Summary Background A non-randomised, phase 2 study showed activity and tolerability of eribulin in advanced or metastatic soft-tissue sarcoma. In this phase 3 study, we aimed to compare overall ...survival in patients with advanced or metastatic soft-tissue sarcoma who received eribulin with that in patients who received dacarbazine (an active control). Methods We did this randomised, open-label, phase 3 study across 110 study sites in 22 countries. We enrolled patients aged 18 years or older with intermediate-grade or high-grade advanced liposarcoma or leiomyosarcoma who had received at least two previous systemic regimens for advanced disease (including an anthracycline). Using an interactive voice and web response system, an independent statistician randomly assigned (1:1) patients to receive eribulin mesilate (1·4 mg/m2 intravenously on days 1 and 8) or dacarbazine (850 mg/m2 , 1000 mg/m2 , or 1200 mg/m2 dose dependent on centre and clinician intravenously on day 1) every 21 days until disease progression. Randomisation was stratified by disease type, geographical region, and number of previous regimens for advanced soft-tissue sarcoma and in blocks of six. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov , number NCT01327885 , and is closed to recruitment, but treatment and follow-up continue. Findings Between March 10, 2011 and May 22, 2013, we randomly assigned patients to eribulin (n=228) or dacarbazine (n=224). Overall survival was significantly improved in patients assigned to eribulin compared with those assigned to dacarbazine (median 13·5 months 95% CI 10·9–15·6 vs 11·5 months 9·6–13·0; hazard ratio 0·77 95% CI 0·62–0·95; p=0·0169). Treatment-emergent adverse events occurred in 224 (99%) of 226 patients who received eribulin and 218 (97%) of 224 who received dacarbazine. Grade 3 or higher adverse events were more common in patients who received eribulin (152 67%) than in those who received dacarbazine (126 56%), as were deaths (10 4% vs 3 1%); one death (in the eribulin group) was considered treatment-related by the investigators. Interpretation Overall survival was improved in patients assigned to eribulin compared with those assigned to an active control, suggesting that eribulin could be a treatment option for advanced soft-tissue sarcoma. Funding Eisai.
Summary Background Until now, only imatinib and sunitinib have proven clinical benefit in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop ...resistance to these agents, resulting in fatal disease progression. We aimed to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib. Methods We did this phase 3 trial at 57 hospitals in 17 countries. Patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomised in a 2:1 ratio (by computer-generated randomisation list and interactive voice response system; preallocated block design (block size 12); stratified by treatment line and geographical region) to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of each 4 week cycle. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was progression-free survival (PFS). At disease progression, patients assigned placebo could crossover to open-label regorafenib. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01271712. Results From Jan 4, to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n=133) or matching placebo (n=66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4·8 months (IQR 1·4–9·2) for regorafenib and 0·9 months (0·9–1·8) for placebo (hazard ratio HR 0·27, 95% CI 0·19–0·39; p<0·0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients assigned regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction (26 of 132, 20%), and diarrhoea (seven of 132, 5%). Interpretation The results of this study show that oral regorafenib can provide a significant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments. As far as we are aware, this is the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients. Funding Bayer HealthCare Pharmaceuticals.
Summary Background Eribulin inhibits microtubule dynamics via a mechanism distinct from that of other tubulin-targeting drugs, inducing cell-cycle arrest and tumour regression in preclinical models. ...We assessed the activity and safety of eribulin in four strata of patients with different types of soft-tissue sarcoma. Methods In this non-randomised multicentre phase 2 study, patients were included if they had progressive or high-grade soft-tissue sarcoma and had received no more than one previous combination chemotherapy or up to two single drugs for advanced disease. They were stratified by the type of soft-tissue sarcoma they had. Eribulin was given intravenously at a concentration of 1·4 mg/m2 over 2–5 min at days 1 and 8 every 3 weeks to primarily assess progression-free survival at 12 weeks (RECIST 1.0), which we evaluated in all patients who started treatment. Safety analyses were done in all patients who started treatment. This trial is registered at ClinicalTrials.gov , number NCT00413192. Findings Of 128 patients included, 37 had adipocytic sarcoma, 40 had leiomyosarcoma, 19 had synovial sarcoma, and 32 had other sarcomas. 12 (31·6%) of 38 patients with leiomyosarcoma evaluable for the primary endpoint, 15 (46·9%) of 32 patients with adipocytic sarcoma, four (21·1%) of 19 with synovial sarcoma, and five (19·2%) of 26 in other sarcomas were progression-free at 12 weeks. The most common grade 3–4 adverse events were neutropenia (66 52% of 127 patients evaluable for safety), leucopenia (44 35%), anaemia (nine 7%), fatigue (nine 7%), febrile neutropenia (eight 6%), abnormal alanine aminotransferase concentrations (six 5%), mucositis (four 3%), and sensory neuropathy (four 3%). Interpretation Eribulin deserves further study in this setting, based on progression-free survival at 12 weeks in leiomyosarcoma and adipocytic sarcoma. Funding Eisai Limited, Hatfield, UK.
