Main Determinant Of Prognosis Research Articles

Assessing microvascular dysfunction and predicting long-term prognosis in patients with cardiac amyloidosis by cardiovascular magnetic resonance quantitative stress perfusion.

Cardiac involvement in light chain amyloidosis (AL) is the main determinant of prognosis. Amyloid can be deposited in the extracellular space and cause an increase in extracellular volume fraction (ECV). At the same time, amyloid can also be deposited in the wall of small vessels and cause microvascular dysfunction. This study sought to investigate the extent of microvascular dysfunction and its incremental prognostic value in cardiac light-chain amyloidosis (AL-CA) by quantitative stress perfusion. A total of 126 AL amyloidosis patients (61.13 ± 8.46 years, 81 male) confirmed by pathology were prospectively recruited. All subjects underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE), T1 mapping, and stress perfusion on a 3T scanner. ECV and myocardial perfusion reserve (MPR) were measured semi-automatically using a dedicated CMR software. Clinical, laboratory, and CMR parameters were analyzed for their prognostic value in the assessment of AL-CA patients. Mortality-associated markers were analyzed by univariate and multivariable Cox regression. The median follow-up time was 37 (33.6-40.4) months, and 62 patients died. The ECV of survivors was significantly reduced, but the stress myocardial blood flow and MPR were higher (P<0.001). The MPR of the transmural LGE group was significantly lower than that of the no LGE and subendocardial LGE groups (P<0.001). In multivariable analysis, ECV, MPR, and LGE were independently predictive. MPR of >1.5 and ECV of ≤53.6% were associated with improved overall survival, both of which provided predictive incremental value in patients with advanced disease. With equal Mayo staging and degree of ECV, MPR improves assessment of patient survival. ECV and MPR showed additive incremental values and further discriminated prognosis of patients in advanced stages. CMR phenotypes with higher ECV and lower MPR had a worse prognosis.

Injection drug use infective endocarditis: clinical features and therapeutic challanges

Abstract Introduction Injection drug use (IDU) is a known risk factor for infective endocarditis (IE) and is associated with frequent recurrences, but its prognostic impact is still debated. Moreover, the potential futility of surgery in this population is an unsolved matter. Purpose We aimed to determine the clinical characteristics, the therapeutic strategy, and the prognostic impact of injection drug use IE (IDUIE). Method We retrospectively included in the analysis 454 consecutive episodes of definite active IE admitted in a single surgical centre from January 2012 to December 2020; 14 out of them where a subsequent infective episode of the same patient. Results IDUIE cases were 63 (13.8%), without significant proportional differences over time. IDUIE patients were significantly younger (43.95±10.12 vs 67.84±13.33, p 0.00) and presented fewer comorbidities (p&amp;lt;0.001). They were admitted with a first episode of IE only in 60.3% of cases vs 92.8% of non-IDU (p&amp;lt;0.001). Embolism was present at admission in a higher percentage (60.3 vs 38.4%, p&amp;lt;0.001). IDUIE was more frequently associated with spondylodiscitis (15.9 vs 7.4%, p=0.026). The infection was less frequently left-sided than in non-IDU patients (57.1 vs 97.2%, p&amp;lt;0.001) and was more often polimicrobic (12.7 vs 4.9%, p=0.015). Most patients were positive for Staphylococcus aureus (54.0 vs 12.8%, p&amp;lt;0.001), while Streptococci were significantly less frequent in patients with IDUIE (11 vs 25%, p=0.015). The proportion of patients undergoing surgery was similar among the two groups (85.5 vs 78.8%, NS). IDUIE patients treated medically for absence of surgical indication had a better survival than patients undergoing surgery for complicated IE (p&amp;lt;0.001). IDUIE was associated with a higher proportion of relapse during follow-up (28.3 vs 3.3%, p&amp;lt;0.001). It was not associated with higher mortality (Figure 1) but was an independent predictor of mortality in multivariable analysis including age (HR per unit 1.048, 95% CI 1.038–1.063, p=0.00) and drug abuse (HR 3.2, 95% CI 1.8–5.6, p=0.00; Figure 2). Among IDUIE patients, we did not find predictors of futility of surgery, not even multiple relapses. Conclusions IDUIE represents a considerable proportion of overall cases of IE, mainly affecting young people. Staphylococcus aureus is the most common microbiologic agent. IDUIE is not associated with higher mortality but drug abuse is an independent predictor of mortality. Considering that patient with uncomplicated IE treated medically have a better prognosis, we should reserve surgery to patients with a strict indication for it. On the other hand, since there are no predictors of futility of surgery, all patients with a complicated IE should undergo surgery without delay. The main determinant of prognosis in these patients is not IE but drug abuse itself. For this reason, increased focus on addiction treatment following hospital discharge is mandatory to improve long term prognosis. Funding Acknowledgement Type of funding sources: None.

