Liver resection (LR) for hepatocellular carcinoma (HCC) as the first‐line treatment in transplantable patients followed by “salvage transplantation” (ST) in case of recurrence is an attractive ...concept. The aim was to identify patients who gain benefit from this approach in an intention‐to‐treat study. From 1998 to 2008, among 329 potential candidates for liver transplantation (LT) with HCC within the Milan criteria (MC), 138 with good liver function were resected (LR group) from a perspective of ST in case of recurrence, and 191 were listed for LT first (LT group). The two groups were compared on an intention‐to‐treat basis with special reference to management of recurrences and transplantability after LR. Univariate and multivariate analyses were performed to identify resected patients who developed recurrence beyond MC. Five‐year overall and disease‐free survival was similar in both groups: LT versus LR group, 60% versus 77% and 56% versus 40%, respectively. Among the 138 patients in the LR group, 20 underwent LT before recurrence, 39 (28%) had ST, and 51 (37%) with recurrence were not transplanted including 21 within MC who were excluded for advanced age, acquired comorbidities, or refusal and 30 (22%) with recurrence beyond MC. Predictive factors for nontransplantability due to recurrence beyond MC included microscopic vascular invasion (hazard ratio HR 2.38 range, 1.10‐7.29), satellite nodules (HR 2.46 range, 1.01‐6.68), tumor size > 3 cm (HR 1.34 range, 1.03‐3.12), poorly differentiated tumor (HR 3.18 range, 1.31‐7.70), and liver cirrhosis (HR 1.90 range, 1.04‐3.12). Conclusion: The high risk of failure of ST after initial LR for HCC within MC suggests the use of tissue analysis as a selection criterion. The salvage LT strategy should be restricted to patients with favorable oncological factors. (HEPATOLOGY 2012;;55:132–140)
Sorafenib is currently the medical treatment of reference for hepatocellular carcinoma (HCC), but it is not known whether sorafenib is equally active in all HCC. Here, our aim was to explore ...intrinsic differences in the response of HCC cells to sorafenib, to identify potential mechanisms leading to primary resistance to this treatment. We analyzed a panel of six human HCC cell lines and compared the activity of the main oncogenic kinase cascades, their clonogenic potential, proliferation and apoptosis upon exposure to sorafenib. We report that HCC cells present important differences in their response to sorafenib, and that some cell lines are more resistant to the actions of sorafenib than others. We identify the activated epidermal growth factor receptor (EGFR) as a parameter that promotes the resistance of HCC cells to sorafenib. In resistant cells, the efficacy of sorafenib was increased when EGFR was inhibited, as was demonstrated using two chemical inhibitors (erlotinib or gefitinib), a monoclonal antibody directed against EGFR (cetuximab), and RNA interference directed against EGFR. A combination of EGFR inhibitors and sorafenib affords a better control over HCC proliferation, most likely through an improved blockade of the RAF kinases. Our findings therefore confirm the importance of RAF kinases as therapeutic targets in HCC, and identify EGFR as a determinant of the sensitivity of HCC cells to sorafenib. Our findings bear possible implications for the improvement of the efficacy of sorafenib in HCC, and might be useful for the identification of predictive biomarkers in this context.
OBJECTIVE:The aim of this study was to compare the survival of patients with stage II obstructing colon cancer (OCC) who had adjuvant chemotherapy with those who did not.
SUMMARY BACKGROUND DATA:The ...need for adjuvant chemotherapy in stage II colon cancer is still debated.
METHODS:All consecutive patients treated for a stage II OCC in a curative intent (with primary tumor resection) between January 2000 and December 2015 were included in this retrospective, multicenter cohort study which included a propensity score analysis using an odds of treatment weighting (Average Treatment effect on the Treated, ATT). The endpoint was the comparison between the 2 groups for overall survival (OS) and disease-free survival (DFS) according to whether or not patients received adjuvant chemotherapy.
RESULTS:During the study period, 504 patients underwent a curative colectomy for a stage II OCC. Among these patients, 179 (35.5%) had adjuvant chemotherapy and 325 (64.5%) had no adjuvant treatment. Among the 179 patients who received adjuvant chemotherapy, 108 patients (60%) received oxaliplatin based regimen and 99 patients (55%) completed all scheduled cycles. At multivariate analysis, after weighting by the odds (ATT analysis) and adjustment, adjuvant chemotherapy after resection of a stage II OCC was associated with improvements in OS hazard ratio (HR) = 0.42 (0.17–0.99), P = 0.0498 and DFS HR = 0.57 (0.37–0.88), P = 0.0116.
CONCLUSION:This study suggests that adjuvant chemotherapy after curative resection of stage II OCC may improve oncological outcomes.
