Morbidity In Long-term Survivors Research Articles

Neurocognitive impairment associated with chronic morbidity in long-term survivors of Hodgkin Lymphoma

AbstractThoracic radiation is associated with significant cardiopulmonary morbidities in survivors of long-term Hodgkin lymphoma and may affect neurocognitive outcomes. Survivors (N = 204; 52.5% female; mean [standard deviation] age, 36.6 [8.01] years) treated with thoracic radiation and age-, sex-, and race/ethnicity-matched community controls (N = 205; 51.7% female; age, 36.7 [9.17] years) completed standardized neurocognitive testing, echocardiography, pulmonary function tests, and vascular studies during the same visit. Treatments were abstracted from medical records. Cardiac (ie, left ventricular ejection fraction [LVEF], global longitudinal strain [GLS]), vascular (ie, large and small artery elasticity [SAE]), pulmonary (ie, diffusing capacity of the lungs for carbon monoxide [DLCO] and forced expiratory volume [FEV1]), and chronic health conditions were evaluated for associations with age-adjusted neurocognitive performance using multivariable linear regression. Compared with controls, survivors had lower performance (P < 0.05) in visuomotor (0.11 vs 0.41), visual processing speed (0.25 vs 0.64), short-term recall (−0.24 vs 0.12), and flexibility (−0.04 vs 0.28). Survivors had lower pulmonary (FEV1, DLCOcorr), cardiac (LVEF, GLS), and vascular function (SAE) than controls (all P < 0.001). FEV1 was associated with visuomotor (P = .008) and visual processing speed (P = .05), and flexibility (P = .05). GLS was associated with short-term recall (P = .03). SAE was associated with flexibility (P = .007). Neurocognitive outcomes were also associated with moderate-to-severe neurologic chronic conditions (P < .05). Findings suggest a link between subclinical cardiopulmonary and vascular findings, neurologic morbidity, and neurocognitive impairments. Prevention of health morbidity may benefit neurocognitive outcomes.

Targeting the Retinoid X Receptor Pathway Prevents and Ameliorates Murine Chronic Graft-Versus-Host Disease.

Most allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients receive peripheral blood stem cell grafts resulting in a 30%–70% incidence of chronic graft-versus-host disease (cGVHD), a major cause of mortality and morbidity in long-term survivors. While systemic steroids remain the standard of care for first-line therapy, patients may require long-term administration, and those with steroid-resistant or refractory cGVHD have a worse prognosis. Although durable and deep responses with second-line therapies can be achieved in some patients, there remains an urgent need for new therapies. In this study, we evaluated the efficacy of IRX4204, a novel agonist that activates RXRs and is in clinical trials for cancer treatment to prevent and treat cGVHD in two complementary murine models. In a major histocompatibility complex mismatched, non-sclerodermatous multiorgan system model with bronchiolitis obliterans, IRX4204 prevented and reversed cGVHD including associated pulmonary dysfunction with restoration of germinal center T-follicular helper: T-follicular regulatory cell balance. In a minor histocompatibility antigen disparate sclerodermatous model, IRX4204 treatment significantly prevented and ameliorated skin cGVHD by reducing Th1 and Th17 differentiation due to anti-inflammatory properties. Together, these results indicate that IRX4204 is a promising therapeutic option to treat cGVHD with bronchiolitis obliterans or sclerodermatous manifestations.

Burden of Morbidity after Allogeneic Blood or Marrow Transplantation for Inborn Errors of Metabolism: A BMT Survivor Study Report