Leflunomide therapy for IgA vasculitis with nephritis in children

BackgroundHenoch-Schönlein purpura (HSP), also called IgA vasculitis, is a systemic vasculitis characterized by deposits of immunoglobulin A in blood vessels. Renal impairment of these patients is the main determinant of prognosis. The optimal treatment of HSP nephritis (HSPN) in children remains controversial, but many clinicians administer an immunosuppressive agent with a corticosteroid. A previous study reported that leflunomide (LEF) with a corticosteroid was effective for adult patients with HSPN and nephrotic proteinuria. However, data on this treatment in pediatric patients is limited.MethodsWe described our experience at a single center on the use of LEF in 5 pediatric patients who had IgA vasculitis with proteinuria that was nearly 50 mg/kg (nephrotic range) and remained high despite administration of intravenous steroid, and biopsy-proven nephritis. All patients had class II to IIIb lesions based on the International Study of Kidney Disease in Children (ISKDC).ResultsWe successfully treated all 5 children who had IgA vasculitis with nephritis using LEF with a corticosteroid. Four patients achieved a complete remission of proteinuria, and 1 patient had significantly reduced proteinuria. The children received LEF for 6 months to 12 months, and none of them had severe adverse events.ConclusionsTo our knowledge, this is the first case series to report successful treatment of pediatric HSPN with LEF in combination with a corticosteroid.

Evaluation of long-term changes of aspartate\u2014platelet ratio index, FIB4, and liver stiffness in chronic hepatitis C patients successfully treated by direct-acting antivirals

BackgroundA large number of chronic hepatitis C patients had been successfully treated by directly acting antivirals; therefore, strategies for the long-term follow-up of these patients have to be planned based on the post-treatment fibrosis stage—the main determinant of prognosis. In this study, we aim to evaluate changes in aspartate-platelet ratio index, FIB4, and liver stiffness in chronic hepatitis C patients who achieved SVR and ended treatment more than 1 year by DAAs.ResultsOne hundred chronic hepatitis C patients who achieved SVR were enrolled at a median of 16 months after the end of treatment by DAAs. According to the baseline liver stiffness, 63 and 37 patients belonged to early (F0, F1, and F2) and advanced (F3 and F4) fibrosis stages, respectively. Both groups showed a decline of the degree of liver stiffness at follow-up compared to the baseline that was statistically significant in the early fibrosis group (5.9±1.5 vs 5.4±2.2 Kpcal, p=0.04), while measurements in the advanced group were (18±8.8 vs 15.9 ± 7.8 Kpcal, p=0.07). Also, serum biomarkers of fibrosis improved in both groups, where the recorded APRI and FIB4 before and after treatment were 0.42±0.3 vs 0.24±0.1, p<0.01 and 1±0.6 vs 0.93 ±0.5, p=0.1 in the early group and 0.85 ±0.5 vs 0.4±0.2, p <0.001 and 2.9±2.3 vs 1.8±1.4, p<0.02) in the advanced group, respectively. Changes in APRI and FIB4 correlated with changes in AST and ALT, but liver stiffness changes were not affected by changes in liver enzymes.ConclusionAlthough long-term improvement of APRI, FIB4, and liver stiffness scores could be achieved in chronic HCV patients after SVR by DAAS. High measurements of liver stiffness before treatment likely persist. We recommend transient elastography as a reliable tool for fibrosis assessment post-treatment.

Abstract P47: Immediate Clinical Improvement Occurs in Patients With Aneurysmal Subarachnoid Hemorrhage and Delayed Cerebral Ischemia Treated With Hypertension Induction or Inotropics

Introduction: Delayed cerebral ischemia (DCI) is one of the main determinants of prognosis in aneurysmal subarachnoid hemorrhage (aSAH). Hypertension induction (HI) and inotropics are frequently used strategies to treat DCI. However, little is known about clinical improvement immediately after those therapies. Methods: All patients with aSAH admitted to our hospital from 2016 to 2018 were evaluated. DCI was defined as a new focal neurological deficit or decrease in level of consciousness or the appearance of new infarctions on brain imaging. Patients who developed DCI and received vasopressors or inotropics and were included in the study. They were evaluated before (t0), 45 (t1) and 90 (t2) minutes after therapy initiation using NIHSS scores and Glasgow Coma Scale (GCS). Results: A total of 98 aSAH were evaluated, and 21 of them developed DCI (21.4%). Six patients received both treatment strategies, leading to a total of 27 DCI treatments (norepinephrine =12, milrinone =15). Mean NIHSS score had a significant decrease in t1 and t2 when compared to t0 (17 [95%CI 13-24], 16 [95%CI 11-23], 15 [95%CI 9-22], p&lt;0.001 and p&lt;0.002). The same happened among those treated with IH (t0=18 [95%CI 13-25]; t1=16 [95%CI 11-23], p=0.002; t2=14 [95%CI 9-22], p=0.027) and with milrinone (t0=17 [95%CI 12-24]; t1=15 [95%CI 10-23], p=0.007; t2=14 [95%CI 9-23], p=0.001). Mean GCS had a significant improvement in t1, that was not sustained in t2 (9 [95%CI 8-11], 10 [95%CI 9-12], 10 [95%CI 9-12], p=0.008 and p=0.098). In those treated with HI GCS scores did not change significantly (t0=9 [95%CI 7-11]; t1=10 [95%CI 8-12], p=0.054; t2=10 [95%CI 8-12], p=0.177). Those treated with inotropics significantly improved across time (t0=10 [95%CI 8-12]; t1=11 [95%CI 9-13], p=0.004; t2=11 [95%CI 9-13], p=0.001). Conclusions: DCI treatment with HI or inotropic therapy seems effective in immediately improving neurological deficits in patients with aSAH and DCI.