To evaluate the influence of advanced modeled iterative reconstruction (ADMIRE) on the coronary artery calcium (CAC) scores by computed tomography (CT).
Sixty patients underwent CAC imaging with ...dual-source 192-slice CT. Agatston, volume and mass score were calculated from filtered back projection (FBP) and iterative reconstructions with different levels of ADMIRE. Friedman test and Wilcoxon rank sum test were used for multiple comparisons of CAC values and the difference ratio among different ADMIRE groups using FBP as reference.
The median Agatston score (range) using FBP was 115 (0.1-3047) and significantly decreased with incremental ADMIRE levels 1-5: 96 (0.1-2813), 91 (0-2764), 87 (0-2699), 80 (0-2590), 70 (0-2440); all P < 0.001. In comparison with FBP Agatston, volume and mass scores significantly decreased with increasing ADMIRE levels 1-5 (P < 0.001): from -12% to -39%, from -14% to -41%, and from -13% to -40%, respectively. In four patients with low calcium burden, the use of ADMIRE 2 or higher resulted in the disappearance of calcium that was detectable using FBP or ADMIRE 1. The decrease of CAC in high-level ADMIRE resulted in a reassignment to a lower Agatston risk group in 27%.
ADMIRE causes a substantial reduction of the CAC scores measured by cardiac CT, which leads to an underestimation of cardiovascular risk scores in some patients.
Objectives We sought to evaluate noninvasive parameters by electrocardiography, echocardiography, technetium-99m–3,3-diphosphono-1,2-propanodicarboxylic acid (99m Tc-DPD) scintigraphy, and cardiac ...magnetic resonance for the prediction of all-cause mortality in patients with cardiac transthyretin amyloidosis (ATTR). Background ATTR may present with highly variable symptoms, including polyneuropathy and cardiomyopathy, the latter being associated with a poor outcome. However, data on noninvasive risk stratification of ATTR are limited. Methods A total of 70 patients with ATTR were evaluated by echocardiography, cardiac biomarkers, and99m Tc-DPD scintigraphy. Cardiac magnetic resonance was performed in 30 patients. Echocardiographic findings and plasma levels of biomarkers were correlated with results of quantitative analysis of scintigraphy using a region-of-interest technique (whole-body as well as heart tracer retention). Receiver-operating characteristic (ROC) analysis was performed to calculate a cutoff value of99m Tc-DPD scintigraphy for heart retention for the diagnosis of cardiac amyloid involvement with the highest sensitivity and specificity. Univariate and multivariate analyses were performed in patients with cardiac involvement (n = 60) to determine noninvasive predictors of all-cause mortality. Results Scintigraphy findings correlated with morphological (interventricular septum thickness, left ventricular hypertrophy index) as well as functional (mitral annular systolic velocity, mitral/tricuspid annular plane systolic excursion) findings, cardiac biomarkers, renal function, and late gadolinium enhancement. The ROC-derived cutoff for the detection of cardiac amyloidosis by scintigraphic heart tracer retention was 4.8%. Univariate Cox regression revealed N-terminal pro–B-type natriuretic peptide, troponin T, mitral annular plane systolic excursion, and left ventricular hypertrophy index as predictors of all-cause mortality. However, on multivariate analysis, troponin T remained the only independent predictor of survival. The ROC-derived cutoff value of troponin T predicting all-cause mortality with the highest sensitivity (80.0%) and specificity (68.7%) was 0.0375 ng/l. Conclusions Quantitative analysis of tracer retention is capable of characterizing the severity of cardiac involvement in ATTR. By multivariate analysis, troponin T remained the only independent predictor of survival.