Survival after blood or marrow transplantation (BMT) for inborn errors of metabolism (IEM) is excellent; however, the burden of morbidity in long-term survivors of BMT for IEM remains understudied. This study examined the risk of chronic health conditions (CHC) in ≥2-year survivors of allogeneic BMT for IEM performed between 1974 and 2014 using the BMT Survivor Study. In this retrospective cohort study, participants (or their parents; n=154) reported demographic data and CHCs (graded using Common Terminology Criteria for Adverse Events version 5), and transplantation characteristics were obtained from institutional databases. Unaffected siblings (n=494) served as a comparison group. Logistic regression was used to estimated the odds of severe/life-threatening CHCs compared with siblings. Cox proportional hazards regression was used to estimate factors associated with severe/life-threatening/fatal CHCs in survivors of BMT for IEM. Survivors of allogeneic BMT for IEM (leukodystrophies, 43.5%; mucopolysaccharidoses, 41.0%) were at 12.5-fold higher odds of severe/life-threatening CHCs (95% confidence interval [CI], 5.4 to 28.9) compared with their siblings. The mean 10-year post-BMT cumulative incidence of grade 3-5 CHCs was 47.5 ± 4.0%. Reduced-intensity conditioning (RIC) was associated with a 2.7-fold higher risk (95% CI, 1.2 to 6.2; P=.02) of any grade 3-5 CHC, a 6.7-fold higher risk of grade 3-5 cardiopulmonary conditions (95% CI, 1.3 to 35.4), and a 3.0-fold higher risk of severe hearing/vision deficits (95% CI, 1.4 to 6.6). Older (age >26 years) BMT survivors were significantly less likely to graduate from college (odds ratio [OR], 0.3; 95% CI, 0.1 to 0.7) or marry (OR, 0.01; 95% CI, 0.004 to 0.07) compared with their siblings. Survivors of BMT for IEM carry a significant burden of morbidities, which affects their ability to attain adult milestones. Efforts to reduce chronic health conditions in this population are needed.

Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) remains an important cause of mortality and long-term morbidity. This article uses a case-based approach to guide readers through the fundamental epidemiology and pathogenesis of SAH, the approach to diagnosis and management, the results of clinical trials and evidence to date, prognostic considerations, controversies, recent developments, and future directions in SAH. Historically, management of SAH focused on prevention and treatment of subsequent cerebral vasospasm, which was thought to be the primary cause of delayed cerebral ischemia. Clinical and translational studies over the past decade, including several therapeutic phase 3 randomized clinical trials, suggest that the pathophysiology of SAH-associated brain injury is multiphasic and multifactorial beyond large vessel cerebral vasospasm. The quest to reduce SAH-associated brain injury and improve outcomes is shifting away from large vessel cerebral vasospasm to a new paradigm targeting multiple brain injury mechanisms, including early brain injury, delayed cerebral ischemia, microcirculatory dysfunction, spreading cortical depolarization, inflammation, and the brain-body interaction in vascular brain injury with critical illness.Despite multiple negative randomized clinical trials in search of potential therapeutic agents ameliorating the downstream effects after SAH, the overall outcome of SAH has improved over recent decades, likely related to improvements in interventional options for ruptured cerebral aneurysms and in critical care management. Emerging clinical evidence also suggests potential harmful impact of historic empiric treatments for SAH-associated vasospasm, such as prophylactic induction of hypertension, hypervolemia, and hemodilution (triple H therapy).With decreasing mortality, long-term SAH survivorship and efforts to reduce chronic morbidity and to improve quality of life and patient-centered outcome are growing areas of unmet need. Despite existing guidelines, significant variabilities in local and regional practices and in scientific terminologies have historically limited advancement in SAH care and therapeutic development. Large global collaborative efforts developed harmonized SAH common data elements in 2019, and studies are under way to examine how existing variabilities in SAH care impact long-term SAH outcomes. Although the overall incidence and mortality of SAH is decreasing with advances in preventive and acute care, SAH remains a major cause of long-term morbidity in survivors. Significant variabilities in care settings and empiric treatment protocols and inconsistent scientific terminologies have limited advancement in patient care and therapeutic clinical studies. Large consensus efforts are under way to introduce clinical guidelines and common data elements to advance therapeutic approaches and improve patient outcome.

Identification of 22 susceptibility loci associated with testicular germ cell tumors

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.

Clinical utility of FDG PET-CT in stage 1 and advanced testicular seminoma.