Post head injury neurobehavioral sequelae: severity among alcoholics

Background: Alcohol use and traumatic brain injury (TBI) are closely linked public health problems. Alcohol intoxication is one of the major risk factor for TBI, and is a main determinant of prognosis in terms of mortality and functional outcome. The aim of the study is to find out the impact of alcoholism in the neurobehavioral outcome following TBI.Methods: A total of 150 head injury patients were divided into two groups: alcoholics and non-alcoholics, and evaluated between six weeks to one year after injury using the revised neurobehavioral rating scale by Levin et al (NRS-R) for the evaluation of neurobehavioral sequelae and the outcome was compared between groups.Results: The study showed significant difference between the groups indicating that the neurobehavioral sequelae were more in the chronic alcoholics group. In the comparison of individual factors, all except factors III (negative symptoms) and IV (mood and affect) were found to be significantly different. The factors I (executive), II (positive symptoms), V (oral and motor), and VI (not loading on any of the factors) were significant at 0.01 level.Conclusions: Chronic alcoholism significantly increases the risk of developing neurobehavioral sequelae after traumatic brain injury.

Functional Progression in Patients with Interstitial Lung Disease Resulted Positive to Antisynthetase Antibodies: A Multicenter, Retrospective Analysis.

Antisynthetase syndrome (ASSD) is a rare autoimmune disease characterized by serologic positivity for antisynthetase antibodies. Anti-Jo1 is the most frequent, followed by anti PL-7, anti PL-12, anti EJ, and anti OJ antibodies. The lung is the most frequently affected organ, usually manifesting with an interstitial lung disease (ILD), which is considered the main determinant of prognosis. Some evidences suggest that non-anti-Jo-1 antibodies may be associated with more severe lung involvement and possibly with poorer outcomes, while other authors do not highlight differences between anti-Jo1 and other antisynthetase antibodies. In a multicenter, retrospective, “real life” study, we compared lung function tests (LFTs) progression in patients with ILD associated with anti-Jo1 and non-anti-Jo1 anti-synthetase antibodies to assess differences in lung function decline between these two groups. Therefore, we analyzed a population of 57 patients (56% anti-Jo1 positive), referred to the outpatient Clinic of four referral Centers in Italy (Modena, Monza, Siena, and Trieste) from 2008 to 2019, with a median follow-up of 36 months. At diagnosis, patients showed a mild ventilatory impairment and experienced an improvement of respiratory function during treatment. We did not observe statistically significant differences in LFTs at baseline or during follow-up between the two groups. Moreover, there were no differences in demographic data, respiratory symptoms onset (acute vs. chronic), extrapulmonary involvement, treatment (steroid and/or another immunosuppressant), or oxygen supplementation. Our study highlights the absence of differences in pulmonary functional progression between patients positive to anti-Jo-1 vs. non anti-Jo-1 antibodies, suggesting that the type of autoantibody detected in the framework of ASSD does not affect lung function decline.

Cardiac Amyloidosis in Patients Undergoing TAVR: Why We Need to Think About It

Systemic amyloidosis encompasses a variety of diseases characterized by extracellular deposition of protein-derived fibrils in different tissues and organs. Immunoglobulin light-chain (AL) and transthyretin (ATTR) amyloid are the two types that more commonly affect the heart and in both subtypes cardiac involvement is the main determinant of prognosis. Recently, several studies have suggested that Cardiac Amyloidosis (CA) and Aortic Stenosis (AS) can coexist more frequently than previously suspected with prevalence ranging from 5,6% to 16% in different cohorts. The unexpected high prevalence of CA in AS and the availability of potentially effective treatment in CA should push us to carefully investigate elderly patients with aortic valve stenosis in order to identify those with coexistent amyloidosis. While the motivation to exclude amyloidosis was in the past their exclusion from active treatment of the valve disease, judged as futile because of their poor unavoidable prognosis, the improved therapeutic options available challenges this conservative approach. Aim of this review is to identify the triggers to investigate AS patients at risk of having concomitant ATTR-CA, to propose a diagnostic path to reach diagnosis and to discuss the changes in the therapeutic strategy caused by this discovery in the era of TAVR and active pharmacological treatments to slow down disease progression.

Improved Quantification of Cardiac Amyloid Burden in Systemic Light Chain Amyloidosis: Redefining Early Disease?