Liposarcomas Henze, Joern; Bauer, Sebastian
Hematology/oncology clinics of North America,
10/2013, Letnik:
27, Številka:
5
Journal Article
Recenzirano
Liposarcoma is one of the most common sarcoma subtypes with a heterogeneous biology and clinical behavior. This article gives a comprehensive overview on clinically relevant aspects of pathology and ...imaging. Prognostic factors and treatment strategies are discussed for different clinical situations and histologic subtypes. This information will be of value to clinicians and interdisciplinary sarcoma teams.
To quantify the change in volume in herniated lumbar disk after computed tomography (CT)-guided intradiscal and periganglionic ozone-oxygen injection and to assess the effects of patient age, sex, ...and initial disk volume on disk volume changes.
A total of 283 patients with lumbar radiculopathy received a single intradiscal (3 mL) and periganglionic (7 mL) injection of an ozone-oxygen mixture (ratio, 3:97; ozone concentration, 30 μg/mL). Under CT guidance, intradiscal and periganglionic injection was performed through an extraspinal lateral approach with a 22-gauge spinal needle. All disk volume changes were evaluated on CT 6 months after the procedure in all patients.
Initial mean disk volume was 17.37 cm(3) ± 4.70 (standard deviation; range, 8.12-29.15 cm(3)). Disk volume reduction (mean, 7.70% ± 5.45; range, 0.29%-22.31%) was seen in 96.1% of treated disks (n = 272) at 6 months after treatment and was found to be statistically significant (P < .0001). In 3.9% of patients (n = 11), disk volume increased (mean, 0.59% ± 0.24; range, 0.11%-0.81%). Patient age correlated negatively with disk volume reduction (r = -0.505; P < .0001) at 6 months after treatment, whereas initial disk volume correlated positively with volume reduction (r = 0.225; P = .00014) after therapy. No correlation was noted between patient sex and disk volume reduction after treatment (P = .09).
Intradiscal administration of medical ozone is associated with a statistically significant volume reduction of the herniated lumbar disk. The volume-reduction effect of ozone correlates negatively with the patient's age and positively with initial disk volume.
Summary Alveolar soft part sarcoma (ASPS) is a distinct type of soft tissue sarcoma holding a specific ASPL-TFE3 fusion transcript. Curative therapy is based on surgical removal, whereas lately, ...antiangiogenic targeted therapy regimens have proven effective. In ASPS, analysis of small series additionally display mTOR (mammalian target of rapamycin) pathway activity, thus making mTOR a possible additive target in ASPS, because it is in other tumor entities. Therefore, we systematically evaluated mTOR pathway activity in a large series of ASPS in comparison with soft tissue sarcomas of other differentiation (non-ASPS). Upstream and downstream factors of mTOR signaling and ancillary targets were analyzed in 103 cases (22 ASPS, 81 non-ASPS) by immunohistochemistry mostly using phospho-specific antibodies. TFE3 (transcription factor for immunoglobulin heavy-chain enhancer 3) translocation status was determined by FISH and RT-PCR. All ASPS were positive in TFE3 break-apart FISH and exhibited specific fusion products when RNA was available (type 1: 9x, type 2: 11x), whereas TFE3-immunoreactive non-ASPS did not. In ASPS, TFE3-, cMET-, pAKT T308- (all P < .0001), pp70S6K- ( P = .002), and p4EBP1 ( P = .087) expression levels were elevated, whereas pAKT S473 was decreased ( P < .0001). In addition, ASPS exhibited higher TFE3-, cMET-, pAKT T308-, and pp70S6K- expression levels compared with TFE3-immunopositive non-ASPS sarcomas (all P < .001). We demonstrate elevated mTOR complex 1 (mTORC1) activity in ASPS independent of mTOR complex 2 (mTORC2) activation. mTORC1 activity seems to be related to the existence of ASPL-TFE3 fusion transcripts because TFE3-immunoreactive non-ASPS without ASPL-TFE3 fusion transcripts exhibit significantly lower mTORC1 activation status. Small molecule–based targeting of mTOR might therefore represent a potential mechanism in ASPS alone or in combination with contemporary upstream approaches.