5027 Background: Testicular seminoma is highly curable; however, treatments can cause long-term morbidity in survivors. Following chemotherapy for advanced seminoma, positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose together with computerised tomography (PET-CT) can identify patients with residual masses who do not need additional treatment. Its role in detecting recurrence during active surveillance, particularly in patients with small indeterminate masses, is unknown. We assessed the clinical utility of PET-CT in testicular seminoma undergoing active surveillance for stage 1 disease and following curative-intent treatment for advanced disease. Methods: An institutional database was interrogated to identify patients with testicular seminoma who underwent PET-CT between 2000-2020. Demographic, clinicopathological, PET-CT findings and outcome data were retrieved. The positive predictive value (PPV) of PET-CT for correctly identifying disease recurrence was calculated, with disease recurrence (true positive) defined as progressive radiological change, response to treatment or histological confirmation. Negative predictive value (NPV) was calculated for correctly identifying non-recurrence (true negative) at 24-months post PET-CT. Results: We identified 193 PET-CT in 181 stage 1 patients. Of these, 18 (10%) PET-CT were positive, with all correctly diagnosing recurrence, PPV 100%. Of the 138 negative PET-CT with at least 24 months follow up, 5 recurrences developed, NPV 96%. In the subset of PET-CT conducted for suspicion of recurrence in stage 1 patients (n = 71: abnormal imaging n = 65, elevated markers n = 4, other clinical suspicion n = 2), 16 (23%) PET-CT were positive, with all correctly diagnosing recurrence, PPV 100%. In this subset, the NPV is 93% at 24 months (3 recurrences in 44 negative PET-CT). We also identified 154 PET-CT in 77 post-treatment, advanced stage patients. Of these, 69 (45%) PET-CT were positive, with 51 correctly diagnosing recurrence, PPV 74%. Of the 66 negative PET-CT with at least 24 months follow up, 5 recurrences developed, NPV 92%. In the subset of PET-CT performed for suspicion of recurrence following treatment for advanced disease (n = 61: abnormal imaging n = 49, elevated markers n = 5, other clinical suspicion n = 7), 41 (67%) PET-CT were positive, with 36 correctly diagnosing recurrence, PPV 88%. In this subset, the NPV is 94% at 24 months (1 recurrence in 17 negative PET-CT). Conclusions: At our centre, PET-CT has a very high PPV for recurrence, particularly in stage 1 disease, and a very high NPV for non-recurrence in all disease settings. In the subset of PET-CT performed for suspicion of recurrence, PPV is &gt; 88% and NPV is &gt; 93%. The role of PET-CT should be considered in patients with suspicion of recurrence where it may prevent over-treatment in up to 70% patients in stage 1 or 30% in advanced disease.

Long-term outcome of posterior fossa medulloblastoma in patients surviving more than 20 years following primary treatment in childhood

The aim of the study was to analyze the long-term outcome (>20 years) after treatment of posterior fossa medulloblastoma (MB) in childhood. We analyzed data from patients treated for posterior fossa MB between 1974 (introduction of the first international treatment protocol in Norway) and 1987 (when use of radiotherapy was abandoned in children under 4 years of age). Out of 47 children, 24 survived >20 years. At the time of analysis, 16 patients (median age 41 years, range 32–52) were alive (median follow-up 34 years, range 30–42), while 8 patients died 22–41 years (median 31 years) after primary treatment: one late death (after 22 years) was due to tumor recurrence whilst other 7 deaths (after 23 to 41 years) were related to the detrimental effects of the treatment (secondary tumors, stroke, severe epilepsy and depression). Observed 20- and 30-year survival rates were 51% and 44%, respectively. Despite successful treatment of MB in childhood and satisfactory tumor control during the first 20 years following primary treatment, our data indicates that even long-term survivors may die from tumor recurrence. However, the main factors causing late mortality and morbidity in long-term survivors seem to be the complications related to radiotherapy given in childhood.

Synergistic effect of novel aspirin analogues in a colorectal cancer cell line

Studies show aspirin, a non-steroidal anti-inflammatory drug (NSAID) has potential to decrease incidence of, or mortality from a number of cancers including colorectal cancer (CRC). With emphasis on the treatment of CRC involving platinum compounds, oxaliplatin has been used in several combinations with other drugs. Unfortunately, these combinations do not improve overall survival and are accompanied with side effects that include gastrointestinal (GI), hematologic, neurologic toxicities, myopathy, and most recently interstitial lung disease, particularly fibrotic hypersensitivity pneumonitis, which has high mortality rates and long-term morbidity in survivors. The need of compounds that will reduce the doses of platinum compounds required for chemotherapy in order to reduce or alleviate these side effects is long overdue. This study investigates the synergistic effect if any, of novel aspirin analogues with platinum compounds cisplatin, oxaliplatin and carboplatin in order to lower doses needed of these platinum compounds and thus reduce or alleviate common debilitating side effects. MTT assay was used to assess cell viability and the CompuSyn software (Paramus, NJ, 2005) was used to calculate CI and DRI at ED50, ED75 and ED90. Oxaliplatin was found to exhibit synergistic effects when combined with p-aspirin (PN549), diaspirin (PN508) and o-thioaspirin (PN590). Although further investigations such as in vivo experiments will be needed to draw any conclusions, this study is a stepping-stone for platinum compounds and aspirin drug combinations in order to decrease doses needed for treatment and thus lessen or alleviate debilitating side effects. Keywords: Colorectal cancer; Aspirin; Aspirin analogues; Oxaliplatin; DMSO

