AA Patients Research Articles

Association between FGFR4 gene polymorphism and high-risk HPV infection cervical cancer.

To discuss the association between FGFR4 gene polymorphism rs351855 (Glu388Aly) and the susceptibility and chemotherapeutic effect of cervical cancer infected by high-risk type HPV. A total of 162 patients with high-risk HPV cervical cancer and 162 healthy women were collected and the genotypes of the FGFR4 rs351855 locus were detected. The genotype distributions in the two groups were compared. The cervical cancer patients were divided into four groups which namely good therapeutic effect group and bad therapeutic effect, recurrence or metastasis and no recurrence or metastasis group respectively, and the risks of different genotype on the curative effect and prognosis were analyzed by Logistic regression. The survival time of patients with different genotypes was compared. There was no statistic difference in FGFR4 rs351855 genotype distribution between the patients group and control group (P>0.05), among which the risk of chemotherapy failure on GA+AA patients was 3.257 times as much as that of the GG patients, and the risk of recurrence or metastasis of GA+AA patients was 2.783 times as much as that of the GG patients. For AA patients, the risk of chemotherapy failure and the risk of relapse and metastasis are 3.833 and 3.406 times, respectively, as much as thatof the GG patients. The overall survival of GA and AA patients was shorter than that of the GG patients, and significant difference was found (χ2=7.098, P=0.029). The difference in overall survival between GA+AA patients and GG patients was almost statistically significant (χ2=3.634, P=0.057). The FGFR4 rs351855 polymorphism is not associated with the susceptibility of high-risk HPV cervical cancer, but patients with gene A was at higher risk of unfavorable chemotherapy prognosis compared with patients with GG.

Prevalence and clinical outcomes of hepatitis B virus infection in patients with aplastic anemia.

The association of HBV infection with other hematopoietic diseases has been discussed previously. However, the clinical significance and clinical outcomes of HBV infection in AA patients have not been clarified. In this study, we sought to investigate the prevalence and related events of HBV in patients with AA who received immunosuppressive therapy. We retrospectively analyzed 245 patients with acquired AA. The HBsAg positivity rate was 14.69% in this group of AA patients. No significant difference was observed in the severity of AA patients with HBV infection and in those without (P=0.6358). HBV reactivation occurred in 4.76% of HBsAg-positive patients who received ATG/ALG+CsA treatment without anti-viral prophylaxis. HBV-infected patients who received CsA alone did not develop reactivation. Patients with HBV reactivation showed favorable clinical outcomes, with no HBV-related deaths. There was no significant difference in overall probability of survival in patients with different HBV infection status (P=0.8617). Given the low rate of reactivation and favorable outcomes after reactivation in AA patients, close monitoring of HBV DNA, hepatic function and patient immune status may be a more effective approach than routine prophylaxis for AA patients with HBV infection undergoing ATG/ALG+CsA treatment. Further studies are warranted to clarify the optimal time to initiate anti-viral treatment.

Triple negative breast cancer (TNBC): Analysis of age and stage distribution and survival between African American and Caucasian women in a predominant low-income population.

e12586 Background: Triple negative breast cancers (TNBC) represent roughly 15% of all breast cancer and are associated with decreased overall survival. A higher incidence of TNBC has been seen in younger and African American patients. We investigated the effect of age and race relative to outcomes of patients with TNBC seen at a state charity hospital system. Methods: This retrospective review identified 194 pts with TNBC diagnosed between 1993-2011 at LSUHSC-Shreveport, a state charity hospital. TNBC was defined as ER/PR both <1% and HER2neu not overexpressed by FISH analysis. The patient’s race, age at diagnosis, stage at diagnosis, treatment, relapse free survival (RFS), overall survival and survival following confirmed metastatic disease were analyzed. Results: There was no statistical difference in frequency of stage between groups. Although not statistically significant, there was a trend to worse RFS in AA and in young pts of both races. Younger age at diagnosis did have an inferior median survival as compared to older pts regardless of race or stage (p=0.0476). There was no difference in median survival following confirmation of metastatic disease between races (p=0.3574) or between age groups (p=0.8548); (median survival = 31 mos, 2.56-204 mos). Conclusions: In a predominantly low income patient population the incidence of TNBC was higher in the AA and in the young (age ≤ 50) as expected. There was no difference in stage or frequency within the populations. However, outcomes appeared to be worse in the younger pts and in AA patients with higher recurrence rate. Survival following first recurrence was similar regardless of age and race. Further analysis of etiologies for racial and age disparities is needed. [Table: see text]

Quadruple Negative Breast Cancers in African American women have an enriched Basal and Immune signature.

Abstract There is increasing evidence that Androgen Receptor (AR) expression has prognostic usefulness in breast cancer suggesting that Triple negative breast cancer (TNBC) which lack AR expression are Quadruple Negative Breast Cancers (QNBC). However, a comprehensive analysis of AR expression within all breast cancer subtypes or stratified by race has not been reported. We assessed AR RNA expression in 925 tumors from The Cancer Genome Atlas, and 136 tumors in 2 confirmation sets. AR protein expression was determined by immunohistochemistry in 197 tumors from a multi-institutional cohort, for a total of 1258 patient analyzed. We used Cox hazard ratios to determine correlations to PAM50 breast cancer subtypes, and TNBC-QNBC subtypes. K-means clustering distincted immune-related gene expression signature in QNBC tumors. AA tumors express the AR at both the RNA and protein levels at lower rates than tumors of White women which is independent of ER and PR expression (p<0.0001). TNBC tumors from both racial groups demonstrate the lowest expression of AR. AR-negative tumors have odds ratio (66.60; 95% CI, 32–146) of being basal-like. QNBC tumors have odds ratio (4.01; 95% CI, 0.88–38.60) of being BL1 subtype. K-means clustering demonstrated that AA patients had a distinctive gene signature that could be subdivided into five signatures; AR pathway, T cell >response pathway, Cancer B cell response, stem cell pathway, and hormone receptors enriched pathways. These observations indicate that AR expression should be included with traditionally used markers and that QNBC should be used as a prognostic marker for breast cancer patients. Further, AR-negative tumors have a characteristic immune signature that could be exploited by targeted immune therapy.