Background Although women represent half of the population burden of aortic stenosis (AS), little is known whether sex affects the presentation, management, and outcome of patients with AS. Methods ...and Results In a cohort of 2429 patients with severe AS (49.5% women) we aimed to evaluate 5-year excess mortality and performance of aortic valve replacement (AVR) stratified by sex. At presentation, women were older (
<0.001), with less comorbidities (
=0.030) and more often symptomatic (
=0.007) than men. Women had smaller aortic valve area (
<0.001) than men but similar mean transaortic pressure gradient (
=0.18). The 5-year survival was lower compared with expected survival, especially for women (62±2% versus 71% for women and 69±1% versus 71% for men). Despite longer life expectancy in women than men, women had lower 5-year survival than men (66±2% expected-75% versus 68±2% expected-70%,
<0.001) after matching for age. Overall, 5-year AVR incidence was 79±2% for men versus 70±2% for women (
<0.001) with male sex being independently associated with more frequent early AVR performance (odds ratio, 1.49; 1.18-1.97). After age matching, women remained more often symptomatic (
=0.004) but also displayed lower AVR use (64.4% versus 69.1%;
=0.018). Conclusions Women with severe AS are diagnosed at later ages and have more symptoms than men. Despite prevalent symptoms, AVR is less often performed in women and 5-year excess mortality is noted in women versus men, even after age matching. These imbalances should be addressed to ensure that both sexes receive equivalent care for severe AS.
To determine the efficacy and safety of bendamustine as a single agent in refractory or relapsed T-cell lymphomas.
Patients with histologically confirmed peripheral T-cell lymphoma (PTCL) or ...cutaneous T-cell lymphoma who progressed after one or more lines of prior chemotherapy received bendamustine at 120 mg/m(2) per day on days 1 through 2 every 3 weeks for six cycles. The primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
Of the 60 patients included, 27 (45%) were refractory to their last prior chemotherapy, and the median duration of the best previous response was 6.6 months. Histology was predominantly angioimmunoblastic lymphadenopathy and PTCL not otherwise specified. The disease was disseminated in the majority of patients (87%). The median number of previous lines of chemotherapy was one (range, one to three). Twenty patients (33%) received fewer than three cycles of bendamustine, mostly because of disease progression. In the intent-to-treat population, the ORR was 50%, including complete response in 17 patients (28%) and partial response in 13 patients (22%). Bendamustine showed consistent efficacy independent of major disease characteristics. The median values for DoR, PFS, and OS were 3.5, 3.6, and 6.2 months, respectively. The most frequent grade 3 to 4 adverse events were neutropenia (30%), thrombocytopenia (24%), and infections (20%).
Bendamustine showed an encouraging high response rate across the two major PTCL subtypes, independent of age and prior treatment, with acceptable toxicity in refractory or relapsed T-cell lymphoma.
Although a variety of non-invasive methods for measuring cardiovascular (CV) risk (such as carotid intima media thickness, pulse wave velocity (PWV), coronary artery and aortic calcification scores ...(measured either by CT scan or X-ray) and the ankle brachial index (ABI)) have been evaluated separately in chronic kidney disease (CKD) cohorts, few studies have evaluated these methods simultaneously. Here, we looked at whether the addition of non-invasive methods to traditional risk factors (TRFs) improves prediction of the CV risk in patients at different CKD stages.
We performed a prospective, observational study of the relationship between the outputs of non-invasive measurement methods on one hand and mortality and CV outcomes in 143 patients at different CKD stages on the other. During the follow-up period, 44 patients died and 30 CV events were recorded. We used Cox models to calculate the relative risk for outcomes. To assess the putative clinical value of each method, we also determined the categorical net reclassification improvement (NRI) and the integrated discrimination improvement.
Vascular calcification, PWV and ABI predicted all-cause mortality and CV events in univariate analyses. However, after adjustment for TRFs, only aortic and coronary artery calcification scores were found to be significant, independent variables. Moreover, the addition of coronary artery calcification scores to TRFs improved the specificity of prediction by 20%.
The addition of vascular calcification scores (especially the coronary artery calcification score) to TRFs appears to improve CV risk assessment in a CKD population.
The severity and course of sepsis-associated acute kidney injury (SA-AKI) are correlated with the mortality rate. Early detection of SA-AKI subphenotypes might facilitate the rapid provision of ...individualized care.
In this
analysis of a multicenter prospective study, we combined conventional kidney function variables with serial measurements of urine (tissue inhibitor of metalloproteinase-2 TIMP-2)* (insulin-like growth factor-binding protein IGFBP7) at 0, 6, 12, and 24 h) and then using an unsupervised hierarchical clustering of principal components (HCPC) approach to identify different phenotypes of SA-AKI. We then compared the subphenotypes with regard to a composite outcome of in-hospital death or the initiation of renal replacement therapy (RRT).
