Subsequent Long-term Survival Research Articles

A retrospective analysis of treatment patterns, overall survival, and real-world disease-free survival in early-stage non-small cell lung cancer following complete resection

BackgroundReal-world data regarding patient characteristics, adjuvant treatment patterns, and long-term survival outcomes are needed to better understand unmet needs among patients with completely resected early-stage non-small cell lung cancer (NSCLC).MethodsElectronic medical records from the U.S.-based ConcertAI Patient360™ database were analyzed in patients with stage IB-IIIA NSCLC who underwent complete resection prior to March 1, 2016. Patients were followed until death or July 1, 2021. This study evaluated adjuvant chemotherapy use, and overall survival (OS) and real-world disease-free survival (rwDFS) outcomes using the Kaplan–Meier method. The correlation between OS and rwDFS was assessed using the Kendall rank test. Among patients who did not recur 5 years following surgery, landmark analyses of OS and rwDFS were conducted to understand the subsequent survival impact of remaining disease-free for at least 5 years.ResultsData from 441 patients with completely resected stage IB-IIIA NSCLC were included. About 35% of patients received adjuvant chemotherapy post-resection. Median OS and rwDFS from resection were 83.1 months and 42.4 months, respectively. The 5-year OS and rwDFS rates were 65.7% and 42.1%, respectively. OS and rwDFS were positively correlated (Kendall rank correlation coefficient = 0.67; p < 0.0001). Among patients without recurrence within 5 years after resection, the subsequent 5-year OS and rwDFS survival rates were 52.9% and 36.6%, respectively.ConclusionsUse of adjuvant chemotherapy was low, and the overall 5-year OS rate remained low despite all patients having undergone complete resection. Patients who remained non-recurrent over time had favorable subsequent long-term survival.

Impact of reintervention after index aortic valve replacement on the risk of subsequent mortality

ObjectivesThe use of bioprosthetic aortic valve replacement (AVR) is inherently associated with a risk of structural valve degeneration (SVD) and the need for aortic valve (AV) reintervention. We sought to evaluate whether AV reintervention, in the form of repeat surgical AVR (SAVR) or valve-in-valve transcatheter aortic valve replacement (ViV-TAVR), negatively affects patients’ subsequent long-term survival after index SAVR. MethodsWe identified patients who had undergone bioprosthetic SAVR from 2002 to 2017 at our institution. Median longitudinal follow-up after index SAVR was 7.3 years (10.9 years for those with and 7.2 years for those without AV reintervention), and median follow-up after AV reintervention was 1.9 years. Cox regression analyses using AV reintervention (re-SAVR and ViV-TAVR) as a time-varying covariate were used to determine the impact of reintervention on subsequent survival. ResultsOf 4167 patients who underwent index SAVR, 139 (3.3%) required AV reintervention for SVD, with re-SAVR being performed in 65 and ViV-TAVR in 74. Median age at the index SAVR was 73 years (interquartile range, 64-79 years), and 2541 (61%) were male. Overall, there were total of 1171 mortalities observed, of which 13 occurred after re-SAVR and 9 after ViV-TAVR. AV reintervention was associated with a greater risk of subsequent mortality compared with those patients who did not require AV reintervention (hazard ratio, 2.53; 95% confidence interval, 1.64-3.88, P < .001). This increased risk of subsequent mortality was more pronounced for those who received their index AVR when <65 years of age (hazard ratio, 5.60; 95% confidence interval, 2.57-12.22, P < .001) versus those ≥65 years (2.06, 1.21-3.52, P = .008). Direct comparison of survival between those who underwent re-SAVR versus ViV-TAVR showed 5-year survival to be comparable (re-SAVR: 74% vs ViV-TAVR: 80%, P = .67). ConclusionsAmong patients receiving bioprosthetic AVR, an AV reintervention for SVD is associated with an increased risk of subsequent mortality, regardless of re-SAVR or ViV-TAVR, and this risk is greater among younger patients. These findings should be balanced with individual preferences at index AVR in the context of patients’ lifetime management of aortic stenosis.