Temperament-Character Profile and Psychopathologies in Patients with Alopecia Areata

ABSTRACTThe aim of this study is to investigate psychopathologies and the temperament-character profile of Alopecia Areata patients and to compare them with healthy controls. Patients and controls who presented at a dermatology clinic were selected by convenience sampling to respond to Temperament and Character Inventory (TCI), SCL-90-R, and a checklist about the demographic data and their dermatologic and psychiatric history. Patients reported higher harm avoidance and reward dependence than controls (Cohen's d = .93 and = .94). A significant correlation between Harm Avoidance (r = −0.33, p = .02) and Reward Dependence (r = −0.28, p = 0.05) with sex was found (females scored higher). Lifetime history of AA relapse was significantly associated with higher psychiatric symptoms; the effect sizes were large for Obsessive-Compulsive (d = .81) and Paranoia Ideation (d = .89). The higher psychological symptoms in AA patients with the history of relapses in this study have a practical message for clinicians.

Fluorescent Aerolysin (FLAER)-based paroxysmal nocturnal hemoglobinuria (PNH) screening: a single center experience from India.

Fluorescent aerolysin (FLAER) has been recommended as an important part of antibody panel used for flow cytometric detection of paroxysmal nocturnal hemoglobinuria (PNH) clone. This study was aimed to observe the frequency of PNH-positive clones and their sizes in patients screened for various indications. A retrospective analysis of 624 patients screened over a period of 30 months. Frequency and size of clone sizes noted, and laboratory parameters were compared among different groups of patient being screened. There were 445 adults and 179 pediatric patients. Indications for screening included AA (n = 433), myelodysplastic syndrome (MDS) (n = 34), hemolytic anemia (n = 84), and thrombophilia workup group (n = 63). PNH clones were found in 39.03%, 5.88%, 26.19%, and 1.59% cases, respectively. No significant difference among adult or pediatric population was noted. The bone marrow failure (BMF) group [AA and MDS] with PNH clone had a significantly lower clone size (Median- 2.7%) as compared to classic PNH group (Median-77.2%). Most of the classic PNH cases (78.26%) and a small proportion of AA (9.9%) showed a large clone size (>50%). In spite of having large clone size, there was a significant difference between the median LDH values of these two groups (2511.5 vs 593 U/L). FLAER-based screening detects the presence of PNH clone in a high proportion of AA patients and some MDS patients. These patients usually have a small clone size. Even if they have a large clone, it does not get translated into a high LDH or severe clinical symptoms.

OS04.1 Survival benefit associated with Gross Total Resection (GTR) in oligodendrogliomas and astrocytomas: a Surveillance, Epidemiology, and End Results Program (SEER) based analysis

AbstractThe available evidence suggests that the clinical benefits of extended surgical resection are limited for chemo-sensitive tumors, such as primary central nervous system lymphoma (PCNSL). Oligodendroglioma is generally thought to be more sensitive to chemotherapy than astrocytoma of ­comparable grades. Here, we compare the survival benefit of gross total resection (GTR) in oligodendroglioma patients relative to astrocytoma patients. Using the Surveillance, Epidemiology, and End Results Program (SEER) database, we identified 2,378 WHO grade II oligodendroglioma patients (O2) and 1,028 WHO grade III oligodendroglioma patients (O3). Surgical resection was defined as GTR, subtotal resection (STR), biopsy only, or no resection. Kaplan-Meier and multivariate Cox regression survival analysis were used to assess survival with respect to extent of resection (EOR). Cox multivariate analysis revealed that the hazard of dying from O2 and O3 was comparable between patients who underwent biopsy only (or STR) and GTR (O2: HR 1.06, 95% CI 0.73–1.53; O3: HR 1.18, 95% CI 0.80–1.72). A comprehensive search of the published literature identified eight articles without compelling evidence that GTR is associated with improved overall survival in oligodendroglioma patients. In contrast, we found that patients afflicted with WHO grade II astrocytoma (A2) benefited significantly from GTR. We identified 4,113 A2 patients in the SEER. A multivariate Cox survival analysis indicated that relative to A2 patients who underwent STR, A2 patients who underwent a GTR showed a 28.3% reduction in the hazard of death. Similar risk reductions were observed in both A2 patients age 4 years, a finding reminiscent of anaplastic astrocytoma patients. In contrast, for A2 patients age ≥ 50, the GTR associated survival benefit was approximately 6 months, resembling that observed in glioblastoma patients. Relative to A2 patients, patients afflicted with WHO grade III astrocytoma (anaplastic astrocytoma or A3) derived greater survival benefit from GTR. We identified 2,755 A3 patients in SEER. The hazard of dying from the A3 was reduced in GTR patients by 40% relative to STR patients. For comparison, the hazard of dying from the glioblastoma was reduced in GTR patients by 24% relative to STR patients. We observed that age <50 and post-TMZ (2005–2010) independently associated with an improved survival benefit for A3 who underwent GTR. The median survival of AA patients age<50 who underwent GTR and STR in the post-TMZ era was not reached for the GTR population and 52 months for the STR population, respectively. For glioblastoma patients, the corresponding numbers for median survival were 21 and 18 months.

OPRM1 c.118A>G Polymorphism and Duration of Morphine Treatment Associated with Morphine Doses and Quality-of-Life in Palliative Cancer Pain Settings.

