Adverse Risk Factor For Survival Research Articles

Cytoreductive Surgery and Hyperthermic Peritoneal Chemotherapy in Appendiceal and Colorectal Cancer: Outcomes and Survival.

We reviewed outcomes following cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with appendiceal or colorectal neoplasms and evaluated key prognostic indicators for treatment. All patients who underwent cytoreductive surgery/HIPEC for appendiceal and colorectal neoplasms were identified from an IRB-approved database. Patient demographics, operative reports, and postoperative outcomes were reviewed. 110 patients [median age 54.5 (18-79) years, 55% male] were included. Primary tumor location was colorectal (58; 52.7%) and appendiceal (52; 47.3%). 28.2%, .9%, and 12.7% had right, left, and sigmoid tumors, respectively; 11.8% had rectal tumors. 12/13 rectal cancer patients underwent preoperative radiotherapy. Mean Peritoneal Cancer Index was 9.6 ± 7.7; complete cytoreduction was achieved in 90.9%. 53.6% developed postoperative complications. Reoperation, perioperative mortality, and 30-day readmission rates were 1.8%, .09%, and 13.6%, respectively. Recurrence at a median of 11.1 months was 48.2%; overall survival at 1 and 2years was 84% and 56.8%, respectively; disease-free survival was 60.8% and 33.7%, respectively, at a median follow-up of 16.8 (0-86.8) months. Univariate analysis of preoperative chemotherapy, primary malignancy location, primary tumor perforated or obstructive, postoperative bleeding complication, and pathology of adenocarcinoma, mucinous adenocarcinoma and negative lymph nodes were identified as possible predictive factors of survival. Multivariate logistic regression analysis showed that preoperative chemotherapy (P < .001), perforated tumor (P = .003), and postoperative intra-abdominal bleeding (P < .001) were independent prognostic indicators for survival. Cytoreductive surgery/HIPEC for colorectal and appendiceal neoplasms has low mortality and high completeness of cytoreduction score. Preoperative chemotherapy, primary tumor perforation, and postoperative bleeding are adverse risk factors for survival.

HigherRUNX1 expression levels are associated with worse overall and leukaemia-free survival in myelodysplastic syndrome patients.

RUNX1 mutations are frequently detected in various myeloid neoplasms and implicate unfavourable clinical outcomes in patients with myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). On the other hand, high expression of RUNX1 is also correlated with poor prognosis in AML patients. However, the clinical relevancy of RUNX1 expression in MDS patients remains elusive. This study aimed to investigate the prognostic and biologic impacts of RUNX1 expression in MDS patients. We recruited 341 MDS patients who had sufficient bone marrow samples for next-generation sequencing. Higher RUNX1 expression occurred more frequently in the patients with Revised International Prognostic Scoring System (IPSS-R) higher-risk MDS than the lower-risk group. It was closely associated with poor-risk cytogenetics and mutations in ASXL1, NPM1, RUNX1, SRSF2, STAG2, TET2 and TP53. Furthermore, patients with higher RUNX1 expression had significantly shorter leukaemia-free survival (LFS) and overall survival (OS) than those with lower expression. Subgroups analysis revealed that higher-RUNX1 group consistently had shorter LFS and OS than the lower-RUNX1 group, no matter RUNX1 was mutated or not. The same findings were observed in IPSS-R subgroups. In multivariable analysis, higher RUNX1 expression appeared as an independent adverse risk factor for survival. The prognostic significance of RUNX1 expression was validated in two external public cohorts, GSE 114922 and GSE15061. In summary, we present the characteristics and prognosis of MDS patients with various RUNX1 expressions and propose that RUNX1 expression complement RUNX1 mutation in MDS prognostication, wherein patients with wild RUNX1 but high expression may need more proactive treatment.

Effectiveness of craniotomy and long-term survival in 35 patients with gestational trophoblastic neoplasia with brain metastases: a clinical retrospective analysis.

ObjectiveTo investigate the clinical characteristics, treatments, and prognostic factors among patients with gestational trophoblastic neoplasia (GTN) exhibiting brain metastases who underwent craniotomy.MethodsThirty-five patients with GTN who had brain metastases and subsequently underwent craniotomies between January 1990 and December 2018 at Peking Union Medical College Hospital were identified using the GTN database. Their clinical manifestations, treatments, outcomes, and prognostic factors were retrospectively analyzed.ResultsAll 35 patients underwent decompressive craniotomy, hematoma removal, and metastatic tumor resection combined with multiagent chemotherapy. Eighty percent (28/35) achieved complete remission, 11.4% (4/35) achieved partial remission, and 8.6% (3/35) had progressive disease. Not counting 2 patients who were lost to follow-up, 81.8% of the patients (27/33) were alive after a median follow-up of 72 months. The 5-year overall survival rate was 80.4%. Univariate analysis revealed that a history of chemotherapy failure (p=0.020) and a >1-week interval between craniotomy and chemotherapy commencement (p=0.027) were adverse risk factors for survival. Multivariate analysis showed that previous chemotherapy failure remained an independent risk factor for poor survival (odds ratio=11.50; 95% confidence interval=1.55–85.15; p=0.017).ConclusionDecompressive craniotomy is a life-saving option if metastatic hemorrhage and intracranial hypertension produce a risk of cerebral hernia in patients with GTN who have brain metastases. Higher survival rates and improved prognoses can be achieved through perioperative multidisciplinary cooperation and timely standard postoperative chemotherapy.