ObjectivesThe purpose of this study was to determine phenotypes characterizing cardiac involvement in AL amyloidosis by using direct (fluorine-18-labeled florbetapir {[18F]florbetapir} positron emission tomography [PET]/computed tomography) and indirect (echocardiography and cardiac magnetic resonance [CMR]) imaging biomarkers of AL amyloidosis. BackgroundCardiac involvement in systemic light chain amyloidosis (AL) is the main determinant of prognosis and, therefore, guides management. The hypothesis of this study was that myocardial AL deposits and expansion of extracellular volume (ECV) could be identified before increases in N-terminal pro–B-type natriuretic peptide or wall thickness. MethodsA total of 45 subjects were prospectively enrolled in 3 groups: 25 with active AL amyloidosis with cardiac involvement (active-CA), 10 with active AL amyloidosis without cardiac involvement by conventional criteria (active-non-CA), and 10 with AL amyloidosis with cardiac involvement in remission for at least 1 year (remission-CA). All subjects underwent echocardiography, CMR, and [18F]florbetapir PET/CT to evaluate cardiac amyloid burden. ResultsThe active-CA group demonstrated the largest myocardial AL amyloid burden, quantified by [18F]florbetapir retention index (RI) 0.110 (interquartile range [IQR]: 0.078 to 0.139) min−1, and the lowest cardiac function by global longitudinal strain (GLS), median GLS −11% (IQR: −8% to −13%). The remission-CA group had expanded extracellular volume (ECV) and [18F]florbetapir RI of 0.097 (IQR: 0.070 to 0.124 min−1), and abnormal GLS despite hematologic remission for >1 year. The active-non-CA cohort had evidence of cardiac amyloid deposition by advanced imaging metrics in 50% of the subjects; cardiac involvement was identified by late gadolinium enhancement in 20%, elevated ECV in 20%, and elevated [18F]florbetapir RI in 50%. ConclusionsEvidence of cardiac amyloid infiltration was found based on direct and indirect imaging biomarkers in subjects without CA by conventional criteria. The findings from [18F]florbetapir PET imaging provided insight into the preclinical disease process and on the basis of interpretation of expanded ECV on CMR and have important implications for future research and clinical management of AL amyloidosis. (Molecular Imaging of Primary Amyloid Cardiomyopathy [MICA]; NCT02641145)

The Prognosis of Patients With Type 2 Diabetes and Nonalbuminuric Diabetic Kidney Disease Is Not Always Poor: Implication of the Effects of Coexisting Macrovascular Complications (JDDM 54).

Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing phenotype in patients with type 2 diabetes. However, it remains unclear whether its prognosis is poorer than that of other DKD phenotypes. A total of 2,953 Japanese patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, enrolled in an observational cohort study in 2004, were followed until 2015. On the basis of albuminuria (>30 mg/g creatinine) and reduced eGFR (<60 mL/min/1.73 m2) at baseline, participants were classified into the four DKD phenotypes-no-DKD, albuminuric DKD without reduced eGFR, nonalbuminuric DKD with reduced eGFR, and albuminuric DKD with reduced eGFR-to assess the risks of mortality, cardiovascular disease (CVD), and renal function decline. During the mean follow-up of 9.7 years, 113 patients died and 263 developed CVD. In nonalbuminuric DKD, the risks of death or CVD were not higher than those in no-DKD (adjusted hazard ratio 1.02 [95% CI 0.66, 1.60]) and the annual decline in eGFR was slower than in other DKD phenotypes. The risks of death or CVD in nonalbuminuric DKD without prior CVD were similar to those in no-DKD without prior CVD, whereas the risks in nonalbuminuric DKD with prior CVD as well as other DKD phenotypes were higher. Nonalbuminuric DKD did not have a higher risk of mortality, CVD events, or renal function decline than the other DKD phenotypes. In nonalbuminuric DKD, the presence of macrovascular complications may be a main determinant of prognosis rather than the renal phenotype.

Intraventricular hemorrhage in preterm babies.

Germinal matrix-intraventricular hemorrhage (GM-IVH) is a major complication of prematurity and inversely associated with gestational age and birth weight. The hemorrhage originates from the germinal matrix with an immature capillary bed where vascularization is intense and active cell proliferation is high. It occurs in around 20% of very low-birth-weight preterm neonates. Germinal matrix-intraventricular hemorrhage is less common in females, the black race, and with antenatal steroid use, but is more common in the presence of mechanical ventilation, respiratory distress, pulmonary bleeding, pneumothorax, chorioamnionitis, asphyxia, and sepsis. Ultrasonography is the diagnostic tool of choice for intraventricular hemorrhage and its complications. Approximately 25–50% of the germinal matrix-intraventricular hemorrhage cases are asymptomatic and diagnosed during routine screening. These cases are usually patients with low-grade hemorrhage. Neurologic findings are prominent in severe intraventricular hemorrhage cases. The major complications of the germinal matrix-intraventricular hemorrhage in preterm babies are periventricular hemorrhagic infarction, posthemorrhagic ventricular dilatation, periventricular leukomalacia, and cerebellar hemorrhage. It is an important cause of mortality and morbidity. The management of hemodynamics and ventilation of patients, appropriate follow-up, and early diagnosis and treatment can minimize morbidity. Prognosis in intraventricular hemorrhage is related to the severity of bleeding, parenchymal damage, and the presence of seizures and shunt surgery. The main determinant of prognosis is periventricular hemorrhagic infarction and its severity. Moderate-severe intraventricular hemorrhage can cause posthemorrhagic hydrocephalus, cerebral palsy, and mental retardation. Even mild germinal matrix-intraventricular hemorrhage can result in developmental disorders. Long-term problems such as neurodevelopmental disorders and cerebral palsy are as important as short-term problems. Improving the quality of life of these babies should be aimed through appropriate treatment and follow-up. In this review, intraventricular hemorrhage and complications are discussed.