Muscle Depletion Is an Important and Clinically Relevant Predictor of Outcomes after Autologous Hematopoietic Cell Transplantation

▪Introduction: High intensity treatments such as autologous hematopoietic cell transplantation (HCT) can be curative for patients with relapsed/refractory lymphoma (Hodgkin [HL], non-Hodgkin [NHL]), but this needs to be balanced by the risk of non-relapse mortality (NRM) associated with HCT and potentially sub-optimal disease response with less intensive treatments. Measures of pre-treatment body composition such as quantity and quality of muscle are prognostic in patients with solid tumors, but their association with post-HCT outcomes is unknown. We examined the prognostic significance of muscle depletion prior to HCT, defined by having both low muscle quantity (lumbar skeletal muscle index [SMI]) and quality (muscle attenuation [MA]) on computed tomography (CT) imaging, in a population-based cohort of patients undergoing autologous HCT for lymphoma. Next, we examined the prognostic significance of muscle depletion after HCT in a subset of patients with normal muscle composition prior to HCT, allowing us to examine the impact of change in body composition over time.Methods: 440 consecutive patients with lymphoma, age ≥18y, who underwent a first HCT between 2009 and 2014 at a single institution were included in the study. Measures of muscle quantity (SMI) and quality (MA) were ascertained from pre- and post-HCT abdominal CT scans using image analysis software (SliceOmatic; Tomovision, Quebec, Canada). SMI was calculated as the ratio of skeletal muscle area (cm2) divided by height (m)2. Sex and body mass index (BMI)-specific cutoff values of low SMI and MA were used to identify patients with muscle depletion (J Clin Oncol 2013 31:1539). Measurements were made by trained researchers blinded to patient demographics and HCT outcome (Figure 1); 3rd lumbar vertebra was used as a landmark because of its high correlation with whole-body muscle mass (J Clin Oncol 2016 34:1339). This report is limited to 321 (73%) patients with CT scans performed ≤90 days from HCT. Cumulative incidence of NRM was calculated taking into consideration competing risk of disease-related mortality. Kaplan-Meier method was used to examine overall survival (OS). Multivariable Cox regression analysis was used to calculate the hazard ratio (HR) estimates and 95% confidence intervals (CI), adjusted for relevant covariates (demographics, diagnosis, pre-HCT Karnofsky performance score [KPS] and comorbidity index [HCT-CI]).Results: Sixty-two (19.3%) patients had muscle depletion pre-HCT. Median age at HCT was 53y (range: 18-78); 62.0% were male; 54.0% were non-Hispanic white; Diagnoses: HL (N=84 [26.2%]), NHL (N=237 [73.8%]); KPS ≤80 (N=87 [27.1%]); HCT-CI ≥3 (N=52 [16.2%]). Impact of pre-HCT muscle depletion: Patients with pre-HCT muscle depletion had significantly worse 5-y OS (56.4% vs. 77.8%, p<0.001; Figure 2) and higher NRM (11.4% vs. 5.1%, p=0.05) when compared to those with normal body composition. OS was especially poor for patients who were obese (BMI ≥30 kg/m2) and had muscle depletion (20.0% vs. 77.1%, p<0.001) pre-HCT. Median length of hospitalization was also significantly longer (27d vs. 23d; p=0.03) among patients with muscle depletion. Muscle depletion was associated with a 2.2-fold (HR=2.2 [CI: 1.0-4.5]) risk of NRM and 1.8-fold (HR=1.8 [CI: 1.1-3.1]) risk of all-cause mortality when compared to those with normal body composition. Impact of post-HCT muscle depletion: Among 223 patients with normal body composition prior to HCT, 24 (9.3%) developed muscle depletion after HCT, detected at a median 63d (range 27-165) from HCT. In these patients, there was a 3-fold (HR=3.1 [CI: 1.5-6.4]) risk of all-cause mortality compared to those who maintained normal muscle composition throughout HCT.Conclusion: Muscle depletion is an important and independent predictor of outcomes after HCT, with potential additional downstream impacts on health-economic outcomes such as length of hospitalization and the burden of chronic morbidity in long-term survivors. Taken together, these data form the basis for real-time decision making prior to HCT (e.g. pre-habilitation, less intensive treatment approaches), or during HCT (e.g. dietary optimization, increased supportive care services, resistance training), setting the stage for innovative strategies to improve outcomes after HCT. DisclosuresChen:Affimed: Research Funding; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech Inc.: Consultancy; Millennium Pharmaceuticals: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