Neuroinflammation After Stereotactic Radiosurgery-Induced Brain Tumor Disintegration Is Linked to Persistent Cognitive Decline in a Mouse Model of Metastatic Disease

Improved efficacy of anticancer therapy and a growing pool of survivors give rise to a question about their quality of life and return to premorbid status. Radiation is effective in brain metastasis eradication, although the optimal approach and long-term effects on brain function are largely unknown. We studied the effects of radiosurgery on brain function. Adult C57BL/6J mice with or without brain metastases (rat 9L gliosarcoma) were treated with cone beam single-arc stereotactic radiosurgery (SRS; 40 Gy). Tumor growth was monitored using bioluminescence, whereas longitudinal magnetic resonance imaging, behavioral studies, and histologic analysis were performed to evaluate brain response to the treatment for up to 18 months. Stereotactic radiosurgery (SRS) resulted in 9L metastases eradication within 4 weeks with subsequent long-term survival of all treated animals, whereas all nontreated animals succumbed to the brain tumor. Behavioral impairment, as measured with a recognition memory test, was observed earlier in mice subjected to radiosurgery of tumors (6 weeks) in comparison to SRS of healthy brain tissue (10 weeks). Notably, the deficit resolved by 18 weeks only in mice not bearing a tumor, whereas tumor eradication was complicated by the persistent cognitive deficits. In addition, the results of magnetic resonance imaging were unremarkable in both groups, and histopathology revealed changes. SRS-induced tumor eradication triggered long-lasting and exacerbated neuroinflammatory response. No demyelination, neuronal loss, or hemorrhage was detected in any of the groups. Tumor disintegration by SRS leads to exacerbated neuroinflammation and persistent cognitive deficits; therefore, methods aiming at reducing inflammationafter tumor eradication or other therapeutic methods should be sought.

4-1BB Agonism Combined With PD-L1 Blockade Increases the Number of Tissue-Resident CD8+ T Cells and Facilitates Tumor Abrogation.

Although the milestone discovery of immune checkpoint blockade (ICB) has been translated into clinical practice, only a fraction of patients can benefit from it with durable responses and subsequent long-term survival. Here, we tested the anti-tumor effect of combining PD-L1 blockade with 4-1BB costimulation in 3LL and 4T1.2 murine tumor models. Dual treatment induced further tumor regression and enhanced survival in tumor-bearing mice more so than PD-L1 and 4-1BB mAb alone. It was demonstrated that dual anti-PD-L1/anti-4-1BB immunotherapy increased the number of intratumoral CD103+CD8+ T cells and altered their distribution. Phenotypically, CD103+CD8+ T cells expressed a higher level of 4-1BB and PD-1 than their CD103− counterparts. Administration of PD-L1 mAb and 4-1BB mAb further increased the cytolytic capacity of CD103+CD8+ T cells. In vivo, CD103−CD8+ T cells could differentiate into CD103+CD8+ progeny cells. In a human setting, more CD8+ T cells differentiated into CD103+CD8+ T cells in the peripheral tumor region of lung cancer tissues than in the central tumor region. Collectively, infiltrated CD103+CD8+ T cells served as a potential effector T cell population. Combining 4-1BB agonism with PD-L1 blockade could increase tumor-infiltrated CD103+CD8+T cells, thereby facilitating tumor regression.

Imbalance of the spindle-assembly checkpoint promotes spindle poison-mediated cytotoxicity with distinct kinetics

Disrupting microtubule dynamics with spindle poisons activates the spindle-assembly checkpoint (SAC) and induces mitotic cell death. However, mitotic exit can occur prematurely without proper chromosomal segregation or cytokinesis by a process termed mitotic slippage. It remains controversial whether mitotic slippage increases the cytotoxicity of spindle poisons or the converse. Altering the SAC induces either mitotic cell death or mitotic slippage. While knockout of MAD2-binding protein p31comet strengthened the SAC and promoted mitotic cell death, knockout of TRIP13 had the opposite effect of triggering mitotic slippage. We demonstrated that mitotic slippage prevented mitotic cell death caused by spindle poisons, but reduced subsequent long-term survival. Weakening of the SAC also reduced cell survival in response to spindle perturbation insufficient for triggering mitotic slippage, of which mitotic exit was characterized by displaced chromosomes during metaphase. In either mitotic slippage or mitotic exit with missegregated chromosomes, cell death occurred only after one cell cycle following mitotic exit and increased progressively during subsequent cell cycles. Consistent with these results, transient inhibition of the SAC using an MPS1 inhibitor acted synergistically with spindle perturbation in inducing chromosome missegregation and cytotoxicity. The specific temporal patterns of cell death after mitotic exit with weakened SAC may reconcile the contradictory results from many previous studies.

Thirteen-year nationwide trends in use of implantable cardioverter-defibrillators and subsequent long-term survival.