Clinical profile, treatment and outcome of pediatric brain tumors in Serbia in a 10-year period: A national referral institution experience.

ObjectiveThis study aimed to evaluate the characteristics of children with primary brain tumors, the effectiveness of treatment modalities, and to detect factors related to the outcome.MethodsA detailed analysis was performed on a series of 173 pediatric patients treated in a Serbian referral oncology institution between 2007 and 2016, based on their clinical, histological, treatment, and follow-up data.ResultsMean survival time of all children was 94.5months. 2-, 5- and 10-year overall survival probabilities were 68.8%, 59.4%, and 52.8%, respectively. Patients with supratentorial tumors had longer survival than patients with infratentorial tumors and patients with tumors in both compartments (p = 0.011). Children with the unknown histopathology (brainstem glioma) and high-grade glioma had a shorter life than embryonal tumors, ependymoma, and low-grade glioma (p<0.001). Survival of the children who underwent gross total resection was longer than the children in whom lesser degrees of resection were achieved (p = 0.015). The extent of the disease is a very important parameter found to be associated with survival. Patients with no evidence of disease after surgery had a mean survival of 123 months, compared with 82 months in patients with local residual disease and 55 months in patients with disseminated disease (p<0.001). By the univariate analysis, factors predicting poor outcome in our series were the presentation of disease with hormonal abnormalities, tumor location, and the extent of the disease, while the factors predicting a better outcome were age at the time of diagnosis, presentation of the disease with neurological deficit, and type of resection. By the multivariate analysis, the extent of the disease remained as the only strong adverse risk factor for survival (HR 2.06; 95% CI = 1.38–3.07; p<0.001).ConclusionsWith an organized and dedicated multidisciplinary team, the adequate outcomes can be achieved in a middle-income country setting. The presence of local residual disease after surgery and disseminated disease has a strong negative effect on survival.

Identification of Adverse Risk Factors for Survival in Acquired Pure Red Cell Aplasia Receiving Immunosuppressive Therapy By the Japan PRCA2004/2006 Study and Introduction to the New Cohort Study PRCA2016

Pure red cell aplasia (PRCA) is characterized by normocytic normochromic anemia associated with reticulocytopenia and erythroid hypoplasia in otherwise normal bone marrow. The acquired chronic PRCA may present as a primary hematological disorder in the absence of any other diseases or develop associated with certain conditions such as thymoma, lymphoproliferative disorders, infections, collagen vascular diseases, or after exposure to a wide variety of drugs. Idiopathic PRCA and secondary PRCA not responding to the treatment of the underlying diseases are generally treated by immunosuppressive therapy and the most patients require long-term treatment. Glucocorticoids, cyclosporine and cyclophosphamide are commonly used for initial treatment as monotherapy or combination therapy and majority of the patients respond to immunosuppression. However, most patients treated with these medications relapse during tapering of the treatment. Because of the extreme rarity of this disease, the long-term outcome of chronic PRCA following immunosuppression remains unclear and the adverse risk factors for survival have to be elucidated.In order to identify the adverse risk factors for survival in acquired chronic PRCA following immunosuppression and improve the prognosis, we have conducted nationwide surveys for adult acquired chronic PRCA in Japan. We conducted the first study for adult chronic PRCA in japan in 2004 and 2006 that had been diagnosed between 1990 and 2006 across 109 institutions, and collected the data on a total of 185 patients (PRCA2004/2006 study). We have also started another cohort study in 2016 in collaboration with the Japanese Society of Hematology (JSH) (PRCA2016 study) that was approved by the institutional review board and the ethical committee of the JSH.In PRCA2004/2006 study 73 patients (39%) were classified as having idiopathic PRCA and 112 patients (61%) as having secondary PRCA, including 42 thymoma- and 14 large granular lymphocyte leukemia (LGL)-associated PRCA. The details on idiopathic, thymoma-associated and LGL-leukemia-associated PRCA have been previously reported (Sawada K, et al. Haematologica 2007;92:1021; Hirokawa M, et al. Haematologica 2008;93:27; Fujishima N, et al. Haematologica 2008;93:1555). The last questionnaires for the patients with these three subtypes of PRCA were sent to the institutions in 2012 for collecting the data on relapse, subsequent treatment and efficacy and outcome.The PRCA2004/2006 study revealed that the median overall survival (OS) has not yet been reached in idiopathic PRCA following immunosuppression and the estimated median OS times in thymoma-associated and LGL leukemia-associated PRCA were 142 and 148 months, respectively. Twenty-two deaths were reported and the major causes of death were infection and organ failure (Hirokawa M, et al. Brit J Haematol 2015;169:879). Poor response to induction therapy and relapse of anemia were demonstrated to be associated with death and this was also confirmed by the Mantel-Byar analysis (p<0.001) (Fig. 1). The efficacy of re-induction therapy for relapsing PRCA was inferior to the initial inductive therapy (p<0.001) (Fig. 2).With the results of this study, we have proposed the clinical guidelines for management of PRCA in 2011 and we conducted another cohort study in 2016 in collaboration with the Japanese Society of Hematology (JSH) (PRCA2016 study). The primary endpoint of this study is the OS in chronic PRCA following immunosuppression and the principal aim is to learn whether or not the prognosis would be improved. Between 2006 and 2014, 554 PRCA patients were registered in the JSH hematological disorder registry and we asked the physicians to participate in this study (Fig. 3). The potential size of patient cohort is 181, including 116 idiopathic and 65 secondary PRCA and these patients will be followed up during the next ten years. The PRCA2016 cohort study is expected to reveal the unbiased results regarding the long-term survival and quality of life in PRCA following immunosuppression. [Display omitted] DisclosuresFujisawa:Bristol myers Squibb: Honoraria; Beckman Coulter: Honoraria; Eisai: Honoraria; Janssen Pharmaceutical: Honoraria; Novartis: Honoraria; Astellas: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Otsuka Pharmaceutical: Honoraria, Research Funding; SHIONOGI CO, LTD: Honoraria, Research Funding; Shire plc: Honoraria; Alexion Pharmaceutical: Honoraria; Pfizer: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceuticals: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Kyowa Hakko Kirin: Research Funding; MSD: Research Funding. Yonemura:Alexion Pharma GK: Honoraria, Research Funding. Kurokawa:Pfizer Inc.: Research Funding; Celgene Corporation: Speakers Bureau; Nippon Shinyaku Co., Ltd.: Other: Scholarship donations for the laboratory, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Takeda Pharmaceutical Company Limited.: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding.