Despite increased attention on assessment and management, pain remains the most persistent symptom in patients with cancer, in particular in end-of-life settings, with detrimental impact on their quality-of-life (QOL). We conducted this study to evaluate the added value of determining some genetic and non-genetic factors to optimize cancer pain treatment. Eighty-nine patients were included in the study for the evaluation of palliative cancer pain management. The regression analysis showed that age, OPRM1 single nucleotide polymorphism (SNP), as well as the duration of morphine treatment were significantly associated with morphine doses at 24 h (given by infusion pump; p = 0.043, 0.029, and <0.001, respectively). The mean doses of morphine decreased with age but increased with the duration of morphine treatment. In addition, patients with AG genotype c.118A>G OPRM1 needed a higher dose of morphine than AA patients. Moreover, metastases, OPRM1 SNP, age, and gender were significantly associated with the QOL in our population. In particular, AA patients for OPRM1 SNP had significantly lower cognitive function than AG patients, a result not previously reported in the literature. These findings could help increase the effectiveness of morphine treatment and enhance the QOL of patients in regards to personalized medicine.

Audiovestibular Handicap and Quality of Life in Patients With Vestibular Schwannoma and "Excellent" Hearing.

Studies examining patient-reported outcomes in subjects with vestibular schwannoma (VS) and "excellent" hearing are lacking. To assess patient-reported audiovestibular handicap and overall quality of life (QoL) in VS patients with class A hearing in both ears. Among 539 VS patients treated during 1998 to 2008, we identified 296 patients with either bilateral class A (AA) hearing or 1 good ear and 1 deaf ear (AD) according to the American Academy of Otolaryngology-Head and Neck Surgery classification. Patients responded to validated hearing, tinnitus, and dizziness handicap inventories and 2 QoL questionnaires, and the 2 groups were compared. A reference group of 103 adults filled out the same questionnaires. Forty-nine patients (16.6%) had class AA and 247 patients (83.4%) had class AD hearing. AA patients scored poorer than control subjects without tumor on all handicap questionnaires ( P < .001) and a VS-specific QoL instrument ( P = .006). Con-versely, AA patients scored significantly better than patients with AD on the hearing inventory and the disease-specific QoL instrument ( P < .001), but no difference was found between these groups with regard to tinnitus and dizziness. The hearing disability score was approximately 3times poorer for AA patients compared with control subjects without tumor; a third of AA patients reported a hearing handicap. Patients with VS and bilateral class A hearing report significantly poorer hearing handicap than control subjects without tumor but better hearing than those with unilateral deafness. When patients with bilateral class A hearing are counseled, it should be noted that one-third of patients experience self-perceived hearing handicap.

Abstract B04: The use of whole genome methylation scanning to define genes preferentially suppressed in African American Prostate Cancer

Abstract Background: The incidence of prostate cancer (PCa) is approximately 60% higher, and the mortality rate is 2 to 3 times greater, among African American men (AA) resident in the U.S. compared with American men with a European background (EA). Men of West African ancestry from the Caribbean and South America share similar incidence and mortality to AAs, suggesting a possible genetic and/or epigenetic contribution to these outcomes. We previously carried out a sensitive expression analysis comparing the expression of both tumor and tumor-adjacent stroma of AA and EA patients by Paired T-tests for matched (age, stage, grade, tumor content, stroma content) patients (1). Remarkably, 92% of expression differences between AA and EA occurred in the stroma component and of these 97% were in the direction of lower expression in AA compared to EA patients. The downregulated genes were dominated by immune regulatory and extracellular matrix genes. This suggests the possibility that decreased immune and inflammatory processes in tumor-adjacent stroma may be responsible for the aggressive nature of prostate cancer in AA patients (1). We have begun to test this possibility by examining whether the down regulated genes are methylated. Methods: Whole Genome FFPE Methylation and Transcriptome Profiling. We used archived FFPE samples where there is a potential to examine many patients. We are in the early methods-development stage of this project. One AA and two EA prostate cancer cases were matched for age, time to relapse/survival and Gleason score. A Norgen kit was used to obtain both DNA and RNA from the same sample. Methylated regions in each case were captured by methylated DNA ChIP using the human Methyl-CpG Binding Domain-2 (hMBD2) protein MBD2 then DNA purification followed by NGS. The transcriptome of tumor stroma was obtained using the TruSeq RNA access kit which is based on capture oligonucleotides to each exon to enrich RNA of coding regions. The method works for low amounts of highly degraded RNA isolated from low quality samples. The kit includes &amp;gt; 425,000 probes each constructed against NCBI377 hg19 reference genome, covering 98.3% of the RefSeq exome. The probes capture &amp;gt;210,000 targets, spanning 21,415 genes. Results: Our preliminary data show that one AA tumor-adjacent stroma has a greater number of hypermethylated regions than in tumor-adjacent stroma of two matched EA patients. Genome-wide methylation analysis revealed 5217 sites of significant (p &amp;lt; 0.001) hypermethylation in AA compared to EA, and 988 other sites of hypermethylation in EA compared AA PCa cases, indicating a marked increase in methylation in this one AA PCa case compared to the two EA cases. Within coding DNA the major classes of methylated genes included immune regulatory, interferon stimulated genes, and genes of the extracellular matrix. Our studies provide the first joint methylation and transcriptome analysis of PCa patients using FFPE samples and support the possibility that epigenetic alterations might be responsible for deficiencies in tumor immunity in AA PCa. Reference: Kinseth M, A., Z. Jia, et al., 2014. Int. J. Cancer 134: 81-91. DOI: 10.1002/ijc.28326. Citation Format: Farah Rahmatpanah, Kathleen McGuire, Michael Lilly, Michael McClelland, Dan Mercola. The use of whole genome methylation scanning to define genes preferentially suppressed in African American Prostate Cancer. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B04.