International Perspectives: Birth-Associated Neonatal Encephalopathy: Postresuscitation Care in West African Newborns

The West African subregion has the highest burden of neonatal mortality globally and the neonatal mortality rate is decreasing very slowly. A high proportion of newborn deaths are preventable and improved quality of care can reduce long-term morbidity in survivors. Perinatal asphyxia is the major cause of death and disability in term infants in the subregion. Neonatal resuscitation training programs have reduced stillbirths and early neonatal mortality but the overall effect on survival to discharge, population-based perinatal mortality, and long-term impairment is uncertain. Gaps in the health system and quality of postresuscitation care for affected newborns may defeat gains from global efforts to improve care around the time of birth. The aim of this review is to discuss the current situation of postresuscitation care of term infants with presumed birth-associated neonatal encephalopathy in West Africa. Limitations in diagnosing and treating affected infants and feasible interventions to improve acute and postdischarge care are discussed.

Quantitative proteomics analysis of differentially expressed proteins in ruptured and unruptured cerebral aneurysms by iTRAQ

The underlying pathophysiological mechanisms involved in cerebral aneurysms rupture remain unclear. This study was performed to investigate the differentially expressed proteins between ruptured and unruptured aneurysms using quantitative proteomics. The aneurysmal walls of six ruptured aneurysms and six unruptured aneurysms were collected during the surgical operation. The isobaric tags for relative and absolute quantification (iTRAQ) were used to identify the differentially expressed proteins and western blotting was performed to validate the expression of the proteins of interest. Bioinformatics analysis of the differentially expressed proteins was also performed using the KEGG database and GO database. Between ruptured and unruptured aneurysms, 169 proteins were found differently expressed, including 74 up-regulated proteins and 95 down-regulated proteins with a fold change ≥ 2 and p value ≤ .05. KEGG pathway analysis revealed that phagosome, focal adhesion and ECM-receptor interaction were the most common pathways involved in aneurysm rupture. In addition, the differential expressions of ITGB3, CRABP1 and S100A9 were validated by western blotting. Through the iTRAQ method, we found that inflammatory responses and cell-matrix interactions may play a significant role in the rupture of cerebral aneurysms. These findings provide a basis for better understanding of pathophysiological mechanisms associated with aneurysm rupture. Biological significanceIntracranial aneurysm is the leading cause of life-threating subarachnoid hemorrhage which can cause 45% patients die within 30 days and severe morbidity in long-term survivors. With a high prevalence ranging from 1% to 5% in general population, cerebral aneurysm has become a widespread health hazard over past decades. Though great advances have been achieved in the diagnosis and treatment of this disease, the underlying pathophysiological mechanisms of aneurysm rupture remains undetermined and a lot of uncertainty still exists surrounding the treatment of unruptured cerebral aneurysms. Clarifying the mechanism associated with aneurysm rupture is important for estimating the rupture risk, as well as the development of new treatment strategy. Some previous studies have analyzed the molecular differences between ruptured and unruptured IAs at gene and mRNA levels, but further comprehensive proteomic studies are relatively rare. Here we performed a comparative proteomics study to investigate the differentially expressed proteins between ruptured IAs (RIAs) and unruptured IAs (UIAs). Results of our present study will provide more insights into the pathogenesis of aneurysm rupture at protein level. With a better understanding of pathophysiological mechanisms associated with aneurysm rupture, some noninvasive treatment strategies may be developed in the future.

Chemotherapy-induced peripheral neuropathy: A current review.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect experienced by patients receiving treatment for cancer. Approximately 30 to 40% of patients treated with neurotoxic chemotherapy will develop CIPN, and there is considerable variability in its severity between patients. It is often sensory-predominant with pain and can lead to long-term morbidity in survivors. The prevalence and burden of CIPN late effects will likely increase as cancer survival rates continue to improve. In this review, we discuss the approach to peripheral neuropathy in patients with cancer and address the clinical phenotypes and pathomechanisms of specific neurotoxic chemotherapeutic agents. Ann Neurol 2017;81:772-781.

Role of Radiation Therapy in the Treatment of Hodgkin Lymphoma.