Overall Survival in Acquired Pure Red Cell Aplasia in Adults Following Immunosuppressive Therapy: Preliminary Results from the Nationwide Cohort Study (PRCA2016)

▪Background.Idiopathic PRCA and secondary PRCA not responding to the treatment of the underlying diseases are generally treated by immunosuppressive therapy. Because of the rarity of this disease, there are few reports regarding the long-term outcome following immunosuppression. We previously conducted the nationwide study for chronic PRCA in Japan that had been diagnosed between 1990 and 2006 across 109 institutions, and collected the data on a total of 185 patients (PRCA2004/2006 study). This study revealed that poor response to induction therapy and relapse of anemia were associated with death. There was no significant difference in survival between idiopathic and secondary PRCA in the PRCA2004/2006 study cohort.Objective.In order to identify the adverse risk factors for survival in acquired PRCA following immunosuppression in a prospective way, we have conducted another nationwide cohort study for acquired PRCA in adults (PRCA2016 study). The primary endpoint is the overall survival (OS) and the secondary endpoints include efficacy of immunosuppression, causes of treatment failure and survival times with iron-chelation therapy.Methods.This is designed as a prospective longitudinal observational study. Between 2006 and 2014, 554 PRCA patients were registered in the hematological disorder registry managed by the Japanese Society of Hematology. We sent the first questionnaires to the physicians asking for collaboration with this study and the responses showed the potential size of cohort was 181 patients (Fig. 1). We then sent the second questionnaires to collect data regarding underlying disease, laboratory findings including CBC and leukocyte differentials, results of bone marrow examination, immunological and cytogenetics, efficacy of immunosuppression, iron-chelation therapy in refractory cases and outcome. The review boards of participating institutions and the ethical committee of the JSH approved this study and informed consent was obtained from the patients.Results.As of June 16, 2018, 103 patients were registered in this study. Fifty-two patients were classified as having idiopathic PRCA and 51 patients as having secondary PRCA, including 16 thymoma- and 5 large granular lymphocyte (LGL) leukemia-associated PRCA. Seventy-one patients were treated with immunosuppressive agents. The response rates of cyclosporine, predonisolone, cyclophosphamide, azathioprine and combination with more than one immunosuppressants were 84% (43/51), 89% (8/9), 100% (2/2), 0% (0/1), 60% (9/15), respectively (Fig. 2). The Kaplan-Meyer estimates of the survival revealed that the estimated median survival time in idiopathic PRCA was 6,430 days and that in secondary PRCA has not yet been reached (Fig. 3). Survival time was not significantly different between the two subtypes of PRCA. Twenty-two deaths were reported and the major causes of death were infection and heart failure.Discussion/Conclusion.The most common subtypes of chronic PRCA in Japan were idiopathic, thymoma-associated and LGL leukemia-associated PRCA and this result was consistent with our observation in the PRCA2004/2006 study. Cyclosporine and prednisolone were frequently chosen for the induction therapy resulting in favorable responses. Preferential use of these two agents might reflect the physician's concern about the toxicity of the cytotoxic drugs. The median survival time of idiopathic PRCA was quite similar to the results in the previous cohort study. No significant difference in survival between idiopathic and secondary PRCA has been confirmed by the present study. These two cohort studies clearly indicate that novel diagnostic and predictive biomarkers should be developed to segregate the good and poor responders to immunosuppressive therapy in PRCA. [Display omitted] DisclosuresNakao:Novartis: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Yonemura:Alexion Pharma: Honoraria, Research Funding. Matsuda:GlaxoSmithKline K.K.: Honoraria; Novartis Pharma K. K.: Honoraria; Chugai Pharmaceutical Co, Ltd.: Honoraria; Kyowa Hakko Kirin Co, Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Celgene Corporation: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria; Sanofi K.K.: Honoraria; Beckman Coulter K.K.: Honoraria. Kurokawa:Otsuka Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; MSD: Honoraria, Research Funding; Pfizer: Research Funding; Eizai: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Research Funding; Teijin Pharma: Research Funding; Nippon Sinyaku: Honoraria, Research Funding; Takeda Pharmaceutical: Research Funding; Chugai Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Arai:Novartis: Research Funding. Mitani:Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau; Bristol-Myesr Squibb: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Chugai: Research Funding; Astellas: Research Funding; Sumitomo Dainippon: Research Funding; Novartis: Research Funding; Toyama Chemical: Research Funding.