Objectives The aim of our study was to investigate whether echocardiographic phase imaging (EPI) can predict response in patients who are considered for cardiac resynchronization therapy (CRT). ...Background CRT improves quality of life, exercise capacity, and outcome in patients with bundle-branch block and advanced heart failure. Previous studies used QRS duration to select patients for CRT; the accuracy of this parameter to predict functional recovery, however, is controversial. Methods We examined 42 patients with advanced heart failure (New York Heart Association NYHA functional class III to IV, QRS duration >130 ms, and ejection fraction <35%) before and 6 to 8 months after CRT. Left ventricular (LV) dyssynchrony was estimated by calculating the SD of time to peak velocities (Ts-SD) by conventional tissue Doppler imaging (TDI), and the mean phase index (mean EPI-Index) was calculated by EPI in 12 mid-ventricular and basal segments. Patients who were alive and had significant relative decrease in end-systolic LV volume of ΔESV ≥15% at 6 to 8 months of follow-up were defined as responders. All others were classified as nonresponders. Results The Ts-SD and the mean EPI-Index were related to ΔESV (r = 0.43 for Ts-SD and r = 0.67 for mean EPI-Index, p < 0.01 for both), and both parameters yielded similar accuracy for the prediction of LV remodeling (area under the curve of 0.87 for TDI vs. 0.90 for EPI, difference between areas = 0.03, p = NS) and ejection fraction (EF) improvement (area under the curve of 0.87 for TDI vs. 0.93 for EPI, difference between areas = 0.06, p = NS). Furthermore, patients classified as responders by EPI (mean EPI-Index ≤59%) showed significant improvement in NYHA functional class and in 6-min walk test (409 ± 88 m at follow-up vs. 312 ± 86 m initially, p < 0.001). Conclusion Echocardiographic phase imaging can predict functional recovery, reverse LV remodeling, and clinical outcomes in patients who undergo CRT. EPI is a method that objectively and accurately quantifies LV dyssynchrony and seems to be noninferior to TDI for the prediction of reverse LV remodeling and functional recovery.
Summary Acquired chromosomal aberrations, including gene copy number alterations, are involved in the development and progression of human malignancies. SOX2 , a transcription factor–coding gene ...located at 3q26.33, is known to be recurrently and specifically amplified in squamous cell carcinomas of the lung, the esophagus, and the oral cavity. In these organs, the SOX2 protein plays an important role in tumorigenesis and tumor survival. The aim of this study was to determine whether SOX2 amplification is also found in squamous cell carcinomas in other organs commonly affected by this tumor entity. In addition, we examined a large spectrum of lung cancer entities with neuroendocrine differentiation (ie, small cell cancers, large cell cancers, typical and atypical carcinoids) for SOX2 and TTF1 copy number gains to reveal potential molecular ties to squamous cell carcinomas or adenocarcinomas of the lung. Applying fluorescence in situ hybridization, we assessed squamous cell carcinomas of the cervix uteri (n = 47), the skin (n = 57), and the penis (n = 53) for SOX2 copy number alterations and detected amplifications in 28%, 28%, and 32% of tumors, respectively. Furthermore, we performed immunohistochemical SOX2 staining and found that SOX2 amplification is significantly associated with overexpression of the corresponding protein in squamous cell carcinomas ( P < .001). Of the lung cancer entities with neuroendocrine differentiation, only small cell cancers and large cell cancers exhibited SOX2 or TTF1 amplifications at significant frequencies, indicating that at least a subset of these might be dedifferentiated forms of squamous cell carcinomas or adenocarcinomas of the lung. We conclude that SOX2 amplification and consequent SOX2 protein overexpression may represent important mechanisms of tumor initiation and progression in a considerable subset of squamous cell carcinomas.
PDF