Radiation therapy has historically been the pillar of curative treatment for Hodgkin lymphoma (HL). With improved efficacy of systemic therapy and the ever-increasing recognition of treatment-related morbidity in long-term survivors, the role of radiotherapy has evolved significantly. Modern combined modality therapy (CMT) with multi-agent chemotherapy followed by involved site radiation therapy (ISRT) to initially involved sites of disease remains the gold standard for the majority of patients with HL. Reduction of long-term treatment-related toxicity has become the major driver in clinical trial design for early-stage HL while improved disease-specific survival remains the goal in patients with more advanced and unfavorable disease. This review will address the data supporting the use of radiotherapy in HL as well as specific methods for reducing late toxicity from radiotherapy.

Treatment of Iron Overload in Transfusion-Dependent Anemias Post Hematopoietic Stem Cell Transplantation: When to Start? When to Stop?

▪IntroductionIron overload (IO) in transfusion-dependent anemias (Thalassemia major, Sickle Cell Disease, Diamond-Blackfan and Fanconi Anemia) persist after hematopoietic stem cell transplantation (HSCT) and can result in increased morbidity in long term survivors, e.g. nonspecific liver dysfunction, hepatic cell carcinoma, heart failure and endocrinological complications. To reduce IO, phlebotomy or iron chelation is a required and effective treatment.Although existing recommendations for screening and prevention of late effects following HSCT suggest determining serum ferritin (SF) levels 1year post transplant, there are no clear guidelines for screening IO and initiating treatment.It is well known that SF levels depend on several factors beyond IO, e.g. infection or graft versus host disease, thus it is very often elevated as an acute phase protein in the post-transplant period.Aim of the StudyIn a multicenter, retrospective study we analyzed the concordance between liver iron concentration (LIC) and SF in 90 measurements of 33 patients (median age 8.9 y, range 1-11 y) with transfusion-dependent anemias (Thalassemia major, Diamond-Blackfan and Fanconi Anemia) who underwent HSCT between 1996 and 2014. LIC was determined either by MRI-R2 (Ferriscan®) or SQUID liver susceptometry.Statistical methodsWe examine the concordance between the classification according to LIC and SF: for SF < 800 μg/L, SF > 800 μg/L, and for the total range of SF levels.Pearson correlation was used to examine the relationship between paired values of LIC and SF.To analyze the classification sensitivity of SF levels according to LIC ≥ 4.5 mg/gdw we applied receiver operating characteristic (ROC) analysis. This approach estimates the sensitivity and the specificity as function of each SF cut-off level. The predictive accuracy of SF measurements in predicting LIC classification was investigated by area under the ROC curve.All statistical tests are two-sided with a significance level of 5%. Data analysis was performed using commercial software (R, ROCR package and Graph Prism software)ResultsCorrelation between serum ferritin and LICA moderate correlation among ferritin and LIC was found for the overall measurements (n=90). The Pearson coefficient correlation was equal to 0.69 (p<0.001), with 95% confidence interval [0.57 - 0.79]. When we analyzed the correlation between ferritin and LIC only for measurements with SF < 800 μg/L (n=25) the correlation coefficient is equal to 0.26. For this group, a very weak association among LIC and SF was found (p=0.2). In the group with SF > 800 μg/L (n=65) the relationship is moderate (p<0.001), with a Pearson correlation coefficient equal to 0.585 (Fig. 1).Concordance of the classification according serum ferritin and LICIn labor analysis and scans via MRI and SQUID technique the paired values of 90 LIC and SF were assessed. In accordance to the LIC threshold ≥4.5 mg/gdw 74 measurements demonstrated a demand of therapy. A total of 16 measurements did not indicate any requirement of therapy. A total of 65 measurements had SF ≥ 800 μg/L and 25 measurements had SF < 800 µg/l, indicated therapy onset and no therapy, respectively. The false positive rate was 22% (16/74) and the false negative rate was 44% (7/16). The overall error was 26% (23/90).The predictive accuracy of SF to predict classification of LIC for the whole measurements was 77.5%. The accuracy for the measurements > 800 μg/L (n=65) was 81%. Instead, ROC analysis for SF measurements < 800 μg/L (n=25) indicates non-informative prediction (area=0.53) (Fig. 2).ConclusionThe values of of SF > 800 μg/L are applicable for predicting the classification according to LIC at a threshold ≥ 4.5 mg/gdw.A SF < 800 μg/L is not appropriate for predicting an initiating treatment of IO, because of a weak correlation (p=0.2) between paired SF and LIC values. Furthermore, the accuracy of SF indicated a non-informative prediction of classification according to LIC (ROC area = 0.53).Our data suggest that initiating and stopping treatment of IO in transfusion dependent patients after HSCT should be done on the basis of LIC measured via MRI or SQUID instead of SF measurements only. [Display omitted] [Display omitted] DisclosuresGrosse:Swedish Orphan Biovitrum: Honoraria; Novartis Oncology: Honoraria, Research Funding.