Caracterización de tumores secretores de hormona de crecimiento de acuerdo al patrón granular y su rol en el pronóstico

Classification of growth hormone (GH) - secreting tumors by the granular pattern might predict their clinical behavior in acromegalic patients. There are several other prognostic factors. To compare the features at presentation and cure rates of patients with GH secreting tumors according to the granular pattern, and to define independent prognostic factors for surgical treatment in these patients. A retrospective, observational study of 85 active acromegalic patients surgically treated in two medical centers. Seventy-four patients (87%) were classified as having densely granulated (DG) and 11 (13%) as sparsely granulated (SG) tumors. The latter were less active biochemically, had a higher rate of macroadenoma and cavernous sinus invasion and had a lower rate of biochemical cure than the DG group. Several characteristics were associated with disease persistence but only age (Odds ratio (OR) = 0.93) and cavernous sinus invasion (OR = 21.7) were independently associated in the logistic regression model. The sparsely granulated pattern is associated with a more aggressive behavior, but the main determinants of prognosis are age and cavernous sinus invasion.

Patterns of local extension and nodal involvement from 1300 nasopharyngeal carcinoma patients: An imaging-based predictor of distant metastases.

e17516 Background: Distant metastasis is a main determinant of prognosis in patients with nasopharyngeal carcinoma(NPC). We explored the patterns of disease spread in NPC patients and identified the pattern correlates with distant metastases. Methods: The imaging documents of 1300 consecutive newly diagnosed nasopharyngeal carcinoma between 2012 and 2016 were reviewed. According to the incidence rates of tumor invasion, the anatomic sites were classified into high-risk group (≥50%), medium-risk group (≥10%~ &lt; 50%) and low-risk group ( &lt; 10%). The location of lymph nodes was determined by 2013 updated guidelines for neck node levels. Additionally, we developed a novel classification based on tumor spreading patterns, as shown in Table. Moreover, we validated the prognostic accuracy of the classification in a validation cohort from a different institution, 241 non-metastatic NPC patients were retrospectively enrolled. Kaplan-Meier method and log-rank test were used to analyze all time-to-event data. Results: The incidence rates of tumor invasion were 0.2% ~91.2%, 95.2% cases across the midline. If anatomic sites in high-risk group or median-risk group were involved, the incidence rates in adjacent medium-risk sites or low-risk group were increased. On the contrary, the incidence rates were decreased when the adjacent high-risk sites or median-risk group were not involved. 85.9% cases had involved lymph nodes. Only 3.9% had skip metastases. The incidence rates of nodal involvement were increased when adjacent upper nodal level was involved. In validation cohort, distant metastases were present in 32/241 NPC patients (13.3%) and 3-year distant metastasis-free survival(DMFS) in local, superior, inferior, and mixed type were 95.0%, 91.3%, 89.0%, and 78.7%, respectively. Cumulative survival curves for former three patterns were relatively similar and were clearly separated from mixed type. DMFS was significantly lower for patients with mixed type pattern than for those with other patterns(P = 0.018). Conclusions: Local disease in NPC patients spreads stepwise from proximal sites to more distal sites. The frequency of metastases in the jugular lymph node chains decreased in the cranio-caudal direction. Based on the patterns of tumor extension, an imaging-based predictor of distant metastases was developed and may be used as a prognostic marker for selecting patients to further systemic treatments. [Table: see text]

Right ventricular function inpulmonary (arterial) hypertension.

The right ventricle (RV) is the main determinant of prognosis in pulmonary hypertension. Adaptation and maladaptation of the RV are of crucial importance. In the course of disease, RV contractility increases through changes in muscle properties and muscle hypertrophy. At acertain point, the point of "uncoupling," the afterload exceeds contractility, and maladaptation as well as dilation occurs to maintain stroke volume (SV). To understand the adaptational processes and to further develop targeted medication directly affecting load-independent contractility, an accurate and precise assessment of contractility and RV-pulmonary artery (PA) coupling should be performed. In this review, we shed light on existing methods to assess RV function, including the gold standard measurement of contractility and RV-PA coupling, and we evaluate existing surrogates of RV-PA coupling.

IMP3 expression in small-intestine neuroendocrine neoplasms: a new predictor of recurrence.

Small-intestine neuroendocrine neoplasms are heterogeneous neoplasms arising from endocrine cells of the intestinal mucosa. Ki-67 is the main determinant of prognosis in neuroendocrine neoplasms. However, the search for new prognostic makers represents a key point with regard to small-intestine neuroendocrine neoplasms. The oncofetal protein IMP3 plays a role in cell growth and its expression has a prognostic value in lung neoplasms. From January 1998 to August 2015, all the consecutive small-intestine neuroendocrine neoplasms patients suitable for surgery were included: 51 patients (32 males, median age 68 years) had small-intestine neuroendocrine neoplasms classified according to the WHO 2010 classification. In all the cases IMP3 expression was evaluated on primary tumors and, when available, on nodal and distant metastases. The medical records and pathological slides of these patients were used to determine the clinical characteristics, pathological diagnoses, and outcome information. The overall 5-year and 10-year survival rate were 53.9 and 42% respectively. At Cox proportional hazards regression grading was the major factor influencing both OS and progression-free survival at univariate (p = 0.0002 and 0.0051, respectively) and multivariate analysis (p = 0.0004 and 0.0043, respectively). Also IMP3 expression at the nodal metastases resulted a factor significantly associated with progression-free survival at both univariate (p = 0.0066) and multivariate analysis (p = 0.0059, HR 3.58). IMP3 expression did not correlate with the Ki-67 (p = n.s.). In this study, IMP3 at the nodal site resulted to be associated with low progression-free survival in small-intestine neuroendocrine neoplasms, independently of the Ki-67 index. We suggest that the integration of IMP3 and Ki-67 would help better stratify the risk of progression in small-intestine neuroendocrine neoplasms.