Long-term trends in use of implantable cardioverter-defibrillators (ICDs) and outcomes are rare. We examined 13-year nationwide trends in ICD implantation and survival rates in Denmark. Using medical databases, we identified all first time ICD recipients in Denmark during 2000-2012 (N = 8460) and ascertained all-cause mortality. We computed standardized annual implantation rates and mortality rate ratios according to age, sex, comorbidity level, indication, and device type. The standardized annual implantation rate increased from 42 per million persons in 2000 to 213 per million persons in 2012 (from 34 to 174 for men and from 8 to 39 for women). The increase was driven by secondary prophylactic ICDs until 2006 and primary prophylactic ICDs thereafter. The increase occurred particularly in older patients and those with a high level of comorbidity. Independent of indication, 76% of all patients with ICD were alive after 5 years. Men had a higher mortality rate compared with women (mortality rate ratio 1.28; 95% confidence interval 1.10-1.49). Compared with low comorbidity level, moderate, severe, and very severe comorbidity levels were associated with 1.6-, 2.5-, and 4.9-fold increased mortality rates, respectively. The most influential individual comorbidities were heart failure, diabetes, liver disease, and renal disease. The annual implantation rate of ICDs increased 5-fold in Denmark between 2000 and 2012. The rate increase occurred for both men and women, but particularly in the elderly and patients with severe comorbidity. Five-year survival probability was high, but severe comorbidity and male sex were associated with shorter survival.

Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab.

We report on posttransplant relapsed pediatric patients with B-precursor acute lymphoblastic leukemia with no further standard of care therapy who were treated with the T-cell engaging CD19/CD3-bispecific single-chain antibody construct blinatumomab on a compassionate use basis. Blast load was assessed prior to, during and after blinatumomab cycle using flow cytometry to detect minimal residual disease, quantitative polymerase chain reaction for rearrangements of the immunoglobulin or T-cell receptor genes, and bcr/abl mutation detection in one patient with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dosage of 5 or 15 μg/m(2)/day. Nine patients received a total of 18 cycles. Four patients achieved complete remission after the first cycle of treatment; 2 patients showed a complete remission from the second cycle after previous reduction of blast load by chemotherapy. Three patients did not respond, of whom one patient proceeded to a second cycle without additional chemotherapy and again did not respond. Four patients were successfully retransplanted in molecular remission from haploidentical donors. After a median follow up of 398 days, the probability of hematologic event-free survival is 30%. Major toxicities were grade 3 seizures in one patient and grade 3 cytokine release syndrome in 2 patients. Blinatumomab can induce molecular remission in pediatric patients with posttransplant relapsed B-precursor acute lymphoblastic leukemia and facilitate subsequent allogeneic hematopoietic stem cell transplantation from haploidentical donor with subsequent long-term leukemia-free survival.

Improved intensive care unit survival for critically ill allogeneic haematopoietic stem cell transplant recipients following reduced intensity conditioning

The use of allogeneic haematopoietic stem cell transplantation (Allo-HSCT) is a standard treatment option for many patients with haematological malignancies. Historically, patients requiring intensive care unit (ICU) admission for transplant-related toxicities have fared extremely poorly, with high ICU mortality rates. Little is known about the impact of reduced intensity Allo-HSCT conditioning regimens in older patients on the ICU and subsequent long-term outcomes. A retrospective analysis of data collected from 164 consecutive Allo-HSCT recipients admitted to ICU for a total of 213 admissions, at a single centre over an 11·5-year study period was performed. Follow-up was recorded until 31 March 2011. Autologous HSCT recipients were excluded. In this study we report favourable ICU survival following Allo-HSCT and, for the first time, demonstrate significantly better survival for patients who underwent Allo-HSCT with reduced intensity conditioning compared to those treated with myeloablative conditioning regimens. In addition, we identified the need for ventilation (invasive or non-invasive) as an independently significant adverse factor affecting short-term ICU outcome. For patients surviving ICU admission, subsequent long-term overall survival was excellent; 61% and 51% at 1 and 5 years, respectively. Reduced intensity Allo-HSCT patients admitted to ICU with critical illness have improved survival compared to myeloablative Allo-HSCT recipients.