Therapeutic exercise in improving acute lung injury: a long distance to be covered.

Skeletal muscle weakness is a common finding among critically ill patients, and many factors have been recognized to trigger its initiation early in the patients’ course in intensive care unit (ICU) (1). In acute respiratory distress syndrome (ARDS), a clinical condition which is characterized by acute respiratory failure, skeletal muscle weakness acquired in ICU is present in 25-50% of patients, and is independently associated with mortality and long term morbidity in survivors (2). Several clinical research studies suggest that early mobilization of critically ill patients improves clinically meaningful outcomes for the patient (3), however, without having clarified the mechanisms underlying this implementation. We read with interest the study by Files et al. (4) who through their experiments suggest a unifying mechanism underlying the beneficial effects of therapeutic exercise in mice with lung injury. In their study authors exercised ALI mice for 2 days after lipopolysaccharides (LPS) instillation. They found that a short duration of moderate intensity exercise attenuated muscle ring finger 1 (MuRF 1)-mediated atrophy of the limb and diaphragm and improved limb muscle force generation. Importantly, exercise also limited neutrophilic influx into the alveolar space through modulation of a co-ordinated systemic neutrophil chemokine response. Furthermore, in ALI mice exercise reduced granulocyte colony-stimulating factor (G-CSF), and in vivo blockade of the G-CSF receptor lead to recapitulation of the lung. Similarly, in humans with acute respiratory failure, early mobility therapy led to greater decrements over time in G-CSF plasma levels compared to control patients, confirming the relevance of G-CSF as a mediator of the improved outcomes of mobilized/exercised critically ill patients.

Late morbidity in long-term survivors of childhood brain tumors: a nationwide registry-based study in Finland.

The population of long-term survivors of childhood brain tumors (BTs) is growing. The aim of our study was to evaluate late-appearing morbidity in BT survivors. Patients diagnosed with a BT at the age of 0-15 years between 1970 and 2004, and surviving at least 5 years, were identified from the Finnish Cancer Registry (n = 740). Their late new morbidity ≥ 5 years after cancer diagnosis was assessed using the Hospital Discharge Registry containing hospitalizations and outpatient visits in specialized health care settings. The morbidity of BT survivors was compared with that of the sibling cohort (n = 3615). The 5-year survivors had a significantly increased hazard ratio (HR) for endocrine diseases (HR, 14.7), psychiatric disorders (HR, 1.8), cognitive and developmental disorders (HR, 16.6), neurological diseases (HR, 9.8), disorders of vision and hearing (HR, 10.5), and diseases of the circulatory system (HR, 2.7) compared with the sibling cohort. The HRs for disorders of musculoskeletal system (HR, 1.4) and diseases of the kidney (HR, 2.1) were not significantly increased. Radiation treatment did not explain all of the excess morbidity. Female survivors had a higher risk for disorders of vision and hearing (P = .046). Age at diagnosis did not show an effect on HRs. The HRs for endocrine diseases and disorders of vision or hearing loss were highest for survivors treated in the 1980s or later. Pediatric BT survivors had significant neurocognitive consequences. This, together with the considerable risk for endocrine morbidity, will motivate us to organize systematic follow-up procedures for pediatric BT survivors.

VAGINAL MICROBIOME–PREGNANT HOST INTERACTIONS DETERMINE A SIGNIFICANT PROPORTION OF PRETERM LABOUR

Preterm birth (PTB) has a global prevalence of 11.1% accounting for almost 15 million babies born each year before 37 weeks of gestation. It is a risk factor in over 50% of all neonatal deaths, which amounts to 1.1 million deaths annually. Preterm birth, especially at early gestational ages is associated with a high risk of long-term morbidity in survivors. Despite much research effort, PTB rates continue to rise, placing immense financial and emotional burden on society. In the US, the annual societal economic cost associated with PTB is $26.2 billion with an average of $51,600 being spent per infant born preterm. Preterm labour (PTL) accounts for 70% of these births, of which 25% are preceded by preterm pre-labour rupture of membranes (PPROM).

Morbidity in long-term survivors after pancreatoduodenectomy for pancreatic adenocarcinoma.