Drop-out between the two liver resections of two-stage hepatectomy. Patient selection or loss of chance?

BackgroundTwo-stage hepatectomy (TSH) is the present standard for multiple bilobar colorectal liver metastases (CLM), but 25–35% of patients fail to complete the scheduled procedure (drop-out). To elucidate if drop-out of TSH is a patient selection (as usually considered) or a loss of chance. MethodsAll the consecutive patients scheduled for a TSH at the Paul Brousse Hospital between 2000 and 2012 were considered. TSH patients were matched 1:1 with patients receiving a one-stage ultrasound-guided hepatectomy (OSH) at the Humanitas Research Hospital in the same period. Matching criteria were: primary tumor N status; timing of CLM diagnosis; CLM number and distribution into the liver. ResultsSixty-three pairs of patients were analyzed. Demographic and tumor characteristics were similar (median 7 CLM), except for more chemotherapy lines and adjuvant chemotherapy in TSH. Drop-out rate of TSH was 38.1% (0% of OSH). The two groups had similar R0 resection rate (19.0% OSH vs. 15.9% TSH). OSH and completed TSH had similar five-year survival (from CLM diagnosis 49.8% vs. 49.7%, from liver resection 36.1% vs. 44.3%), superior to drop-out (10% three-year survival, p < 0.001). OSH and completed TSH had similar recurrence-free survival (at three years 21.7% vs. 20.5%) and recurrence sites. The completion of resection (drop-out vs. OSH/completed TSH) was the only independent prognostic factor (p = 0.003). ConclusionsDrop-out of TSH could be a loss of chance rather than a criteria for patient selection. “Unselected” OSH patients had the same outcomes of selected patients who completed TSH. A complete resection is the main determinant of prognosis.

Elevated Serum Levels Of Von Willebrand Factor (vWF) Predict For Early Death and Shorter Survival In Patients With Primary Systemic Light Chain (AL) Amyloidosis Independently Of Cardiac Biomarkers

Organ dysfunction in systemic light chain (AL) amyloidosis is caused by the deposition of amyloid fibrils composed of immunoglobulin light chains in tissue microcirculation. vWF is mainly produced, stored and secreted by endothelial cells (ECs) and it is critical for thrombus formation. The secretion of vWF by ECs is triggered by several conditions and it has been proposed that changes in the levels of circulating vWF may reflect a state of “stimulation” of the endothelium. Cardiac involvement is the main determinant of prognosis in AL amyloidosis, but the role of endothelium in this disease has not been extensively studied and no marker of endothelial dysfunction has been evaluated, as yet. Thus, we studied the prognostic role of vWF in patients with AL amyloidosis who were treated with novel agents.The vWF antigen (vWFag) levels were measured using a latex particle-enhanced immunoturbidimetric assay (HemosIL vWF antigen) with an automated coagulometer (ACL Top 3G, Instrumentation Laboratory, Lexington, MA, USA). The inter- and intra-assay CVs were 2% and 3% at a concentration of 123.5 U/dL, respectively, and the lower limit of detection was 2.2 U/dL.The analysis included 81 consecutive patients with newly diagnosed AL amyloidosis who were treated in a single center (Department of Clinical Therapeutics, University of Athens, Greece) from 2005 to 2012. Median age of the patients was 68 years (range 42-82 years) and the median number of involved organs was 2; heart was involved in 62%, kidneys in 74%, peripheral nerve in 24%, liver in 9% and soft tissue in 21% of patients. Median NTproBNP level was 2,318 pg/mL (range 33-75,000 pg/mL); 36% had NTproBNP levels ≥4,000 pg/mL and 28%, 38% and 34% of patients had Mayo stage -1, -2 and -3, respectively. Primary therapy based on bortezomib was given in 52% of patients, on lenalidomide in 44%, while 4% received MDex. Median survival of the cohort was 47 months; 3- and 6-month mortality was 12% and 20%, respectively.The median serum level of vWFag in patients with AL amyloidosis was 181 (range 20-557) U/dL and was significantly higher than that measured in healthy controls (median: 84 U/dL, range 48-124; p <0.001). There was no significant association of vWFag levels with renal, cardiac, nerve or liver involvement. There was no significant correlation of vWFag levels with the levels of NTproBNP (or BNP) or Mayo stage and there was no significant correlation with the degree of renal dysfunction, serum albumin levels or proteinuria. Levels of involved free light chains did not have any correlation with vWFag levels either.We then examined the prognostic significance of vWFag and we found that levels of vWFag within the top quartile (≥230 U/dL) were associated with a very poor outcome (median survival 4 months vs. 47 months, p=0.001). Because the most important predictor of early death in patients with AL amyloidosis is cardiac involvement, we performed a multivariate analysis which included NTproBNP levels: vWFag levels ≥230 U/dL were independently associated with survival (HR: 2.64, 95% CI 1.2-5.8, p=0.01), along with NTproBNP levels ≥4,000 pg/ml (HR: 4.17, 95% CI 1.98- 8.8, p<0.001). Because the survival curves indicated that patients with vWFag ≥230 U/dL had a significant probability of early death, we performed an analysis to identify whether vWFag is a significant predictor of early death, adjusting for the levels of NTproBNP ≥4000 pg/mL. Thus, in multivariate analysis, vWFag ≥230 U/dL was independent predictor of death within 6 months from initiation of therapy (HR: 15, 95% CI 2.6-84, p=0.002) together with NTproBNP ≥4,000 pg/mL (HR: 16.8, 95% CI 3- 94, p=0.001). A combination of the two risk factors was able to identify patients at a very high risk of early death: 75% of patients with both risk factors present died within 3 months from initiation of therapy (figure).In conclusion, vWFag levels are elevated in patients with AL amyloidosis but are not correlated with other features of the disease, such as pattern of organ involvement and cardiac biomarkers. For the first time, we found that high levels of vWFag are associated with a high risk of early death and shorter survival in patients with AL amyloidosis, independently of cardiac biomarkers. In addition, wWFag levels improve the prognostic ability of cardiac biomarkers in patients with AL amyloidosis. Our data also justify the investigation of the role of endothelial dysfunction in AL amyloidosis. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Characteristics and clinical outcome of T1 breast cancer: A national multicenter retrospective cohort study.