Nine years interval between first and second bone marrow transplantations and subsequent long-term survival—a case of acute myeloid leukemia with MLL-AF6 fusion gene

Nine years interval between first and second bone marrow transplantations and subsequent long-term survival—a case of acute myeloid leukemia with MLL-AF6 fusion gene

A Simple Prognostic Score to Predict Short and Long-Term Survival Following ICU Admission in Critically Ill Adult Allogeneic Hematopoietic Stem Cell Transplant Recipients: Improved Survival Following Reduced Intensity Conditioning

Abstract 146▪▪This icon denotes a clinically relevant abstractTransplant-related complications necessitate intensive care unit (ICU) admission in a significant proportion of patients undergoing allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Historically patients requiring ICU admission for transplant related toxicities have fared extremely poorly with very high ICU mortality rates. Although recent reports have indicated improvements in short-term survival for Allo-HSCT patients admitted to ICU there are little data on the subsequent long-term survival of ICU survivors and the impact of reduced intensity conditioning regimens in this cohort of patients. Methods:A retrospective analysis of data collected from 164 consecutive adult Allo-HSCT recipients admitted to ICU (with a total of 214 ICU admissions), at a single centre, University College London Hospitals NHS Foundation Trust (UCLH) between June 1996 and December 2007 (11.5 year study period) was performed. Follow-up of surviving patients was recorded until 31 March 2011. Results:29% of all patients undergoing Allo-HSCT at our centre during the study period required one or more ICU admission. The ICU admission rate was significantly lower for patients undergoing reduced intensity conditioning (RIC) than myeloablative conditioning (17% vs. 38%, p<0.001). The median age of RIC-Allo recipients was significantly older than patients who received myeloablative conditioning (47 vs 36 years, P<0.0001). The most frequent reasons for ICU admission were sepsis (67%) and respiratory failure (55%), not mutually exclusive. Mechanical ventilation (MV) was required in 53% of admissions, inotropic support was required in 47%. Median acute physiology and chronic health score (APACHEII) was 23 (range 0–51). Overall ICU survival for all admissions was 48% (n=214). 35 patients (21%) had more 1 or more ICU admissions. Survival by patient (measured at discharge from final ICU admission) was 32%. ICU survival was significantly better after RIC Allo-HSCT than following myeloablative conditioning (OR 3.27, p=0.023). There was no difference in ICU outcome by stem cell source (sibling vs. unrelated). Patients who did not require ventilatory support (non-invasive ventilation and/or MV) had significantly better ICU outcome (OR 12.7, p<0.001). Multivariate analysis by Cox regression revealed raised urea, inotropic support and MV as independent determinants of death on ICU. Long term survival was significantly better for patients who underwent RIC Allo-HSCT (p=0.0055) (Figure 1). The subsequent long term survival for patients who survived ICU admission was excellent; 1, 2, and 5 year survival rates were 60%, 55%, and 50% respectively (median follow-up 3 years, 7 months).A simple prognostic scoring system has been derived which is predictive of both ICU survival and long term outcome (Table 1). Patients with 2 or more of the following factors: myeloablative conditioning, MV, elevated serum urea, score 1. Patients with <2 of these factors score 0. In our patient population, this binary index has been shown to be predictive of both death on ICU (OR 7.24, p=0.001) or poorer overall survival after ICU discharge (OR 3.04, p=0.01). [Display omitted] Table 1:Prognostic score for prediction of short and long term outcome for allo-HSCT patients admitted to ICU. Score 1 if 2 or more of the following factors are present: Myeloablative conditioning, mechanical ventilation, elevated serum urea.ScoreSurvival to discharge2y OS from discharge5y OS from discharge061%71%65%118%35%26% Conclusion:In this study we report favourable ICU survival following allogeneic HSCT and for the first time report significantly better short and long-term outcome for patients who underwent RIC Allo-HSCT compared to those treated with myeolablative conditioning regimens despite a higher median age in the patients undergoing RIC transplants. For patients surviving ICU admission, subsequent long-term overall survival was excellent at 50% at 5 years, comparing favourably with other critically ill non-surgical patients admitted to ICU. A simple prognostic score has been generated which can be used to predict outcome in critically ill patients admitted to ICU following Allo-HSCT. Disclosures:No relevant conflicts of interest to declare.