We included 184 patients presenting SA-AKI within 6 h of the initiation of catecholamines. Three distinct subphenotypes were identified: subphenotype A (99 patients) was characterized by a normal urine output (UO), a low SCr and a low TIMP-2*IGFBP7 level; subphenotype B (74 patients) was characterized by existing chronic kidney disease (CKD), a higher SCr, a low UO, and an intermediate TIMP-2*IGFBP7 level; and subphenotype C was characterized by very low UO, a very high TIMP-2*IGFBP7 level, and an intermediate SCr level. With subphenotype A as the reference, the adjusted hazard ratio (aHR) 95%CI for the composite outcome was 3.77 1.92-7.42 (
< 0.001) for subphenotype B and 4.80 1.67-13.82 (
= 0.004) for subphenotype C.
Combining conventional kidney function variables with urine measurements of TIMP-2*IGFBP7 might help to identify distinct SA-AKI subphenotypes with different short-term courses and survival rates.
Disruptions in cerebrospinal fluid (CSF) flow during aging could compromise protein clearance from the brain and contribute to the etiology of Alzheimer's Disease (AD).
To determine whether CSF flow ...is associated with cognitive deficit in elderly patients (>70 years).
We studied 92 patients admitted to our geriatric unit for non-acute reasons using phase-contrast magnetic resonance imaging (PC-MRI) to calculate their ventricular and spinal CSF flow, and assessed their global cognitive status, memory, executive functions, and praxis. Multivariable regressions with backward selection (criterion
< 0.15) were performed to determine associations between cognitive tests and ventricular and spinal CSF flow, adjusting for depression, anxiety, and cardiovascular risk factors.
The cohort comprised 71 women (77%) and 21 (33%) men, aged 84.1 ± 5.2 years (range, 73-96). Net ventricular CSF flow was 52 ± 40 μL/cc (range, 0-210), and net spinal CSF flow was 500 ± 295 μL/cc (range, 0-1420). Ventricular CSF flow was associated with the number of BEC96 figures recognized (β = 0.18, CI, 0.02-0.33;
= 0.025). Spinal CSF flow was associated with the WAIS Digit Span Backward test (β = 0.06, CI, 0.01-0.12;
= 0.034), and categoric verbal fluency (β = 0.53, CI, 0.07-0.98;
= 0.024) and semantic verbal fluency (β = 0.55, CI, 0.07-1.02;
= 0.024).
Patients with lower CSF flow had significantly worse memory, visuo-constructive capacities, and verbal fluency. Alterations in CSF flow could contribute to some of the cognitive deficit observed in patients with AD. Diagnosis and treatment of CSF flow alterations in geriatric patients with neurocognitive disorders could contribute to the prevention of their cognitive decline.
Midostaurin in Advanced Systemic Mastocytosis Chandesris, Marie-Olivia; Damaj, Gandhi; Canioni, Danielle ...
New England journal of medicine/The New England journal of medicine,
06/2016, Letnik:
374, Številka:
26
Journal Article
Recenzirano
Odprti dostop
To the Editor:
Advanced systemic mastocytosis
1
carries a poor prognosis.
2
Midostaurin, an inhibitor of tyrosine kinases, targets KIT mutants associated with mastocytosis.
3
The French National ...Reference Center for Mastocytosis (CEREMAST) conducted a prospective survey of patients with mastocytosis who were treated with midostaurin under a transitory-use authorization program. All the patients provided written informed consent.
From August 2012 through April 2015, a total of 28 patients with mastocytosis (including 4 with aggressive disease, 18 with associated hematologic non–mast-cell disease, 3 with mast-cell leukemia, 1 with mast-cell sarcoma, and 2 with progressive smoldering disease) received midostaurin at a dose of 100 . . .
Chronic kidney disease (CKD) is a major cause of death worldwide and is associated with a high risk for cardiovascular and all-cause mortality. In CKD, endothelial dysfunction occurs and uremic ...toxins accumulate in the blood. miR-126 is a regulator of endothelial dysfunction and its blood level is decreased in CKD patients. In order to obtain a better understanding of the physiopathology of the disease, we correlated the levels of miR-126 with several markers of endothelial dysfunction, as well as the representative uremic toxins, in a large cohort of CKD patients at all stages of the disease. Using a univariate analysis, we found a correlation between eGFR and most markers of endothelial dysfunction markers evaluated in this study. An association of miR-126 with all the evaluated uremic toxins was also found, while uremic toxins were not associated with the internal control, specifically cel-miR-39. The correlation between the expression of endothelial dysfunction biomarker Syndecan-1, free indoxyl sulfate, and total p-cresyl glucuronide on one side, and miR-126 on the other side was confirmed using multivariate analysis. As CKD is associated with reduced endothelial glycocalyx (eGC), our results justify further evaluation of the role of correlated parameters in the pathophysiology of CKD.
PDF