566 Background: T1N0M0 breast cancer (BC) are generally considered as carrying good prognosis and cancer-specific survival rates after 5 to 10 years are as high as 90 or 95% in many studies. However, they constitute a heterogeneous group and many studies identified biologically-defined at-risk patients within T1 BC. The objectives of our study were to describe the main characteristics of T1a, b, and c (11-15mm) BC and to identify prognostic factors for survival. Methods: We retrospectively collected the medical files of all patients diagnosed with BC who underwent sentinel lymph node biopsy (SLNB) between January 1999 and December 2008 in 13 French sites and examined overall survival (OS) and Relapse-free survival (RFS) in T1a, T1b and T1c 11-15 mm. Results: Among 8,100 women operated, 5,423 had T1 tumors (708 T1a, 2,208 T1b and 2,508 T1c 11-15mm). T1a differed significantly from T1b tumors with respect to several parameters : younger age, more frequent negative hormonal status and positive HER2 status, less frequent lymphovascular invasion (LVI), exhibiting a mix of favorable and poor prognosis factors. After a median follow-up of 60.5 months, OS rate was 97.6% (95CI: 97.1-98) at 60 months, 95.4%(94.5-96.4) at 84 months and 90.7% (85.2-96.4) at 120 months. No significant difference was observed between T1a, T1b and T1c tumors (p=0.335). RFS rates were 94% (95CI: 93.8-95.2), 92.1% [91.1-93.2] and 83.8% (77.6-90.5) at 60, 84 and 120 months respectively. RFS was significantly higher in T1b tumors (95.9%, 95CI: 95-96.9) as compared to T1a (93.2%, 91-95.4) or T1c tumors (93.8%, 92.8-94.9), p=0.0099. In multivariate analysis, SBR tumor grade, hormone therapy and LVI were independent prognostic factors for RFS, while hormone therapy and SBR grade were independently associated with OS. Conclusions: Relatively poor outcome of patients with T1a tumors might be explained by a high frequency of risk factors in this subgroup (frequent negative hormone receptors and HER2 overexpression) and by a less frequent administration of adjuvant systemic therapy (endocrine treatment and chemotherapy). Tumor size might not be the main determinant of prognosis in T1 breast cancer.

Role of HGF/MET axis in resistance of lung cancer to contemporary management.

Lung cancer is the number one cause of cancer related mortality with over 1 million cancer deaths worldwide. Numerous therapies have been developed for the treatment of lung cancer including radiation, cytotoxic chemotherapy and targeted therapies. Histology, stage of presentation and molecular aberrations are main determinants of prognosis and treatment strategy. Despite the advances that have been made, overall prognosis for lung cancer patients remains dismal. Chemotherapy and/or targeted therapy yield objective response rates of about 35% to 60% in advanced stage non-small cell lung cancer (NSCLC). Even with good initial responses, median overall survival of is limited to about 12 months. This reflects that current therapies are not universally effective and resistance develops quickly. Multiple mechanisms of resistance have been proposed and the MET/HGF axis is a potential key contributor. The proto-oncogene MET (mesenchymal-epithelial transition factor gene) and its ligand hepatocyte growth factor (HGF) interact and activate downstream signaling via the mitogen-activated protein kinase (ERK/MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K/AKT) pathways that regulate gene expression that promotes carcinogenesis. Aberrant MET/HGF signaling promotes emergence of an oncogenic phenotype by promoting cellular proliferation, survival, migration, invasion and angiogenesis. The MET/HGF axis has been implicated in various tumor types including lung cancers and is associated with adverse clinicopathological profile and poor outcomes. The MET/HGF axis plays a major role in development of radioresistance and chemoresistance to platinums, taxanes, camtothecins and anthracyclines by inhibiting apoptosis via activation of PI3K-AKT pathway. DNA damage from these agents induces MET and/or HGF expression. Another resistance mechanism is inhibition of chemoradiation induced translocation of apoptosis-inducing factor (AIF) thereby preventing apoptosis. Furthermore, this MET/HGF axis interacts with other oncogenic signaling pathways such as the epidermal growth factor receptor (EGFR) pathway and the vascular endothelial growth factor receptor (VEGFR) pathway. This functional cross-talk forms the basis for the role of MET/HGF axis in resistance against anti-EGFR and anti-VEGF targeted therapies. MET and/or HGF overexpression from gene amplification and activation are mechanisms of resistance to cetuximab and EGFR-TKIs. VEGF inhibition promotes hypoxia induced transcriptional activation of MET proto-oncogene that promotes angiogenesis and confers resistance to anti-angiogenic therapy. An extensive understanding of these resistance mechanisms is essential to design combinations with enhanced cytotoxic effects. Lung cancer treatment is challenging. Current therapies have limited efficacy due to primary and acquired resistance. The MET/HGF axis plays a key role in development of this resistance. Combining MET/HGF inhibitors with chemotherapy, radiotherapy and targeted therapy holds promise for improving outcomes.