Melanocortin Receptor-4 Gene Polymorphisms in Glioblastoma Patients Treated with Concomitant Radio-Chemotherapy.

Melanocortins are peptides with well-recognized antiinflammatory and neuroprotective activity. No data are currently available on melanocortin receptor-4 (MC4R) gene polymorphisms and tumors, including glioblastomas (GBMs), or their relationship with radiotherapy or chemotherapy. The aim of this study was to evaluate the possible predictive/prognostic role of the MC4R SNPs on GBM patients. Fifty-five patients with a proven diagnosis of GBM, treated with radiotherapy and temozolomide, were consecutively enrolled. MC4R gene SNPs (rs17782313, rs489693, rs8087522, rs17700633) were analyzed by a validated TaqMan® SNP genotyping assays. Univariate and multivariate analyses were performed. A P<0.0125 (Bonferroni's correction) was considered significant ( Clinicaltrial.gov identifier NCT02458508). The median progression-free survival (PFS) and median overall survival (OS) of these patients were 9.54 (95% CI 5.4-14.3)months and 24.9 (95% CI 17.8-34.6)months, respectively. The MC4R rs489693 AA genotype was significantly associated with a shorter PFS and OS. Indeed, with regard to PFS, patients harboring the rs489693 AA genotype had a median PFS of 2.99months whereas patients with AC/CC genotypes had a median PFS of 10.82months (P=0.009). Interestingly, the rs489693 AA patients also had a lower median OS as compared with the median OS of the AC/CC genotypes (10.75 vs. 29.5months, respectively, P=0.0001). This study suggests that the MC4R rs489693 AA genotype is significantly associated with a shorter PFS and OS in patients treated with radiotherapy and temozolomide. These findings represent a relevant effort to identify novel clinical markers for RT-CT therapy in GBM to be validated in future pharmacogenetic clinical trials.

Interleukin-2 and Interleukin-8 Gene Polymorphisms and Acquired Aplastic Anemia Risk in a Chinese Population

Background/Aims: Cytokines IL-2 and IL-8 both participate in immune regulation. However, the relationship between polymorphisms in these two cytokines and the risk of acquired aplastic anemia (acquired AA) has not been explored. Methods: We selected five SNPs including rs11575812, rs2069772 and rs2069762 of IL-2, rs2227306 and rs2227543 of IL-8. SNaPshot genotyping was used to test the genotypes of IL-2 and IL-8 polymorphisms in a population of 101 acquired AA patients and 165 healthy controls. Results: The rs2069762 G allele appeared to be a protective mutation, but no significant differences were found in other four SNPs. We also found that rs2069762 had an impact on the transcriptional regulation. Conclusions: It could be assumed that the rs2069762 polymorphism might reduce the risk of acquired aplastic anemia, while the remaining four SNPs might not contribute to susceptibility to acquired AA in a Chinese population.

Aplastic Anemia in the Context of Hemolytic Paroxysmal Nocturnal Hemoglobinuria: Feasibility of Antibody-Based Intensive Immunosuppression during Eculizumab Treatment

Paroxysmal nocturnal hemoglobinuria (PNH) may present as hemolytic (classical PNH) or aplastic (AA/PNH syndrome) PNH. While classical PNH patients requires anti-complement treatment (eculizumab), the treatment of AA/PNH patients should target their bone marrow failure (BMF) by immunosuppression (IST), or even bone marrow transplantation (BMT). However, in a few patients clinically meaningful AA and hemolysis may be concomitant, eventually justifying both IST and eculizumab. To date there is no standard treatment for this rare condition. Here we investigated the prevalence of this condition based on a large cohort of PNH patients seen at our reference centers at St. Louis Hospital (Paris) and Federico II University (Naples), looking for patients who have received "intensive IST" in combination with eculizumab. Amongst a total of 145 PNH patients seen between 2007 and 2016, we have identified 6 patients who have received intensive IST during eculizumab treatment ; thus, roughly the prevalence of severe BMF associated with hemolysis is around 5%. All the 6 patients have been initially classified as AA/PNH syndrome at time of eculizumab starting, but did not require specific treatment before; they were all on eculizumab treatment at the standard dose of 900 mg fortnightly, with adequate control of intravascular hemolysis. Five of the patients fulfilled the criteria of severe AA, the latter had very severe isolated neutropenia, and was diagnosed with an immune-mediated agranulocytosis. Since no patient had a HLA-matched related donor for BMT, all the patients received intensive IST according to different institutional regimens; eculizumab was not discontinued to minimize the risk of rebound intravascular hemolysis and thrombotic complications. Three patients (2 AA and 1 agranulocytosis) received standard IST with horse-antithymocyte globulin (h-ATG, 40 mg/kg for 4 consecutive days) combined cyclosporine A (CsA). The 3 other AA patients received alemtuzumab (3-10-30-30 mg subcutaneously in 4 consecutive days) and CsA within the prospective trial NCT00895739; one of these patients a few months later also received a second IST course with rabbit-ATG (3.5 mg/kg for 5 consecutive days) and CsA. All the patients completed the scheduled treatment without any side effect, including infusion-related reactions. Lymphocyte depletion was observed in all patients irrespective of sustained therapeutic complement blockade, with lymphocyte count dropping <100/μL in all cases and lasting for several days (or even months in the case of alemtuzumab). All patients remained on eculizumab treatment, even if one AA patient required an increase of the dose up to 1200 mg because of pharmacokinetic breakthrough; in 2 patients 50% hemolytic complement (CH50) was systematically monitored during the treatment course, without showing any significant change from status at pre-IST treatment. All the patients were available for response assessment at 6 months; globally, 3 out of 6 showed a hematological response. The agranulocytosis patient achieved a partial response (PR) requiring G-CSF chronic treatment. Among the 5 AA patients, we observed 2 CR (1 with h-ATG and 1 with alemtuzumab) and 1 PR (after alemtuzumab); this latter was converted into a CR after a second IST course with r-ATG. One of the CR relapsed at 3 years showing clonal evolution toward a myelodysplastic syndrome, and finally died. All the other patients are alive, keeping their hematological response; of the 3 non-responders, 1 was rescued with an unrelated transplantation, and 2 remain on eculizumab treatment (one has developed thromboembolic complications).This is the first systematic description of the management of severe BMF in PNH patients on anti-complement treatment; we first observed that this rare challenging condition may pertain to about 5% of PNH patients. Then we demonstrated that intensive IST, based on either polyclonal or monoclonal anti-lymphocyte antibodies can be safely delivered even in concomitance of eculizumab. Pharmacological lymphocyte depletion was achieved irrespective of terminal complement inhibition. Clinical efficacy was in the expected range as in broader AA populations, with an overall reponse rate of 50%. Based on these data, intensive IST delivered on top of eculizumab should be considered in PNH patients who develop severe AA during eculizumab treatment lacking a low-risk bone marrow transplant procedure. DisclosuresPeffault de Latour:Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding. Risitano:Alnylam: Research Funding; Novartis: Research Funding; Alexion Pharmaceuticals: Other: lecture fees, Research Funding; Rapharma: Research Funding.

