female (25% vs. 34%, p&lt;0.01). Following age-adjusted analysis, the cardiovascular risk factors were similar between CR referral and non-CR referral patients including: diabetes (29% vs. 30%, p&gt;0.5), hypertension (61% vs. 64%, p&gt;0.5), and dyslipidaemia (59% vs. 60%, p&gt;0.5), but CR referral patients were more likely to be active smokers (40% vs. 33%, p&lt;0.01). CR referral patients were less likely to have additional comorbidities including current dialysis (0.9% vs. 2.2%, p&lt;0.01) and cerebrovascular disease (6.0% vs. 8.8%, p&lt;0.01). In multivariable analyses, factors associated with increased CR referral were (c statistic 0.68): presentation with ST-elevation MI (STEMI) (1.4, 1.2-1.7, p&lt;0.01), undergoing percutaneous coronary intervention (PCI) following angiography (1.6, 1.4-1.9, p&lt;0.01) and younger age (1.0, 0.98-1.0, p&lt;0.01). Prior CABG (0.6, 0.5-0.8, p&lt;0.01) and absence of significant coronary artery disease, defined by stenosis &lt;50%, (0.2, 0.1-0.3, p&lt;0.01) were associated with decreased referral. Lastly, secondary prevention therapies were more often prescribed at discharge in patients with CR referral compared to patients without referral including: aspirin (93% vs. 82%, p&lt;0.01), beta-blockers (64% vs. 61%, p&lt;0.05), statin (92% vs. 78%, p&lt;0.01), and ACE-inhibitor/angiotensin receptor blocker (84% vs. 74%, p&lt;0.01). Conclusion: This study highlights a significant disparity in cardiovascular care with approximately half of AMI patients not referred to CR, despite it being a key performance measure. STEMI presentation, younger age and undergoing PCI are associated with increased referral. Alarmingly, AMI patients not referred to CR are also less likely to receive other guideline-based therapies. Increased physician awareness about the benefits of CR is required and initiatives to overcome barriers to referral may improve the delivery of evidence-based care.