307 Background: Because the focus of pancreatoduodenectomy for pancreatic adenocarcinoma is placed on disease-free and overall survival, morbidity in long-term survivors is not well described. We sought to evaluate outcomes of long-term survivors of pancreatic cancer after pancreatoduodenectomy. Methods: We identified 30 patients from our prospectively collected database of patients with pancreatic adenocarcinoma who had undergone pancreatoduodenectomy, and who were without evidence of disease with at least 40 months of follow-up. Demographics, treatment and pathologic characteristics were collected for review. Data with regards to long-term sequelae were also collected, particularly those complications requiring additional procedures and the development of metachronous cancers. Results: The median length of follow up was 83 months, with 60% of patients still alive. Half the patients were male, and the median age at diagnosis was 70 years. With regard to treatment, 80% of patients received chemoradiation, with half of these patients receiving it in the neoadjuvant setting. All patients received an R0 resection, although two patients required at least partial resection of the superior mesenteric or portal veins. Thirty-three percent of patients had N1 disease. Forty-four percent of patients did not have any significant subsequent sequelae. In the remainder, four patients (13%) developed ascites requiring repeated paracentesis or Denver shunt, with median time to development (MTD) of 63 months. Six patients (20%) developed a biliary stricture requiring stent placement (MTD 56 months), one patient developed portal venous thrombosis requiring a venous stent (MTD 52 months), and 3 patients (10%) experienced clinically significant gastric anastomotic ulcers (MTD 47 months). With regards to metachronous cancers, 2 patients developed subsequent lymphomas (MTD 92 months). Conclusions: Long-term survivors of patients who undergo pancreatoduodenectomy for pancreatic adenocarcinoma can develop significant late sequelae, which often can manifest more than three to five years after surgery. Continued follow-up and counseling is warranted.

Neonatal epilepsy and underlying aetiology: to what extent do seizures and EEG abnormalities influence outcome?

Neonatal seizures constitute the most common and distinctive sign of neurological dysfunction in the first weeks of life and reflect a wide variety of underlying central nervous system disorders. Acute symptomatic seizures occur more often during the neonatal period than at any period of life and are associated with adverse long-term neurodevelopmental sequelae and an increased risk of post-neonatal epilepsy. The improvements of neonatal care in the last decades have changed the spectrum of insults to which the immature brain is exposed and facilitated a decrease in mortality of newborns with seizures. However, the prevalence of long-term morbidity in survivors remains unchanged. Whereas aetiology is presumed to be the main predictor of long-term outcome in neonates with seizures, there is converging evidence that specific electroencephalographic (EEG) abnormalities are related to unfavourable outcomes. Interictal EEG abnormalities, especially concerning background activity patterns, thus constitute a major indicator of disease severity and predictor of outcome, while the added value of sequential EEG assessments is so far controversial. Moreover, experimental as well as clinical studies of hypoxic-ischaemic encephalopathy support the notion that recurrent seizures may amplify injury to the developing brain beyond that associated with the underlying aetiology, thus justifying antiepileptic drug treatment. To date, unresolved issues in seizure detection and classification, in addition to the significant variation in gestational ages and brain insults of neonates, still impede clinical research of neonatal seizures. The wider use of long-term EEG or amplitude integrated EEG monitoring may prove crucial for timely neonatal seizure identification and treatment initiation, and thus ultimately improve outcome.

Hernie de coupole diaphragmatique : devenir à long terme

The increased survival rate reached in infants with congenital diaphragmatic hernia (CDH) has shown a concomitant increase in late morbidity. Many complications including pulmonary damage, cardiovascular disease, gastro-intestinal disease, failure to thrive, neurocognitive defects and musculoskeletal abnormalities have been described. Long-term pulmonary morbidity in CDH consists of obstructive and restrictive lung function impairments due to altered lung structure and prolonged ventilatory support. Long-term consequences of pulmonary hypertension are unknown. Gastro-esophageal reflux disease (GERD) is also an important contributor to overall morbidity. Failure to thrive may be caused by GERD, insufficient intake due to oral aversion and increased caloric requirements due to pulmonary morbidity. Neurological outcome is determined by an increased risk of perinatal and neonatal hypoxemia in the first days of life of CDH patients. Many studies have addressed the substantial impact of the health problems described above, on the overall well-being of CDH patients, but only a few studies focus on the health-related quality of life. Considering the scattered data indicating substantial morbidity in long-term survivors of CDH, follow-up studies that systematically assess long-term sequelae are needed. Based on such studies, a more focused approach for routine multidisciplinary follow-up programs could be established. It is the goal of the French Collaborative Network to promote exchange of knowledge, future research and development of treatment protocols.