Clonal Dynamics of Refractory Aplastic Anemia in Patients Treated with Eltrombopag

Despite documented success of immunosuppressive therapy (IST) in the treatment of AA, a minority of patients remain refractory, most responses are incomplete, and use of hematopoietic cell transplantation (HCT) is limited in older patients or those with significant comorbidities. While the introduction of the cMpl agonist eltrombopag (EPG) as salvage therapy or in conjunction with IST has revolutionized treatment for refractory AA. It may be effective in improving primary response rates to IST, engaging growth factor receptors with agonistic therapeutics (such as EPG) and also has the potential to promote evolution/expansion of mutant clones, thereby increasing the rate of progression to secondary myelodysplastic syndromes (MDS), a serious complication of AA occurring in 10-20% of patients. Clonogenic somatic mutations typical of MDS in patients with AA and PNH may increase the risk of progression to MDS.DNA from marrow samples of primary refractory AA patients was subjected to analysis before and after initiation of EPG to evaluate clonal expansion or evolution using a targeted multi-amplicon deep NGS panel of all ORFs of the top 60 most commonly mutated genes in MDS. In addition to the EPG treatment group, a case control cohort matched for age and duration from AA diagnosis to last clinical follow up (who did not receive EPG), was studied.Among 210 AA patients treated at Cleveland Clinic, we identified 26 who were treated with EPG for IST-refractory AA; median duration of treatment was 56 wks. The overall response rate after 12 weeks of therapy was 58% (15/26), while 31% of patients (8/26) showed stable disease with intermittent transfusions (one of whom underwent HCT). In 3 non-responders, one developed PNH, one had refractory AA/PNH, and one progressed to AML (see below). Expansion of PNH granulocytes after EPG treatment was observed in 23% of patients (6/26). In addition, 15% (4/26) had atypical subclonal chromosomal abnormalities.Prior to EPG, at least a single somatic event was found in 31% of patients (8/26), with 2 patients harboring 2 mutations. Events included CEBPA, EZH2, BCOR/BCORL1, ASXL1, U2AF1/2, TET2, and DNMT3A mutations. Following EPG therapy, acquisition of new somatic mutations was observed in 23% of cases, including RUNX1, U2AF1, BCOR, RIT1, and CEBPA. In cases with pre-existing clones, 6 clones expanded (e.g., BCOR or ASXL1 from VAF of 8 to 21% and 9 to 29%, respectively) despite clinical hematologic response, while in 2 cases clones disappeared (e.g., U2AF2 and BCORL1). In 54% of cases (14/26), we found detectable levels of a PNH clone at the time of diagnosis. Six of those cases had PNH clonal expansion post-EPG treatment, of which two developed clinically significant PNH clonal burden requiring eculizumab therapy.In the case-control cohort, 26 AA patients who received IST but were not treated with EPG, were followed for comparable time periods, and no evidence of progression to MDS was recorded. One patient was noted to have trisomy 15 on cytogenetics at diagnosis. "MDS type" molecular mutations were present in 10 patients similar to EPG cohort. Among these patients, 3 had persistent clones of U2AF1, DNMT3A, and STAT3 over one year without acquisition of any new molecular mutations. . PNH granulocytes expanded in 50% of AA cases, decreased in 30% and stayed stable in 20%. Thus, we did not observe any difference in expansion of PNH clones between those treated and untreated with EPG (p=0.73). Unlike for PNH clones, accounting for both new evolution and expansion of preexisting molecular mutations, the frequency of these clonal events was significantly higher in the EPG treated group (p=0.009).In conclusion, we observed occasional expansion of clones with potentially leukemogenic mutations during treatment with EPG in pts with AA. While higher rates of MDS evolution were not observed in this cohort of EPG treated patients, we found that serial evaluation of somatic mutations can inform clonal evolution and can potentially be used as abiomarker for evaluation of risk for post-AA MDS. Continued use of EPG in such patients should be judicious. DisclosuresCarraway:Celgene: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Clonal Events of Aplastic Anemia Related to the Evolution to Myelodysplastic Syndrome