Role of positive peritoneal cytology in FIGO stage IB to IIB cervical adenocarcinoma.

To evaluate the prognostic relevance of positive peritoneal cytology in patients with cervical adenocarcinoma. The present study included patients diagnosed with FIGO stage IB to IIB cervical adenocarcinoma who underwent surgery at a hospital in Beijing, China, between December 1, 2000, and December 31, 2015. Baseline data were retrieved from patient medical records and follow-up data were collected through telephone interviews. The relationship between positive peritoneal cytology and the patients' clinicopathological features, and their prognosis was analyzed using Kaplan-Meier and Cox proportional hazards modeling. There were 136 patients who met the inclusion criteria and participated in interviews. Peritoneal cytology was positive in 13 (9.6%) patients. The 5-year survival rate of patients with positive and negative cytology was 69.2% and 95.7%, respectively (P<0.001). The 3-year recurrence-free survival rate in the two groups was 76.2% and 91.3%, respectively (P=0.041). Cox regression analysis showed pelvic lymph node involvement and vaginal invasion to be independent adverse risk factors for survival. The recurrence rate in the positive cytology group was significantly higher than that in the negative cytology group (38.5% vs 7.3%; P=0.002). Positive peritoneal cytology in patients with cervical adenocarcinoma was associated with a poor prognosis and a higher recurrence rate, but it was not an independent prognostic factor.

Hodgkin lymphoma variant of Richter transformation: morphology, Epstein-Barr virus status, clonality, and survival analysis—with comparison to Hodgkin-like lesion

Hodgkin/Reed-Sternberg (HRS) cells in the setting of chronic lymphocytic leukemia (CLL) exist in 2 forms: type I with isolated HRS cells in a CLL background (Hodgkin-like lesion) and type II with typical classic Hodgkin lymphoma, a variant of Richter transformation (CHL-RT). The clinical significance of the 2 morphological patterns is unclear, and their biological features have not been compared. We retrospectively reviewed 77 cases: 26 of type I and 51 of type II CHL-RT; 3 cases progressed from type I to type II. We examined clinical features, Epstein-Barr virus (EBV) status, and clonal relatedness after microdissection. Median age for type I was 62 years versus 73 years for type II (P=.01); 27% (type I) versus 73% (type II) had a history of CLL. HRS cells were positive for EBV in 71% (55/77), similar in types I and II. Clonality analysis was performed in 33 cases (type I and type II combined): HRS cells were clonally related to the underlying CLL in 14 and unrelated in 19. ZAP-70 expression of the CLL cells but not EBV status or morphological pattern was correlated with clonal relatedness: all 14 clonally related cases were ZAP-70 negative, whereas 74% (14/19) of clonally unrelated cases were ZAP-70 positive. Overall median survival (types I and II) after diagnosis was 44 months. Advanced age was an adverse risk factor for survival, but not histologic pattern, type I versus type II. HRS-like cells in a background of CLL carries a similar clinical risk to that of CHL-RT and may progress to classic Hodgkin lymphoma in some cases.

Hodgkin Lymphoma Variant of Richter Transformation: Morphology, EBV Status, Clonality and Survival Analysis a Retrospective Study of 77 Patients

▪The classical Hodgkin lymphoma variant of Richter transformation (CHL-RT) occurs rarely in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Two morphological patterns have been described: type I with Hodgkin/Reed-Sternberg (HRS) cells scattered in a CLL background, and type II with typical CHL morphology. HRS cells are frequently positive for EBV and can be clonally related or unrelated to CLL. The clinical significance of the different morphological patterns is unclear. What factors dictate the cellular derivation of the HRS cells remains elusive.We retrospectively reviewed 77 cases of CHL-RT submitted to our consultation service. Clinicopathological characteristics were summarized, EBV status was examined, and clonality was analyzed after microdissection of HRS-cells and CLL cells.Patients with the type I pattern (N=26) had a significantly shorter time to progression from CLL to CHL-RT than those with type II pattern (N=51, 15 vs. 49 months, p<0.0001, see Figure 1A). Consistent with these data, 27% of patients with the type I pattern had a prior CLL history as compared to 73% with the type II pattern. 12% (6/51) of type II cases had extranodal involvement (sites other than bone marrow) while none of type I cases did. Three patients with sequential biopsies progressed from type I to II and 2 had an aggressive clinical course. HRS cells were positive for EBV in 71% (55/77) of patients. Clonality analysis was performed in 33 cases: HRS cells were clonally related to the underlying CLL in 14 cases and unrelated in 19 cases. Among all the features examined, ZAP-70 expression of the CLL cells, but not EBV status or morphological pattern, was strongly correlated with clonal relationship: all 14 clonally related cases were negative for ZAP-70 while 74% (14/19) of the clonally unrelated cases were positive for ZAP-70. Overall median survival after the diagnosis of CHL-RT was 44 months. Advanced age was an adverse risk factor for survival (p<0.05, see Figure 1B).In conclusion, we provide evidence that type I morphology is more likely an early stage of CHL-RT and can progress to type II. The majority of CHL-RT cases are EBV positive. Clonal relationship in RT is determined by ZAP-70 and thus likely IGHV mutational status. Advanced age is associated with inferior survival. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Unsustained complete response of less than 24 months after autologous stem cell transplantation predicts aggressive myeloma with short survival