Surgery in Adults With Congenital Heart Disease

A significant proportion of patients with congenital heart disease require surgery in adulthood. We aimed to give an overview of the prevalence, distribution, and outcome of cardiovascular surgery for congenital heart disease. We specifically questioned whether the effects of surgical treatment on subsequent long-term survival depend on sex. From the Dutch Congenital Corvitia (CONCOR) registry for adults with congenital heart disease, we identified 10 300 patients; their median age was 33.1 years. Logistic and Cox regression models were used to assess the association of surgery in adulthood with sex and with long-term survival. In total, 2015 patients (20%) underwent surgery for congenital heart disease in adulthood during a median follow-up period of 15.1 years; in 812 patients (40%), it was a reoperation. Overall, both first operations and reoperations in adulthood were performed significantly more often in men compared with women (adjusted odds ratio=1.4 [95% confidence interval, 1.2-1.6] and 1.2 [95% confidence interval, 1.0-1.4], respectively). Patients with their third and fourth or more surgery in adulthood had a 2- and 3-times-higher risk of death compared with patients never operated on (adjusted hazard ratio=1.9 [95% confidence interval, 1.0-3.6] and 2.7 [95% confidence interval, 1.1-6.3], respectively). Men with a reoperation in adulthood had a 2-times-higher risk of death than women (adjusted hazard ratio=1.9; 95% confidence interval, 1.0-3.5). Of predominantly young adults with congenital heart disease, one fifth required cardiovascular surgery during a 15-year period; in 40%, the surgery was a reoperation. Men with congenital heart disease have a higher chance of undergoing surgery in adulthood and have a consistently worse long-term survival after reoperations in adulthood compared with women.

Fatigue after Stroke: Baseline Predictors and Influence on Survival. Analysis of Data from UK Patients Recruited in the International Stroke Trial

Background and PurposeLittle is known about the associations of post-stroke fatigue or its influence on survival. The vitality component of the Short Form 36 (SF-36) is a valid and reliable measure of post-stroke fatigue. We sought to identify associates of post-stroke fatigue and determine whether fatigue predicted survival.MethodsWe used SF-36 vitality scores obtained by postal questionnaires from 1080 UK patients randomised in the International Stroke Trial, at a mean of 64 weeks after stroke onset. We used logistic regression to explore factors at randomisation which predicted SF-36 vitality at follow-up, and the relationship between SF-36 vitality and both SF-36 mental health and SF-36 emotional role function at follow-up. We used Cox proportional hazards to explore the influence of SF-36 vitality at follow-up on subsequent survival, using four different statistical models for handling missing data.ResultsFemale sex, increasing age, lower mental health and lower emotional role function scores were associated with greater degrees of fatigue after stroke (i.e. lower vitality scores) but these factors explained <30% of the variance (R2) in fatigue. In two models, fatigue at follow-up was associated with shorter subsequent survival.ConclusionIncreasing age, female sex, emotional role function and mental health were associated with increased fatigue at a mean of 64 weeks after stroke onset, but explained less than 30% of the variance. Fatigue was associated with reduced subsequent long-term survival in 2/4 models. Further work is needed to identify the biological substrate of fatigue and to clarify its influence on survival.

The descent of memory T cells

Our T cell repertoire is shaped by antigen encounter. From a naive T cell pool that contains millions of different T cells with unknown specificities, pathogen infection leads to selection of those T cells that can detect pathogen-derived antigens. Following clearance of infection, a population of memory T cells remains and protects the individual from severe reinfection. A central question in the field has been how the generation of long-lived memory T cells, versus short-lived ("terminally differentiated") T cells, is controlled. In this review we discuss the models that have been put forward to explain the generation of memory T cells after infection and the experimental evidence supporting these hypotheses. Based on the available data we propose a new model that stipulates that during immune responses T cells do not acquire different fates that determine their subsequent long-term survival but rather T cells assume different states that simply reflect the likelihood of future survival, states that can still be modulated by external signals.

Relapse and Late Mortality in 5-Year Survivors of Myeloablative Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia in First Chronic Phase

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) is curative therapy for chronic myeloid leukemia (CML), but its long-term outcomes are not well described. We studied the long-term outcomes of CML patients in first chronic phase who receive an allogeneic HCT. PATIENTS AND METHODS Our study included 2,444 patients who received myeloablative HCT for CML in first chronic phase between 1978 and 1998 and survived in continuous complete remission for at least 5 years (median follow-up, 11 years; range, 5 to 25 years). Donor sources were human leukocyte antigen-matched siblings in 1,692 patients, unrelated donors in 639 patients, and other related donors in 113 patients. RESULTS Overall survival rates at 15 years were 88% (95% CI, 86% to 90%) for sibling HCT and 87% (95% CI, 83% to 90%) for unrelated donor HCT. Corresponding cumulative incidences of relapse were 8% (95% CI, 7% to 10%) and 2% (95% CI, 1% to 4%), respectively. The latest relapse was reported 18 years post-HCT. In multivariable analyses, history of chronic graft-versus-host disease increased risks of late overall mortality and nonrelapse mortality but reduced risks of relapse. In comparison with age-, race-, and sex-adjusted normal populations, the mortality of HCT recipients was significantly higher until 14 years post-HCT; thereafter, mortality rates were similar to those of the general population (relative mortality ratio at 15 years, 2.3; 95% CI, 0 to 4.9). CONCLUSION Recipients of allogeneic HCT for CML in first chronic phase who remain in remission for at least 5 years have favorable subsequent long-term survival, and their mortality rates eventually approach those of the general population.