Somatic mutations constitute clonal markers now amenable to monitoring by deep NGS. While transient and low frequency clones have been described in AA, their pathophysiologic link to the overtly clonal complication of AA, secondary MDS following AA (sMDS), has not been established. Clarification of this relationship may provide clues as to the genesis of sMDS. Identification of predictive markers for AA patients at risk for this complication is necessary. The etiology of sMDS within AA may include either expansion of a preexisting clone or truly late clonogenic events. In both instances, progression may result in clonal escape. To address these questions we studied 258 AA and 60 PNH patients, identifying 35 patients (11%) who evolved to sMDS. Cytogenetic analysis showed abnormal karyotype in 76% cases; 5% had complex karyotype and -7/del(7q) was present in 67% of cases. The presence of a PNH clone was detected in a similar proportion of cases that transformed to sMDS vs. those that did not (P=.76). For comparison, we have also analyzed primary de novo cases of MDS (pMDS) with (N=19) and without (N=161) -7/del(7q). In contrast to sMDS, -7/del(7q) was present in 12% of cases of pMDS. Using WES on 8 cases and a 60 gene targeted panel on 15 cases, confirmed mutational events and chromosomal aberrations were found in 21/23 patients with sMDS; 18/23 cases of sMDS had at least 1 confirmed somatic mutation.By comparison of mutational profiles ASXL1, RUNX1, PIGA, SETBP1, and CBL were most common in sMDS (26.1%, 21.7%, 18%, 13% and 13%, respectively). Because sMDS included a high proportion of patients with -7/del(7q), we compared sMDS with -7/del(7q) to pMDS with -7/del(7q) for coexisting mutational events. Mutations in RUNX1 appeared to be more frequent in sMDS vs. pMDS (27% vs. 0%, P=.03). In contrast, TP53 was more common in pMDS (7% vs. 32%, P=.1). Similarly, there were several other distinctive differences between all sMDS and pMDS irrespective of cytogenetics: mutations in U2AF1 were common in pMDS, mutations in RUNX1 appeared to be more frequent in sMDS vs. pMDS (22% vs. 5.5%, P=.02). Mutations in PIGA gene constituted a marker for sMDS derivation from AA. To discern a possible biological relationship we have also compared mutational profiles of hypocellular pMDS and sMDS, but no significant differences aside from PIGA prevalence were found.If sMDS is derived from mutations present at the AA stage, one would expect overlaps in the mutational spectrum of AA before and after evolution to MDS. DNMT3A, BCOR/BCORL1, and PDGFR family mutations were found at higher frequency in AA while ASXL1, RUNX1, SETBP1, PIGA, and CBL were higher in sMDS. Thus, cross-sectional analysis suggests that most of the clonal events occurring during the course of AA do not initiate sMDS. To further examine these findings we performed serial sequencing analyses: in 7 patients with sMDS WES was performed and clonal architecture was analyzed. We then queried whether mutations present in MDS were detected in archival samples at presentation using deep targeted NGS (depth 5-10x104 rds. In 4/7 cases the alterations appeared to be ancestral events for sMDS evolution. When an additional 68 AA cases were studied by deep NGS, somatic mutations were present in 31% of AA patients at presentation. Patients with clonal events at presentation tended toward worse progression free survival compared to patients without mutations (P=.1). Mutations found at both initial presentation and upon evolution were suggestive of a slow expansion of previously cryptic clones (ASXL1, CUX1, TET2, CBL, RUNX1, and SETBP1). Patients with these gene mutations (n=21) before immunosuppressive therapies (IST) had worseoverall survival compared to patients without these mutations (n=47; P=.009). To assess the potential impact of IST, we also investigated a subset of 37 patients (25 responders/ 12 refractory) following IST. Clonal somatic events were identified in 42 of them, but there was no association between the response to IST and somatic mutations at presentation (P=.7).Our results demonstrate that while subclonal mutations indicative of oligoclonal hematopoiesis are frequent in AA, the presence of specific permissive ancestral somatic events at the outset of AA predisposes patients to sMDS, a feature that has diagnostic and prognostic implications. DisclosuresMakishima:The Yasuda Medical Foundation: Research Funding. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau.

Long-Term Outcome after Immunosuppressive Therapy with Rabbit ΑΤG for Pediatric Aplastic Anemia: A Single-Center Retrospective Study in China