Complete response (CR) predicts superior survivals in myeloma. To define the impact of duration of CR posttransplantation on survivals, 71 myeloma patients, who underwent an intended early (a staged approach) or frontline use of bortezomib-based induction, followed by autologous stem cell transplantation (ASCT) were studied. Achievement of CR was assessed every 4-weekly until maximal response after ASCT and then 6-weekly thereafter. All patients had follow-up time of ≥24 months from time of best response, of whom 27 failed to attain CR (non-CR) whereas 44 achieved CR. At 12, 18 and 24 months post-ASCT, 3 (4.2%), 6 (8.4%) and 11 (15.4%) patients lost CR, respectively, with maximal survival difference observed in the group with CR durations of ≥24 or <24 months. Patients with unsustained CR had survival inferior to those never achieving CR (p = 0.05). Unsustained CR of <24 months was associated with international staging system stage III (p = 0.007) and shorter postrelapse survival (p < 0.001). Both overall survival and event-free survival were superior in myeloma patients with CR of ≥24 months (p < 0.001). In multivariate analysis, international staging system stage I/II, CR/nCR post-ASCT and CR duration of ≥24 months remained favourable prognostic factors for both overall survival and event-free survival. In conclusion, CR of <24 months is an independent adverse risk factor for survival with a short postrelapse survival.

A systematic method for using 3D echocardiography to evaluate tricuspid valve insufficiency in hypoplastic left heart syndrome.

With surgical palliation of hypoplastic left heart syndrome (HLHS), the tricuspid valve (TV) becomes the systemic atrioventricular valve and moderate/severe TV insufficiency (TVI), an adverse risk factor for survival to Fontan, has been reported in up to 35% of patients prior to stage I palliation. Precise echocardiographic identification of the mechanism of TVI cannot be determined by two-dimensional echocardiography. Three-dimensional echocardiography (3DE) can provide significant insight into the mechanisms of TVI. It is the intent of this report to propose a systematic method on how to evaluate and display 3DE images of the TV in HLHS which has not been done previously.TV anatomy, function, and the known mechanisms of insufficiency are reviewed. We defined three regions of the TV (anterior, posterior, septal) that can help define valve “leaflets” that incorporates the many variations of TV anatomy. To determine how the surgeon views the TV, a picture of a pathologic specimen of the TV was placed on a computer screen and rotated until it was oriented as it appears during surgery, the “surgeons view.”We have proposed a systematic method for evaluating and displaying the TV using 3DE which can provide significant insight into the mechanisms causing TVI in HLHS. This has the potential to improve both the surgical approach to repairing the valve and, ultimately, patient outcomes.

Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party

AbstractRabbit antithymocyte globulin (rATG; thymoglobulin, Genzyme) in combination with cyclosporine, as first-line immunosuppressive therapy, was evaluated prospectively in a multicenter, European, phase 2 pilot study, in 35 patients with aplastic anemia. Results were compared with 105 age- and disease severity–matched patients from the European Blood and Marrow Transplant registry, treated with horse ATG (hATG; lymphoglobulin) and cyclosporine. The primary end point was response at 6 months. At 3 months, no patients had achieved a complete response to rATG. Partial response occurred in 11 (34%). At 6 months, complete response rate was 3% and partial response rate 37%. There were 10 deaths after rATG (28.5%) and 1 after subsequent HSCT. Infections were the main cause of death in 9 of 10 patients. The best response rate was 60% for rATG and 67% for hATG. For rATG, overall survival at 2 years was 68%, compared with 86% for hATG (P = .009). Transplant-free survival was 52% for rATG and 76% for hATG (P = .002). On multivariate analysis, rATG (hazard ratio = 3.9, P = .003) and age more than 37 years (hazard ratio = 4.7, P = .0008) were independent adverse risk factors for survival. This study was registered at www.clinicaltrials.gov as NCT00471848.