Mitoxantrone and Etoposide with or without Intermediate-Dose Cytarabine for the Treatment of Patients with Primary Induction Failure or Relapsed Acute Myeloid Leukemia

AbstractAbstract 2174 Introduction:The prognosis for patients with primary induction failure (PIF) or relapsed acute myeloid (Rel-AML) is poor. Mitoxantrone (M) plus etoposide (E)- based salvage regimens (ME), in particular, either alone or with intermediate dose cytarabine (MEC) are effective in these high risk patients; However, these regimens have not been directly compared. Heterogeneity in chemotherapy dose, dose escalation and age have been important limitations in the evaluation of previous studies. Also problematic, historically patients were classified according to FAB criteria. Since then, karyotype has been shown to be a main determinant of prognosis. The influence of karyotype on response to ME or MEC is currently unknown. Herein, we report the response to treatment with a fixed dosing schedule of ME or MEC in 66 patients treated for PIF or Rel-AML with intermediate(intermed-) or unfavorable(unfav-) risk cytogenetics. Differences in CR between ME and MEC subsets were analyzed to determine the effect of adding of C to ME. Methods:66 consecutive patients with PIF or Rel-AML treated with either ME(n=37)or MEC(n=29) between 10/2004-12/2008 were evaluated. All patients had received initial induction therapy with daunorubicin 45–60mg/m2 IV bolus d1-3 and cytarabine 100mg/m2 CI d1-7(7+3), and consolidation with HIDAC if CR was achieved. ME and MEC were dosed according to previously published studies. The decision to use a given salvage was left to the discretion of the treating physician. Chi-Square test was used for statistical analysis. Results:Table1 shows there was no difference between the ME and MEC groups with regards to age, sex, % blasts at initial diagnosis, and %CR after initial induction with 7+3, or % patients who received inter- to high dose C prior to ME or MEC. Length of CR (after 7+ 3 and consolidation) was significantly longer in the MEC group. A significantly higher number of CR's was observed in the MEC group compared to ME(p=0.05). Within the MEC group, no difference in CR was observed between patients with intermed- and unfav-risk cytogenetics(p=0.96). The same was true within the ME group(p=0.13). When MEC was compared to ME, a significant difference in CR was observed in patients with unfav-risk cytogenetics(p=0.044) and patients <60years old. Prior to therapy, MEC patients had higher number of blasts. MEC patients had a significantly longer duration of remission. One patient in both the ME and MEC group died before hematopoetic reconstitution. Conclusion:In clinical practice, as observed in the present study, we observed a greater overall CR rate in patients who received MEC compared to those treated with ME, particularly in younger patients with unfav-risk cytogenetics. For those who achieved CR after MEC or ME, a longer duration of CR was observed in the MEC group compared to ME. These results could be particularly beneficial for those patients receiving salvage therapy as a temporizing measure prior to allogeneic hematopoetic stem cell transplant ion, and encourages confirmation from a prospective trial.Table 12937Male:Female13/1623/13NSAge(yr/range)54 (21–77)58 (24–79)NS>60yr10/2914/370.8Complete Remission after 1st induction(%)20 (69)27 (75)0.78Number of Chemotx regimens prior to ME/MECn=28150.2n=3280.16n=4140.36Prior treatment with intermediate or high dose Cytarabine24/2934/370.285TreatmentCytogenetics (n=MEC=28:ME=34)*Favorable(respnse,%)1/1 (100)1/1 (100)1Intermediate9/16 (56)7/22 (32)0.13Unfavorable7/11 (64)2/10 (20)0.044Age<6012/19 (63)6/21 (29)0.028Intermediate cytogenetics5/10 (50)3/16 (19)0.19Unfavorable cytogenetics6/8 (75)1/2 (33)0.49Age>605/10 (50)3/16 (19)0.99Intermediate cytogenetics4/6 (66)4/6 (66)1Unfavorable cytogenetics1/2 (50)1/7 (14)0.99Complete remission(%)17 (58)12 (33)0.049Time to relapse(months)2.5 (1–14)1.5 (1–33)0.049Table 2Kaplan-Meier survival percentages from diagnosis to last follow-upKaplan-Meier survival percentages from MEC/ME to last follow-up6m94%55%1 year71%31%2 years42%22%3 years19%18%5 years12%no follow-up beyond 5 years from MEC/ME7 years8%no follow-up beyond 5 years from MEC/ME Disclosures:No relevant conflicts of interest to declare.