▪Background: Antithymocyte globulin (ATG)-based immunosuppressive therapy (IST) has been successfully used as the first-line treatment for severe / very severe aplastic anemia (SAA/VSAA) patients if no HLA-matched sibling donor was eligible for HSCT as a first choice. It was reported rabbit ATG (rATG) produced more profound immunosuppressive activity compared to horse ATG (hATG). However, recent clinical studies indicated that the stronger lympholytic activity did not mean that rATG was more effective. Most experiences from adult SAA/VSAA implied the efficacy of rATG was worse than hATG. However, susceptibility of children to intensive IST might not be exactly the same as adult patients, long-term efficacy of rATG in historic studies for children with SAA/VSAA was still elusive.Purpose: This study includes the largest cohort of pediatric AA patients treated with first-line rATG+CSA regimen published to date after a median follow-up of 69 months, aiming to assess the long-term outcome of rATG for children, and to identify the significant prior factors in clinical decision making.Methods: We reviewed 231 SAA/VSAA patients under 18 years old assigned to rATG+CSA from February 2000 to May 2014 in Department of Pediatrics, the Blood Diseases Hospital & Institute of Hematology, CAMS & PUMC. Response was evaluated 3, 6, 9, 12 24, 36 and 60 months after IST. We separately defined SAA-II as a specific type of gradually progressed SAA from a NSAA status within a longer period for at least 6 months. Multivariate logistic regression models were used to evaluate the effects of variables on the responses at different time points. Multivariate Cox model analysis of overall survival (OS) and failure-free survival (FFS) was calculated for variables with a log rank P value less than 0.1 in Kaplan-Meier analysis.Results: Of the overall patients, the total responded patients were 79(34.3%), 110(51.6%), and 129 (60.6%) at 6, 9, 12 months following IST, respectively. Intriguingly, 22 patients achieved delayed response between 12 months and 24months after IST, which increased the overall response rate by 10.2%, afterwards the rate reached a plateau by 3 years with the best response rate of 74.6% (Figure 1). Differences in baseline clinical parameters pre-IST were associated with response to IST. Absolute neutrophil count (ANC) less than 0.1*109/L was associated with an unfavorable early response rate at 6 months (P=0.009); absolute lymphocyte count (ALC) less than 1.6*109/L was a significant predictor for better response by 6 months and 12 months in multivariate analysis [6 months, P=0.033 vs. 12 months, P=0.021]. Lower absolute reticulocyte count (ARC no more than 18.5*109/L) predicted worse late IST response by 2 years and 3 years. In our large series of cohort, 5-year OS and FFS were 82.7% and 61.9%. Patients with VSAA as a significantly unfavorable prognostic factor had a much lower probability of 5-year survival when compared to patients diagnosed with SAA (76.4% vs. 87.2%, P<0.001, Figure2A). In multivariate analysis, SAA-II (P=0.021, Figure2B), and a pretreatment lower ARC (P=0.020, Figure2C) were independent unfavorable prognostic factors for FFS, but moderate PNH clone size (more than 5%) was verified as a good predictor for FFS (P=0.006, Figure 2D). At the last follow-up, twelve of the 135 responders relapsed after IST, meanwhile eight patients in responders and seven patients in non-responders experienced clonal evolution after IST, corresponding to cumulative incidences at 5.2% of relapse and 6.5% of evolution, which were obviously lower than previous reports.Conclusions: The combination of rATG and CSA was confirmed as an effective first-line therapy for children with SAA/VSAA in our cohort. We discerned a protracted recovery but an ultimately comparable long-term outcome of rATG. Baseline blood parameters (ANC, ALC, ARC) were predictive factors of response rate. Intensive supportive care may be necessarily pivotal to survival in cases of VSAA. Importantly, moderate PNH clone might be beneficial to FFS. Besides, for those who experienced gradually progressed disease course, early HSCT might be a more preferable option than receiving IST although further validation remains to be done. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

First LINE Treatment of Aplastic Anemia with Thymoglobuline in Europe and ASIA: Outcome of 976 Patients Treated 2001-2012.

▪Background. Recent studies have suggested inferior outcome of patients treated with rabbit ATG (Thymoglobulin) as compared to horse ATG (ATGAM , Pfizer or Lymphoglobulin, Genzyme- the latter no longer available); other studies have shown comparable responses and survival. However these studies are based on a relatively small number of patients and a short follow up.Aim of the study. The aim of this study was to assess real life outcome of a large number of AA patients , treated in Europe and Asia with rabbit ATG (Thymoglobulin, SANOFI) and cyclosporin, as first line treatment .Methods and patients Eligible for this study were patients with AA treated with Thymoglobulin between 2001 and 2008 (n=501) and 2009-2012 (n=473) in Europe (n=519) or Asia (n=457). Median year of treatment was 2008 : median age (20 and 21 years), interval diagnosis treatment (23 and 25 days) and severity of the disease (46% and 48% with vSAA) were comparable in the 2 time periods.Early mortality. Mortality <90 days was 5,5% and 2.1% in the time period 2001-2008 and 2009-2012 (p=0.007). In patients aged 0-60 early mortality was reduced from 3.5% to 1.4% and in patients over 60 , from 22% to 9%.Response. Overall response was recorded in 799 patients. At 6 months , responses were comparable in the 2 time periods: 56% vs 57%, and at 1 year, 75% vs 73%. Response rates at 6 months were age dependent: 60%, 58%, 52%, 40% respectively in patients aged 0-20, 21-40, 41-60, >60. When non responders at 3 months were re-evaluated at 1 year, 59% had responded , 26% were non responders , 5% had died, and 10% had received other treatment.Survival: The actuarial 10 year survival for the entire population was 73%, and 72%, when patients were censored as surviving at transplant. The actuarial survival has significantly improved after year 2008, from 71% to 81% , not because of more transplants, which have remained stable (29% vs 30% before or after 2008). Other predictors of 10 year survival in univariate analysis were the following : 89%, 86%, 59% for complete, partial responders and non responders (p<0.01), 68% vs 80% for males versus females (p=0.07); 69%, 77%, 78% in patients with neutrophils <0.2x10^9/L, 02-05x10^9/L and >0.5x10^9/L (p<0.001); 77%, 75%, 68% for patients with an interval diagnosis-treatment of <30 days, 31-60 days or > 60 days (p=0.002); 82%, 72%, 66%, 27% in patients aged 0-20, 21-40, 41-60, > 60 years (p<0.001). Survival at 5 years for patients aged 1-60 in the recent period (2009-2012) was 83% and 62% for patients over 60 years; for patients treated within 60 days from diagnosis these figures are 86% and 83%. In multivariate Cox analysis the following variables remained independent predictors of survival : patient age, year of treatment , severity of the disease, interval diagnosis treatment, gender.Conclusions. With a current overall early mortality (<day 90) of 1.4% , a response rate at 6 months of 58% and 5 year survival of 81%, the combination of CsA and Thymoglobulin appears to be safe and effective as first line treatment in patients aged 1-60. In patients over 60 years of age, early mortality is higher , response rate and 5 year survival is lower, but results have improved after year 2008 , and current 5 year survival is 69%, for older patients treated within 2 months from diagnosis. Finally, response rates and survival, in this large retrospective analysis are quite favourable , compared to other recent publications, although a comparison with horse ATG was not the aim of the present study. DisclosuresBacigalupo:PIERRE FABRE: Speakers Bureau; SANOFI: Speakers Bureau. Carlo:Pfizer, Novartis: Consultancy. Kojima:SANOFI: Honoraria, Research Funding.