Long-Term Survival and Late Relapse in 5-Year Survivors of Allogeneic Hematopoietic-Cell Transplantation (HCT) for Chronic Myeloid Leukemia (CML) in First Chronic Phase.

Abstract 3321Poster Board III-209▪▪This icon denotes an abstract that is clinically relevant.Prior to the advent of tyrosine kinase inhibitors, allogeneic HCT was standard therapy for CML. However, very long-term outcomes of allogeneic HCT for CML are not well described. To evaluate the probability and risk factors for late mortality and relapse in this patient population, we conducted a retrospective cohort study that included 2444 patients who received a myeloablative allogeneic HCT for CML in first chronic phase between 1978 and 1998 and had survived in continuous complete remission for at least 5 years. Relapse was considered the earliest reported date of the following: hematologic recurrence, cytogenetic recurrence or initiation of therapy for recurrence. The median followup of our cohort was 11 years (range, 5-25) from HCT; 377 patients had followup >15 years. Donor sources were HLA-matched siblings (MSD) in 1692, unrelated donors (URD) in 639 and other related donors in 113 patients. The median age at HCT was 35 years and patients primarily received bone marrow grafts (96%) and conditioning using either total-body irradiation (TBI, 61%) or BuCy (38%) regimens. Acute and chronic graft-versus-host disease (GVHD) occurred in 43% and 62% of patients, respectively. The probabilities of overall survival at 15 years were 88% (95% CI, 86-90%) for MSD and 87% (83-90%) for URD recipients. Corresponding cumulative incidences of relapse at 15 years were 8% (7-10%) and 2% (1-4%), respectively. The latest reported relapse occurred 18 years post-HCT. In multivariable analyses addressing the importance of patient, disease and transplant related factors for long-term survival, older age at HCT, use of female donor for a male recipient, use of TBI based conditioning, acute GVHD and chronic GVHD all independently increased the risk of late mortality. Chronic GVHD reduced the risk of relapse, but increased the risk of non-relapse mortality. Recipients of MSD and URD had similar risks of long-term mortality, relapse and non-relapse mortality. Compared to an age, gender and race adjusted general population, 5 year survivors of HCT for CML were 2.9 times (95% CI, 1.9-3.9) more likely to die at 6 years and 2.5 times (1.3-3.7) more likely to die at 10 years after HCT. However, by 15 years after HCT, their relatively mortality (2.3 [0-4.9]) was not significantly different than the general population. In summary, recipients of allogeneic HCT for CML in first chronic phase who remain in remission for at least 5 years after HCT have very favorable subsequent long-term survival with mortality rates eventually approaching those of the general population. There is a small but continuing risk of relapse even in these long-term survivors. Chronic GVHD protects against relapse but increases the risks of non-relapse mortality. DisclosuresNo relevant conflicts of interest to declare.

Long-Term Survival and Late Deaths in 2-Year Survivors of Myeloablative Allogeneic Hematopoietic-Cell Transplantation for Hematologic Disorders.