Risk Factor Analysis for Second-Stage Palliation of Single Ventricle Anatomy

Single ventricle hearts can be surgically palliated by a series of operations culminating in the Fontan procedure, which establishes a total cavopulmonary connection. The second-stage procedure creates a physiologic connection between the superior vena cava and the pulmonary artery. From 1998 to 2010, 557 patients with single ventricle heart disease underwent second-stage surgical palliation. This cohort was retrospectively analyzed to assess patient outcome by a number of anatomic, physiologic, and procedural factors. The analysis excluded patients undergoing hybrid first-stage procedures. The median age at operation was 165 days (range, 59 days to 49 years). The most common anatomic subtypes were hypoplastic left heart syndrome (52%), tricuspid atresia (12%), unbalanced atrioventricular septal defect (10%), double inlet left ventricle (9%), or other (17%). Left ventricular hypoplasia was present in 70%. A hemi-Fontan procedure was done in 89%, and 11% received a bidirectional Glenn. Concomitant atrioventricular valve repair was necessary in 9%. Early mortality was 4.7%, and 5.9% died after discharge but before Fontan. No early or late deaths occurred in patients with tricuspid atresia and double inlet left ventricle. Multivariate analysis demonstrated ventricular dysfunction, atrioventricular valve regurgitation, and unbalanced atrioventricular septal defect were significant adverse risk factors for survival to Fontan. Second-stage palliation can be performed at low risk for patients with left ventricular dominance, but significant risk remains for patients with left ventricular hypoplasia and unbalanced atrioventricular septal defect. Atrioventricular valve insufficiency is a persistent problem that has not been neutralized by repair strategies.

Prospective Phase II Pilot Study of Rabbit Antithymocyte Globulin (ATG, Thymoglobuline) with Ciclosporin for Patients with Acquired Aplastic Anemia and Matched Pair Analysis with Patients Treated with Horse ATG (Lymphoglobuline) and Ciclosporin: A Study From the EBMT Severe Aplastic Anemia Working Party (RATGAA07)

Abstract 2408 BackgroundPreviously, horse antithymocyte globulin (hATG) with ciclosporin (CSA) was the standard immunosuppressive therapy (IST) for patients with aplastic anemia (AA) ineligible for HSCT, with response rates of 60–75% within 3–4 months. Rabbit ATG (rATG, Thymoglobuline, Genzyme) was reserved for non-response or relapse after a course of hATG. Following the withdrawal of hATG (Lymphoglobuline) from the market, the use of rATG as first line IST has been evaluated prospectively with hATG (ATGAM, Pfizer) in a randomised study from NIH (Scheinberg et al, NEJM, 2011), reporting significantly lower response rate and worse outcome after rATG. We report here the results of a multicenter, EBMT, phase II pilot study of 35 patients with AA enrolled between August 2008 and August 2010 at 10 centres (EUdraCT number 2007–000902–55). Patients enrolled were ineligible for matched sibling HSCT, had not received prior ATG or CSA and included both severe AA (SAA) and transfusion dependent non-severe AA (NSAA). The median age was 36 years (range 17–75). Six (17%) patients had very severe AA, 20 (57%) SAA and 9 (26%) had NSAA. Primary endpoint was response at 6 months. Dose of rATG was 3.75mg/kg daily for 5 days. CSA dose was 5mg/kg daily from day +1. For prevention of serum sickness, prednisolone was given at 1–2mg/kg daily from day 1–5, then the dose halved every 5 days. Results were compared in a 3: 1 ratio with 105 historical patients from the EBMT registry, matched for categorised age and disease severity, and who had been treated with hATG (Lymphoglobuline, Genzyme) and CSA. The study was designed to demonstrate a 25% difference in total response to rATG, with 80% power at a 5% level of significance. The median follow up for all patients treated with rATG is 285 days (6–781). ResultsAt 3 months, no patients had achieved a complete response (CR). Partial response (PR) occurred in 11 (34%). Two patients died, on day +6 and +9, and one was lost to follow up. At 6 months, CR rate was 7% (n=2) and PR rate 32% (n=11). One patient relapsed at 59 days. Five patients underwent unrelated donor HSCT for non-response to rATG, at day +153, 168, 321, 322 and 460 post rATG. Infections occurred in 22 (63%), elevated liver function in 10 (29%), rash in 8 (23%), haemorrhage in 7 (20%), hypertension in 6 (17%), abnormal renal function in 6 (17%), arthralgia in 5 (14%), avascular bone necrosis in one. There were 10 deaths after rATG (28.5%) and one following subsequent HSCT. Infections were the main cause of death in 9/10 patients. For rATG, overall survival at 2 yr was 56%, compared to 78% for hATG, p=0.001. Overall survival after censoring HSCT patients was 39% for rATG and 72% for hATG, p=0.0005. On multivariate analysis, rATG (RR = 3.4, p=0.003) and age > 37 years (RR = 3.8, p=0.002), were independent adverse risk factors for survival. Disease severity and time from diagnosis to treatment were not significant risk factors. CR at a given time was 11% for rATG and 44% for hATG, and PR for rATG was 43% and 23% for hATG. There were 19/105 (18%) deaths after hATG.Changes in CD4+ T-cells were analysed in a subset of 5 patients from a single center, prior to rATG (n=5) and post rATG (n=8). The relevant (preliminary) findings are:pre-ATG therapy, number of Tregs was significantly lower in AA compared to healthy age-matched controls (p=0.009), while Th17 (p=0.014), Th1 cells (p=0.014) and Th2/Tregs ratio (p=0.025) were higher in AA patients. Following treatment with ATG, the frequency of Th1 (p=0.002) and B-cells (p=0.007) was reduced but there was no significant change in the frequency of Tregs, Th17/Tregs or T-helpers/Tregs ratios. However, the frequency of cytokine secreting non-Tregs (CD4+ CD25high CD45 RA− Foxp3low) studied in 5 patients was significantly increased in post treatment samples (p=0.02) and there was a trend for a higher frequency in non-responders compared to responders. ConclusionsWe report significantly inferior response and survival with rATG (Thymoglobuline) compared to hATG (Lymphoglobuline), and a high incidence of serious infections with rATG, in association with significant changes in CD4+ T-cell subsets. These results have major implications for future treatment algorithms for AA and improve further our understanding of the mechanism of action of rATG in AA. Disclosures:Marsh:Genzyme: Consultancy, Research Funding. Off Label Use: ATG used in treatment of aplastic anemia. Schrezenmeier:Genzyme: Research Funding. Risitano:Genzyme: Honoraria. Dufour:Pfizer: Research Funding. Elebute:Alexion: Honoraria. Mufti:Celgene: Consultancy, Research Funding; Genzyme: Research Funding. Bacigalupo:Genzyme: Speakers Bureau; Pfizer: Research Funding.