SURG-29. PERSONALIZING THE DECISION GROSS TOTAL RESECTION (GTR) IN NEURO-ONCOLOGY

Since glial tumors are inherently infiltrative, microscopic total resection is not possible without significant morbidity. The efficacy of cyto-reduction through gross total resection (GTR) largely depends on the chemo-sensitivity of the remaining tumor. For instance, GTR of primary CNS lymphoma (PCNSL) is rarely desired. Since chemo-sensitivity differ depending on glioma histology, we hypothesized that the survival benefit of GTR differ accordingly. We identified patients who underwent surgery for WHO grade II diffuse astrocytoma (DA, n= 4,113), WHO grade III anaplastic astrocytoma (AA, n=2,755), glioblastoma (n=21,962), and oligodendroglioma (grade II n=2,378; grade III n=11,028) in the Surveillance, Epidemiology, and End Results Program (SEER, 1999-2012). Median survival and hazard ratio (HR) for dying from the disease after correction of pertinent clinical/demographic variables was determined as a function of GTR, and subtotal resection (STR). Pertinent results were assessed against published literature. Based on hazard ratio analysis, DA and AA patients derived the greatest survival benefit from GTR. The median survival for patients with DA who underwent GTR and STR were >60 and 48 months, respectively. The median survival for patients with AA who underwent GTR and STR were 54 and 24 months, respectively. Glioblastoma patients derived modest survival benefit from GTR, with median survival of 13 months for GTR patients and 9 months for STR patients. In contrast, for grade II or III oligodendrogliomas, survival of GTR patients did not significantly differ irrespective of the extent of resection. Meta-analysis of articles identified from a comprehensive search of the published literature yield results comparable to the SEER database. Our study suggest that surgeons should take tumor histopathology into account when deciding upon the extent of surgical resection of glial tumors and the critical need for real-time intra-operative histologic diagnosis.

African Americans and Short-Term Outcomes after Surgery for Crohn's Disease: An ACS-NSQIP Analysis.

Previous reports on racial disparities in the treatment of Crohn's disease [CD] in African American [AA] patients have shown differences in both medical and surgical treatments in this population. No study thus far has examined the effect of AA race on outcomes after surgery for CD. Utilizing the National Surgical Quality Improvement Program [NSQIP] Participant User File [PUF] for the years 2005-2013, we examined the effect of AA race on postoperative complications in patients with CD undergoing intestinal surgery. AA patients had a significantly higher rate of complications overall compared to non-AA patients [23.5% vs 18.9%, p = 0.002]. Postoperative sepsis [10.9% vs 6.6%, p < 0.001] and surgical site infection [17.6% vs 14.8%, p = 0.037] were most significant. After adjustment for age, sex, preoperative disease severity and lifestyle factors [smoking], race remained a statistically significant factor in postoperative complication rate. Only after additional adjustment was made for comorbidities and American Society of Anesthesiologists class did race lose significance within our model. African Americans experience a greater amount of postoperative complications following surgery for Crohn's disease. Preoperative disease management, addressing smoking status and control of comorbid disease are important factors in addressing the racial disparities in the surgical treatment of Crohn's disease.

Subsequent Chemotherapy and Treatment Patterns After Abiraterone Acetate in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302

BackgroundTreatment patterns for metastatic castration-resistant prostate cancer (mCRPC) have changed substantially in the last few years. In trial COU-AA-302 (chemotherapy-naïve men with mCRPC), abiraterone acetate plus prednisone (AA) significantly improved radiographic progression-free survival and overall survival (OS) when compared to placebo plus prednisone (P). ObjectiveThis post hoc analysis investigated clinical responses to docetaxel as first subsequent therapy (FST) among patients who progressed following protocol-specified treatment with AA, and characterized subsequent treatment patterns among older (≥75 yr) and younger (<75 yr) patient subgroups. Design, setting, and participantsData were collected at the final OS analysis (96% of expected death events). Subsequent therapy data were prospectively collected, while response and discontinuation data were collected retrospectively following discontinuation of the study drug. InterventionAt the discretion of the investigator, 67% (365/546) of patients from the AA arm received subsequent treatment with one or more agents approved for mCRPC. Outcome measurements and statistical analysisEfficacy analysis was performed for patients for whom baseline and at least one post-baseline prostate-specific antigen (PSA) values were available. Results and limitationsBaseline and at least one post-baseline PSA values were available for 100 AA patients who received docetaxel as FST. While acknowledging the limitations of post hoc analyses, 40% (40/100) of these patients had an unconfirmed ≥50% PSA decline with first subsequent docetaxel therapy, and 27% (27/100) had a confirmed ≥50% PSA decline. The median docetaxel treatment duration among these 100 patients was 4.2 mo. Docetaxel was the most common FST among older and younger patients from each treatment arm. However, 43% (79/185) of older patients who progressed on AA received no subsequent therapy for mCRPC, compared with 17% (60/361) of younger patients. ConclusionsPatients with mCRPC who progress with AA treatment may still derive benefit from subsequent docetaxel therapy. These data support further assessment of treatment patterns following AA treatment for mCRPC, particularly among older patients. Trial registrationClinicalTrials.gov NCT00887198. Patient summaryTreatment patterns for advanced prostate cancer have changed substantially in the last few years. This additional analysis provides evidence of clinical benefit for subsequent chemotherapy in men with advanced prostate cancer whose disease progressed after treatment with abiraterone acetate. Older patients were less likely to be treated with subsequent therapy.