Abstract 520Allogeneic hematopoietic-cell transplantation (HCT) is potentially curative therapy for a variety of hematologic disorders. Most deaths after HCT occur within the first 2-years, due to relapse, acute or chronic graft-versus-host disease (GVHD) or regimen-related toxicities. Among allogeneic HCT recipients who had survived in complete remission (CR) for at least 2-years following transplantation, we (1) investigated their long-term survival, (2) evaluated risk factors for late mortality, and (3) compared their long-term survival to that of the general population. Our study cohort consisted of 10,632 patients who received a myeloablative allogeneic HCT through 2003, surviving in CR for 2-years after transplant reported to the CIBMTR. The median followup of our cohort was 9 (range, 2-31) years; 37% of survivors were followed for ≥10-years and 12% for ≥15-years. Diagnoses included acute myeloid leukemia (AML, N=4,017), acute lymphoblastic leukemia (ALL, N=2,895), myelodysplastic syndrome (MDS, N=930), lymphoma (N=619) and severe aplastic anemia (SAA, N=2,171). Donors were HLA-identical siblings (72%), unrelated donors (22%) or other related donors (6%). Patients <20 years of age comprised 45% of our cohort and 17% were >40 years at HCT. Total body irradiation (TBI) based conditioning regimens were given to 60% of patients. Most frequent conditioning regimens were cyclophosphamide + TBI for AML, ALL and lymphoma, busulfan + cyclophosphamide for MDS and cyclophosphamide alone for SAA. Acute grade 2-4 GVHD had occurred in 39% and 43% patients experienced chronic GVHD by 2-years after HCT. Probability of overall survival at 10-years after HCT was 84% (95% CI, 82-85%) for AML, 84% (82-85%) for ALL, 80% (77-83%) for MDS, 84% (81-87%) for lymphoma and 92% (91-93%) for SAA. Disease relapse was the most common cause of death for AML, ALL, MDS, and lymphoma while GVHD was the most common cause of death for SAA. The cumulative incidence of relapse at 10-years post-HCT was 10% (9-11%) for AML, 9% (8-10%) for ALL, 10% (8-12%) for MDS and 6% (4-8%) for lymphoma. Older age at HCT and chronic GVHD were both associated with greater late mortality for all diseases in Cox-regression analyses that accounted for important patient, disease and transplant related factors (Table). Furthermore, some risk factors were associated with increased mortality for specific diseases only, including: more advanced disease (AML, ALL), peripheral blood as graft source (ALL), acute GVHD (MDS and SAA), unrelated donor (lymphoma) and longer time from diagnosis (SAA). Overall survival rates at 10-years post-HCT for patients with and without chronic GVHD were 79% and 89% for AML, 80% and 87% for ALL, 75% and 87% for MDS, 80% and 90% for lymphoma and 87% and 95% for SAA. At 15-years after HCT, the relative mortality of patients who had received HCT for AML, ALL, MDS and SAA remained significantly higher than in age-, race- and gender-matched normal populations. Mortality rates for lymphoma patients were not significantly different than those of the matched general population after 8-years post-HCT. Recipients of myeloablative allogeneic HCT for AML, ALL, MDS, lymphoma and SAA who remain in remission for at least 2-years have favorable subsequent long-term survival. Older age at HCT and chronic GVHD are important risk factors for late deaths in all diseases evaluated.Risk factors (present at 2-years post-HCT) for late mortalityDiseaseAge (Relative risk [95% CI])Chronic GVHD (Relative risk [95% CI])Other factors increasing risk of deathAML<15 yrs: 1.01.6 (1.4-1.9)Advanced disease, certain geographical regions15-30 yrs: 1.5 (1.1-2.1)30-45 yrs: 2.2 (1.7-3.0)>45 yrs: 3.2 (2.4-4.4)ALL<15 yrs: 1.01.3 (1.1-1.6)Advanced disease, peripheral blood as graft source15-45 yrs: 1.7 (1.4-2.2)>45 yrs: 3.8 (2.4-5.8)MDS<30 yrs: 1.01.7 (1.1-2.4)Acute GVHD, earlier year of HCT30-55 yrs: 1.6 (1.1-2.3)>55 yrs: 3.5 (1.9-6.2)Lymphoma<25 yrs: 1.01.6 (1.0-2.6)Unrelated donor≥25 yrs: 2.3 (1.3-4.1)SAA<20 yrs: 1.02.2 (1.5-3.0)Greater time between diagnosis and HCT, acute GVHD20-40 yrs:1.4 (1.0-2.0)>40 yrs: 3.3 (2.0-5.3) Disclosures:No relevant conflicts of interest to declare.

The role of p53 in the efficiency of photodynamic therapy with hypericin and subsequent long-term survival of colon cancer cells

Photodynamic therapy with hypericin (HY-PDT) is known as an efficient modality for treatment of various cancerous and non-cancerous diseases. Although the role of p53 protein in cell death signaling is well established, relatively little is known of its impact on the efficiency of HY-PDT. Comparison of sensitivity and long-term survival of p53-null versus wt-p53-expressing HCT-116 cells is reported here. The lack of p53 function did not affect cell proliferation or attenuate the initial phases of programmed cell death. However, analyses of apoptosis in the final stages revealed suppression of its incidence and delayed activation of caspase-3 in p53-null cells. Significantly higher clonogenic ability, especially in hypoxia, was identified in the case of p53-null cells. Induction of Mcl-1 and Bax levels were more prominent in wt-pt53 cells. Interestingly, the level of Bcl-2 did not react to HY-PDT at all, in both cell lines. Bringing the evidence together, we prove that despite insignificant impact on overall toxicity, expression of p53 affects the clonogenic efficiency of HCT-116 cells. Since destruction of tumor tissue and its vascular system by PDT tends to lead to hypoxia, superior survival of p53-deficient tumor cells under given conditions might result in recurrence of cancer diseases.