Tumor Necrosis as a Prognostic Factor for Stage IA Non-Small Cell Lung Cancer

In stage IA non-small cell lung cancer (NSCLC), lobectomy and mediastinal lymph node dissection is considered the standard treatment. However, 20% to 30% of patients have cancer recurrences. The purpose of this study was to determine the patterns and risk factors for recurrence in patients with stage IA NSCLC. We retrospectively reviewed the medical records of 201 patients who had confirmed stage IA NSCLC by lobectomy and complete lymph node dissection. There were 131 male patients with a mean age of 60.68±9.26 years. The median follow-up period was 41.4 months. Recurrences were reported in 16 patients. One hundred fourteen and 87 patients were T1a (≤2 cm) and T1b (>2 cm to ≤3 cm), respectively. The pathologic results were as follows: adenocarcinomas and bronchioloalveolar carcinomas (n=134); squamous cell carcinomas (n=57); and other diagnoses (n=10). Tumor necrosis and lymphatic invasion were significant adverse risk factors for recurrence based on univariate analysis. Multivariate analysis showed that tumor necrosis was the only significant risk factor to predict cancer recurrence (hazard ratio, 4.336; p=0.032). The 5-year overall survival was 94.8% for necrosis-negative patients and 86.2% for necrosis-positive patients (p=0.04). The 5-year disease-free survival was 92.1% for necrosis-negative patients and 78.9% for necrosis-positive patients (p=0.016). Tumor necrosis was shown to be an adverse risk factor for survival and recurrence in patients with stage IA NSCLC. Thus, close observation and individualized adjuvant therapy might be helpful for patients with stage IA NSCLC with tumor necrosis.

Prognostic significance of positive peritoneal cytology in adenocarcinoma of the uterine cervix

Objective A retrospective analysis was carried out to evaluate the prognostic significance of peritoneal cytology in cervical adenocarcinoma. Methods The records of 107 patients with FIGO stage IB to IIB cervical adenocarcinoma who underwent hysterectomy were reviewed. Results Sixteen patients (15%) had positive peritoneal cytology. The 5-year survival rate among patients with positive or negative cytology was 50% or 87%, respectively, showing a significant difference (log-rank, P < 0.001). The recurrence-free survival (RFS) rate at 36 months in the cytology-positive or –negative group was 53% or 87%, respectively, the difference being significant (log-rank, P = < 0.001). Cox model analysis revealed positive cytology [hazards ratio (HR) 6.27, 95% confidence interval (CI) 2.13–18.41], positive lymph node (HR 6.20, 95% CI 1.87–20.57), ovarian metastasis (HR 5.20, 95% CI 1.18-22.82), and histological grade (HR 5.97, 95% CI 2.00-17.78) to be independent adverse risk factors for survival among the factors analyzed (lymph node status, lymph-vascular space invasion, tumor size, depth in cervical wall, pathological parametrial involvement, infiltration to vagina, ovarian metastasis, and histological grade). Cox model analysis showed that positive cytology (HR 4.58, 95% CI 1.48–14.16), positive lymph node (HR 7.61, 95% CI 2.69–21.54), and histological grade (HR6.13, 95% CI 2.14–17.77) were independent adverse risk factors for RFS. The incidence of peritoneal spread at the first recurrence among the cytology-positive group (62.5%) was significantly higher than that among the cytology-negative group (12.5%) (Fisher's exact test, P = 0.021). Conclusion The presence of positive peritoneal cytology appears to be an independent prognostic risk factor in patients with cervical adenocarcinoma.