Long‐term survival and late relapse in 2‐year survivors of autologous haematopoietic cell transplantation for Hodgkin and non‐Hodgkin lymphoma

This study described long-term outcomes of autologous haematopoietic-cell transplantation (HCT) for advanced Hodgkin (HL) and non-Hodgkin lymphoma (NHL). The study included recipients of autologous HCT for HL (N = 407) and NHL (N = 960) from 1990-98 who were in continuous complete remission for at least 2 years post-HCT. Median follow-up was 104 months for HL and 107 months for NHL. Overall survival at 10-years was 77% (72-82%) for HL, 78% (73-82%) for diffuse large-cell NHL, 77% (71-83%) for follicular NHL, 85% (75-93%) for lymphoblastic/Burkitt NHL, 52% (37-67%) for mantle-cell NHL and 77% (67-85%) for other NHL. On multivariate analysis, mantle-cell NHL had the highest relative-risk for late mortality [2.87 (1.70-4.87)], while the risks of death for other histologies were comparable. Relapse was the most common cause of death. Relative mortality compared to age, race and gender adjusted normal population remained significantly elevated and was 14.8 (6.3-23.3) for HL and 5.9 (3.6-8.2) for NHL at 10-years post-HCT. Recipients of autologous HCT for HL and NHL who remain in remission for at least 2-years have favourable subsequent long-term survival but remain at risk for late relapse. Compared to the general population, mortality rates continue to remain elevated at 10-years post-transplantation.

Coronary heart disease in women: Less extensive disease and improved long-term survival compared to men

Objectives. The aim of the study was to compare extent of coronary disease and subsequent long-term survival in women compared to men adjusted for baseline differences in demographics and morbidity. Design. In the database at Feiring Heart Clinic 18 767 patients had a coronary angiographic examination in the period from March 1999 to December 31, 2006. Their survival status as of May 31, 2007 was ascertained through the Norwegian National Registry. Survival was compared using age stratified analyses and Cox regression adjusting for baseline differences. Results. Significantly more women than men had no coronary disease (28.7 vs. 10.5%, p <0.001), while three vessel disease was more frequently present in men (38.7 vs. 21.8%, p <0.001), as judged by coronary angiography. Covariate adjusted survival was significantly better in women compared to men with an overall hazard ratio of 1.29 (p <0.001), but with no significant difference in the subgroup with high left ventricular end diastolic pressure. Conclusions. At the time of referral to invasive examination women had less extensive coronary artery disease than men as judged by coronary angiography and improved long-term survival when baseline differences were accounted for.

Potent Systemic Anticancer Activity of Adenovirally Expressed EGFR-Selective TRAIL Fusion Protein

Previously, we demonstrated potent tumor cell-selective pro-apoptotic activity of scFv425:sTRAIL, a recombinant fusion protein comprised of EGFR-directed antibody fragment (scFv425) genetically fused to human soluble TNF-related apoptosis-inducing ligand (sTRAIL). Here, we report on the promising therapeutic systemic tumoricidal activity of scFv425:sTRAIL when produced by the replication-deficient adenovirus Ad-scFv425:sTRAIL. In vitro treatment of EGFR-positive tumor cells with Ad-scFv425:sTRAIL resulted in the potent induction of apoptosis of not only infected tumor cells, but importantly also of up to 60% of noninfected EGFR-positive tumor cells. A single intraocular injection of Ad-scFv425:sTRAIL in tumor-free nu/nu mice resulted in predominant liver infection and concomitant high blood plasma levels of scFv425:sTRAIL. These mice showed no sign of Ad-scFv425:sTRAIL-related liver toxicity. Identical treatment of mice with established intraperitoneal renal cell carcinoma xenografts resulted in rapid and massive tumor load reduction and subsequent long-term survival. Taken together, adenoviral-mediated in vivo production of scFv425:sTRAIL may be exploitable for systemic treatment of EGFR-positive cancer.