Epigenetic inactivation of secreted Frizzled‐related proteins in acute myeloid leukaemia

The Wnt signalling pathway has a key function in stem cell maintenance and differentiation of haematopoietic progenitors. Secreted Frizzled-related protein genes (SFRPs), functioning as Wnt signalling antagonists, have been found to be downregulated by promoter hypermethylation in many tumours. To analyse epigenetic dysregulation of SFRPs in acute myeloid leukaemia (AML), we examined the promoter methylation status of SFRP1, -2, -4 and -5 in AML cell lines by methylation-specific polymerase chain reaction (MSP). Aberrant CpG island methylation was found for all four SFRP genes. By real-time reverse transcription-PCR, corresponding transcriptional silencing for SFRP1 and -2 was demonstrated and treatment of cell lines with 5-aza-2'-deoxycytidine resulted in re-expression. The methylation status of the SFRP genes was analysed in 100 specimens obtained from AML patients at diagnosis. The frequencies of aberrant methylation among the patient samples were 29% for SFRP1, 19% for SFRP2, 0% for SFRP4 and 9% for SFRP5. For SFRP2, a correlation between promoter hypermethylation and transcriptional downregulation was found in primary AML samples. Among AML cases with a favourable karyotype, hypermethylation of SFRP genes was restricted to patients with core binding factor (CBF) leukaemia, and aberrant methylation of the SFRP2 promoter was an adverse risk factor for survival in CBF leukaemia.

Elevated lactate dehydrogenase is an adverse predictor of outcome in HLA-matched sibling bone marrow transplant for acute myelogenous leukemia

Prognostic factors for survival following allogeneic BMT for AML include age, disease status and cytogenetic risk classification. Lactate dehydrogenase (LDH) levels have not been studied as a potential risk factor. We reviewed our experience with BMT for AML and included LDH at the time of admission in an analysis of prognostic factors for survival. We found that LDH >330 U/l (1.5 times the upper limit of normal at our institution), older age, active disease, peripheral stem cell graft and male-to-male transplant were significant adverse predictors of survival. After accounting for LDH, other factors such as disease status and cytogenetics were not significantly associated with the outcome of BMT. All but one patient with an LDH >330 U/l had active disease. However, when patients in CR were excluded, LDH >330 U/l remained a significant adverse predictor of overall survival (hazard ratio 2.70, 95% confidence interval 1.41-5.16, P=0.003). We conclude that LDH is an important adverse risk factor for survival and should be included in future studies of risk performed on larger patient cohorts.

60: A high lactate dehydrogenase (LDH) level predicts for shorter survival following HLA-matched sibling bone marrow transplant (BMT) for patients with acute myelogenous leukemia (AML)

Historically, the most important adverse risk factors for survival after BMT for AML are Active disease (ActDis), poor-risk cytogenetics, and older age. High serum LDH at the time of diagnosis is an adverse risk factor for survival for AML in the absence of BMT, but has not been explored as a risk factor in setting of BMT. We performed a multivariable analysis of these and other potential risk factors for overall and progression-free survival. From August 1992 to July 2005, we treated 87 patients with AML, who also had informative cytogenetic studies from the time of diagnosis, with high-dose busulfan-containing preparative regimens and an HLA-matched sibling BMT.

Lactate Dehydrogenase (LDH) Level Predicts the Outcome of Patients with Acute Myelogenous Leukemia (AML) Following HLA-Matched Sibling Bone Marrow Transplant (BMT).

Active disease (ActDis), poor-risk cytogenetics, and older age have historically been considered the most important adverse risk factors for survival after BMT for AML. We performed a multivariable analysis of these and other potential risk factors for overall and progression-free survival. From August 1992 to July 2005, we treated 87 patients with AML, who also had informative cytogenetic studies, with high-dose busulfan-containing preparative regimens and an HLA-matched sibling BMT. The median age was 43 years (range 19 to 62). The median LDH level at the time of BMT was 204 U/L (range 93–1555 U/L; normal 100–220 U/L). Forty-one patients were in either first (n= 30) or second complete remission (n=11; CR). 46 patients with ActDis were treated. The 87 patients were then classified according to the SWOG/ECOG (Blood 96:4075, 2000), MRC (Blood 92:2322, 1998), and CALGB (Blood 100:4325, 2002) cytogenetic classification systems. With a median follow-up of 56.0 months (range 4.5–107.8 months), the median relapse-free survival is 13.5 months for patients in CR1 and 4.1 months for patients in CR2. The relapse-free survival of patients with ActDis was 5.5 months. A Cox proportional hazards analysis that included gender, age, LDH, disease status, cytogenetic risk group, preparative regimen, source of stem cells, and CMV status was performed for overall and relapse-free survival. Significant risk factors for shorter survival in univariate analysis included male gender, LDH >330 U/L (but not LDH >220 U/L or per 100 U/L increase), and peripheral stem cells as a source of hematopoietic reconstitution (n = 7). Surprisingly, a male donor to a male recipient was also an adverse risk factor (p<0.001). However, in multivariable analysis, only LDH >330 U/L (p=0.002), source of stem cells (p=0.019), and male donor to male recipient (p<0.001) remained as significant adverse risk factors. In fact, patients with ActDis and an LDH ≤ 330 U/L had similar survival to patients treated in remission, while patients with ActDis and LDH > 330 U/L had significantly worse survival as shown below. We conclude that high LDH (>1.5X upper limit of normal) is a significant adverse risk factor for survival after BMT for AML and predicts outcome better than more traditional risk factors such as age, disease status, and cytogenetic risk profile. [Display omitted]